ReviewArticle · Melorheostosis is a rare genetic bone disease of unknown etiology in which...

Review ArticleMolecular Phenotypic Aspects and Therapeutic Horizons ofRare Genetic Bone Disorders

Taha Faruqi1 Naveen Dhawan1 Jaya Bahl2 Vineet Gupta3 Shivani Vohra4

Khin Tu1 and Samir M Abdelmagid5

1 Nova Southeastern University Health Sciences Division Fort-Lauderdale-Davie FL 33314 USA2 Florida International University (FIU) Miami FL 33174 USA3Department of Medicine University of California San Diego (UCSD) 200 West Arbor Drive MC 8485 San Diego CA 92103 USA4University of Pennsylvania School of Dental Medicine Philadelphia PA 19104 USA5Northeast Ohio Medical University (NEOMED) School of Medicine Rootstown OH 44272 USA

Correspondence should be addressed to Vineet Gupta vineetgsvmgmailcom

Received 28 February 2014 Revised 12 August 2014 Accepted 24 August 2014 Published 22 October 2014

Academic Editor Vasiliki Galani

Copyright copy 2014 Taha Faruqi et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

A rare disease afflicts less than 200000 individuals according to theNational Organization for RareDiseases (NORD) of theUnitedStates Over 6000 rare disorders affect approximately 1 in 10 Americans Rare genetic bone disorders remain the major causes ofdisability inUS patientsThese rare bone disorders also represent a therapeutic challenge for clinicians due to lack of understandingof underlying mechanisms This systematic review explored current literature on therapeutic directions for the following raregenetic bone disorders fibrous dysplasia Gorham-Stout syndrome fibrodysplasia ossificans progressiva melorheostosis multiplehereditary exostosis osteogenesis imperfecta craniometaphyseal dysplasia achondroplasia and hypophosphatasia The diseasemechanisms of Gorham-Stout disease melorheostosis and multiple hereditary exostosis are not fully elucidated Inhibitors of theACVR1ALK2 pathway may serve as possible therapeutic intervention for FOP The use of bisphosphonates and IL-6 inhibitorshas been explored to be useful in the treatment of fibrous dysplasia but more research is warranted Cell therapy bisphosphonatepolytherapy and human growth hormonemay avert the pathology in osteogenesis imperfecta but further studies are neededThereare still no current effective treatments for these bone disorders however significant promising advances in therapeutic modalitieswere developed that will limit patient suffering and treat their skeletal disabilities

1 Introduction

In the spectrum of orthopaedic diseases rare genetic bonedisorders are often ignored as major diseases such as osteo-porosis generally attract more research funding and attentionfrom the research community A rare disease is defined asone affecting less than 200000 individuals according to theUS National Organization of Rare Diseases (NORD) Rarebone disorders remain a serious problem in orthopaedicsand result in significant morbidity and mortality in patientsaround the world

Often a primary problemwith rare bone diseases remainsto be a lack of understanding of the underlying mechanismYet in recent years many advances have occurred that arepromising for the prospect of finding cures In 2006 the gene

for fibrodysplasia ossificans progressiva (FOP) was identifiedby researchers at the University of Pennsylvania marking asignificant milestone in the understanding of this diseasePrior to this its etiology remained elusive While this doesnot in and of itself translate to a cure the discovery providesdirection for researchers to investigate possible points ofdisruption of the basic pathway of FOP Yet other raredisorders still remain mysteries

This review summarizes the most current trends in thesearch for therapeutic interventions for nine rare bone dis-orders fibrous dysplasia Gorham-Stout syndrome fibrodys-plasia ossificans progressiva melorheostosis multiple hered-itary exostosis osteogenesis imperfecta and craniometaphy-seal dysplasia

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 670842 16 pageshttpdxdoiorg1011552014670842

2 BioMed Research International

2 Fibrous Dysplasia

Fibrous dysplasia (FD) is a rare bone disease characterized byreplacement of the medullary cavity with fibrous tissue Anyregion of the skeleton can be affected by FD where the mostcommon areas involved include facial bones the tibia femurand the ribs [1] Several forms of FD exist The monostoticform of FD is limited to one bone whereas the polyostoticform is manifest in multiple bones [2] McCune-Albrightsyndrome is another variant of FD and in addition to boneinvolvement is associated with endocrine dysfunctions suchas Cushing syndrome hyperthyroidism and acromegaly [12] FD causes chronic pain in patients due to bone over-growth Other long term problems include bony deformitiesunequal limb lengths and diminished bone strength leadingto a high risk of fractures

FDdisplays no predilection for either genderThemonos-totic form is more prevalent than the polyostotic form withthe variants occurring at a ratio of 7 3 respectively [3] Themonostotic form classically occurs in individuals in their20s to 30s whereas the polyostotic form is usually seen inchildren Polyostotic FD usually enters dormancy at the onsetof puberty but pregnancy may result in reactivation of thedisease [1]

FD results of mutations in the guanine nucleotide bind-ing alpha stimulating (GNAS) complex locus located onchromosome 20 [4]Themutations occur postzygotically andlead to constitutive activation of G120572s resulting in stimulationof the Wnt120573-catenin signaling pathway [4 5] Mutationactivation of G120572s subunit leads to high levels of cyclicadenosine monophosphate (cAMP) levels that mediate thedownstream functions in the affected cells In particular thetranscription factors cFos and cJun and the cytokine IL-6are upregulated in osteoclasts resulting in excessive boneresorption and dysplastic fibrous growth [1 6]

Recent study showed that transgenic mice with consti-tutive expression of the G120572s subunit developed an inheritedpathologically replication of human FD The characteristicFD lesions in mice developed only in postnatal life as inhuman FD [6] In the affected bone the lesions developthrough a sequence of three consecutive stages a primarymodeling phase characterized by excess medullary boneformation a secondary phase with excess inappropriateremodeling and a tertiary phase of fibrous dysplastic in themarrow cavity that replicates the human bone pathology inmice of more than 1 year old [6 7]

X-ray diagnostic features of FD are a characteristic hazybone lesion (ground glass) For most parts this radiologicentity is sufficient for the initial diagnosis of the diseaseHow-ever in patients where metastasis may pose a viable concerna PETCT may be considered However Su et al concludedthat this alone may not be enough [8] They conducted F-fluoro-2-deoxy-glucose positron emission tomography (F-FDG PETCT) on a female patient in whom breast cancerrecurrence was suspected FD was an incidental findingon PETCT However they noted that the dysplastic lesionmimicked metastasis MRI proved to be a useful modality indifferentiating FD from metastasis Other novel approaches

of detecting the disease are also being pursued Tabareau-Delalande et al [9] demonstrated that GNAS mutationsare specific for fibrous dysplasia among other fibroossifyinglesions Thus DNA markers for the GNAS mutation mayprovide an alternate means of diagnosing the disease in morecomplicated cases of FD

In the present there is no cure for FD and the manage-ment is composed largely of reduction of pain preventingfurther degeneration of bone and surgical intervention toreshape and restore the functionality of the affected boneA current approach that aims at both strengthening boneand reducing pain is bisphosphonate therapy Makitie et al[10] administered bisphosphonates intravenously in a patientwith mandibular FD The therapeutic approach resulted inrapid reduction of pain stabilized turnover of bone andeven proved to be cosmetically beneficial In patients thatare nonresponsive to bisphosphonates Chapurlat et al [11]suggested the use of IL-6 inhibitors such as tocilizumab amonoclonal antibody used to treat rheumatoid arthritis (RA)A study investigating the effect of tocilizumab on systemicbone resorption through tracking serum cross-linked C-terminal telopeptide of type I collagen (CTX and ICTP)revealed a significant decrease in bone resorption with thetherapy [12] Therefore this approach could also be useful inpreventing the bone resorption seen in FD

Several potential therapeutic interventions may beemployed (Figure 1) A possible therapeutic strategy tobe pursued in the future could be targeting the Wnt120573-catenin pathway If the Wnt signaling pathway is halted120573-catenin will not accumulate within the cell since it ismarked for ubiquitination by casein kinase 1120572 (CK1120572)protein phosphatase 2A (PP2A) adenomatosis polyposis coli(APC) Axin and glycogen synthase kinase 3 (GSK3) [13]Ubiquitination of 120573-catenin would lead to its proteasomaldegradation thus preventing it from eliciting a cellularresponse contributing to FD Therefore if Wnt proteins canbe selectively bound by ligand analogs and inactivated thetumorigenic fibrous growth will be diminished (Figure 2)

3 Gorham-Stout Disease

Gorhamrsquos disease (GD) also known as vanishing bonedisease is a rare genetic disorder characterized by boneresorption and localized lymphangiogenic proliferation [14]This lymphatic and vascular proliferation within bone isthought to aid in osteolysis GD shows no preference forgender or race and occurs more often in children and youngadults Although GD manifests itself as a monostotic orpolyostotic disease it more commonly involves the flat bonesthat form by intermembranous ossification [15]

Diagnosis of GD is challenging it is often a diagnosisof exclusion Other differentials such as endocrinopathiesmalignancies and immunologic infectious and metabolicetiologies need to be ruled out before a diagnosis of GD canbe made [15 16]

A study conducted by Venkatramani et al [17] revealedinsights about GD manifestations Of the eight patients(median age at diagnosis was 115 years) who were part ofthe study seven presented with lymphangiomatous lesions in

BioMed Research International 3

ACReceptor

ATP

cAMP

Wnt120573-catenin in OB cFoscJun in OC

Excessive modeling Excessive remodeling

Intracellular

ExtracellularLigand

120574120573 120572

Figure 1 Schematic diagram of the pathogenesis of FD mutationof the 120572 subunit in GNAS (blue arrow) results in autonomousactivation of adenylate cyclase (AC) and increased cAMP levelsCyclic AMP stimulates Wnt120573-catenin signaling in osteoblastsleading to excessive bone formation In addition cAMP activatescJun and cFos of AP-1 complex in osteoclasts resulting in excessivebone remodeling

the soft tissues adjacent to the involved bone This findingis particularly interesting since Bruch-Gerharz et al [18]also found that skin and soft tissues adjacent to the bonelesions have remarkable lymphatic vascular malformationsFurthermore the skin and soft tissue involvement precededbone osteolysis by several years Therefore one can concludethat the lymphatic vascular malformations presenting in GDcan potentially serve as an early diagnostic sign Bruch-Gerharz et al also demonstrated that magnetic resonanceimaging (MRI) was essential in characterizing the extentof GD progression by tracking lymphatic malformation intissues [18]

The pathogenesis of GD is not well understood andtherefore not many therapeutic modalities are currentlyavailable Recent study showed that lymphatic endothelialcells (LECs) and blood endothelial cells (BECs) in additionto macrophages secrete TNF120572 and IL-6 that stimulate osteo-clast formation with excessive osteolysis [19] Macrophagesproduce VEGF-C and -D that stimulate proliferation of LECsandBECsMoreovermacrophages produceVEGF-A -C and-D and IL-6 that directly stimulate osteoclast differentiation[20] (Figure 3) Furthermore TNF120572 secreted by LECs andmacrophages inhibits osteoblast differentiation and newboneformation [21] Devlin et al [22] demonstrated that theserum from a patient with GD caused increased proliferationof osteoclast-like multinucleated cells when cultured withnormal human bone marrow Furthermore the levels of IL-6 were significantly higher in the serum of GD patientsThis suggests that bone resorption observed in GD could bea direct result of increased multinucleated cell activity dueto increased IL-6 levels Therefore local inhibition of IL-6production or administration of a drug such as tocilizumabwill be beneficial

Today there are no set guidelines for the treatmentand management of GD To prevent the production ofIL-6 by proliferating vasculature radiation therapy andchemotherapy with interferon 120572-2b is commonly employed[23] although it is contraindicated in growing children Dif-ferent treatment modalities that include surgical resectionarthroplasty calcitonin calcium and vitamin D have beenutilized and the results are variable Bone grafts have also beenused with a debatable successful rate Hirayama et al [16]reported that despite the use of a bone graft GD recurredin the grafted bone In a revealing case described by Hammeret al [24] clinical improvement followed by stabilization ofthe disease occurred solely after use of low-dose pamidronatetherapy To our knowledge this is the only known case ofa bisphosphonate monotherapy leading to remission of GD(Figure 4)

Other efforts include the identification of diagnosticmarkers of GD In a study conducted by Franchi et al [25]CD105endoglin a marker for vascular endothelial cells wasused to assess the nature of the endothelial cells proliferatingin GD CD105 expression was found to be significantly higherin GD vessels compared to those found in osseous heman-gioma ( positive was 589 versus 172 resp) Therefore thismarker may offer a potential means of diagnosing patientswith GD

4 Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare devas-tating autosomal dominant disease that is characterized byheterotrophic ossification (HO) in the soft tissues followinga simple injury [26] The disease affects 1 in 2 millionindividuals [27] There are currently about 700 known casesaround the world FOP displays no predilection for genderrace or geographic location [28] Although episodic flare-upsoccur in FOP the damage is cumulative leading to increasingdisability Individuals with FOP display no abnormality atbirth with the exception of congenital great toe malforma-tions [27] Painful transformation of soft connective tissueinto bone begins in the first decade of life [29] Surgicalintervention leads to a sever rebound response marked byrapid bone growth [28]

HO in FOP is seen initially in the cranial dorsal axialand proximal regions of the body and then later occurs incaudal ventral and distal regions Since there are episodicflare-ups the disease progressionmay vary and not follow theprevious order in all cases Skeletal muscles are also involvedin the ossification process however smooth muscle andcardiac muscle are spared [28] Kaplan et al [30] conducteda study to determine the cause of death and lifespan ofindividuals with FOP The most common cause of deathin FOP was cardiorespiratory failure as a result of thoracicinsufficiency syndrome and the median lifespan of the 371individuals in the international FOP community was 56years

The diagnosis of FOP can be made by the associationof progressive ossifying soft tissue swellings and great toemalformations [31] This association is not often made byclinicians and thus FOP is frequently missed The affected


Fibrous dysplasia

Mutation in guanine nucleotide binding alpha stimulating (GNAS) complex locus on chromosome 20

Underlying pathologic mechanism

Bisphosphonates (IV) IL6 inhibitors (ie toclizumab)disrupting the Wnt120573-catenin pathway gene therapy-replacing the GNAS-1 geneHigh levels of cyclic adenosine

Transcription factors Cfos and CJun and cytokine IL-6 are upregulated and are implicated in the resulting bone resorptionand dysplastic fibrous growth (1 6)

Increased activity of Wnt120573-catenin signaling

pathway (4 5)

Potential therapeutic intervention

Upregulation of G120572s

Activating mutations in G120572s

monophosphates (cAMP)

Figure 2 Summary of the pathological mechanisms underlying FD and potential therapeutic strategies that may be pursued

Mac

OC

OB

LEC

BEC

IL-6

VEGF-A -C and -D

VEGF-C -D

VEGF-A

IL-6 TNF120572 TNF120572

Figure 3 Schematic diagramof the pathogenesis ofGSD Lymphaticand blood endothelial cells (LECs) BECs and macrophages (Mac)secrete TNF120572 that stimulate OB to release IL-6 Mac producesVEGF-C and -D that stimulate proliferation of LECs and BECsMacalso produces VEGF-A -C and -D and IL-6 that directly stimulateosteoclast-mediated bone resorption

individuals are often exposed to unwarranted trauma due tounneeded biopsies of the soft tissue swellings thereby leadingto further exacerbation of the disease

There is no current cure for FOP The current manage-ment of FOP is early diagnosis preventing iatrogenic traumaand alleviating pain during episodic flare-ups Several studieshave indicated that FOP is associated with the bone morpho-genetic protein (BMP) signaling pathway BMPs are respon-sible for the stimulation of bone formation through bindingto the activin receptor type 1 (encoded by the AVCR1 genereceptor) a BMP type 1 receptor Thus in 2006 Kaplan et al

[26] identified a mutation in activin receptor IAactivin-like kinase 2 (AVCR1ALK2) in all patients presenting withFOP (Figure 5) DNA sequencing displayed the occurrenceof missense mutation in the glycine-serine activation domainin individuals with FOP Not all FOP cases are caused bythe common mutation as there are several FOP variantswith varying phenotypes Importantly Chakkalakal et al [32]further elucidated themechanismof FOPusing a FOPknock-in mouse model Thus FOP results from a mutation in thegene ACVR1ALK2 which causes the amino acid histidineto be substituted in place of arginine at the 206 codon Dueto the discovery of this highly specific mutation in the FOPgene therapeutic modalities can now be aimed at blockingthe AVCR1ALK2 pathwayThus the identification of factorsthat are a part of or that aid the BMP signaling pathway hasbeen the focus of recent studies Mao et al suggested thepotential role of matrix metalloproteinase-10 (MMP-10) intheHOofmuscle in FOP patientsThey showed thatMMP-10stimulated myoblast differentiation into osteoblasts throughthe interactions with BMP pathway [33] Thus MMP-10may serve as a potential therapeutic target Giacopelli et al[34] recently reported a significant finding that transcriptionfactors including Egr-1 Egr-2 ZBTB7ALRF Hey1 and Sp1are responsible for the regulation of the ACVR1 promoterthrough binding to the minus762minus308 region Furthermoreadditional studies have shown thatmiR-148amay be a criticalmediatory agent of ACVR1 [35 36] Thus disruption of thepathway through blocking or slowing down any of thesetranscription factors presents the most promising form ofpotential therapy to date

Importantly while inhibitors of ALK2 including LDN-193189 and dorsomorphin are effective in reducing ALK2activity they also block the activity of another BMP receptorBMPR1 (ALK3) activity [37] Thus any viable therapeuticintervention would be one that blocks the hyperactivity ofALK2 without impacting the other kinases in the pathway[33] Kaplan et al were able to identify siRNAs whichtarget the ALK2 causing pathology while the normal ALK2remained unaffected [37 38] Thus siRNAs from FOPpatients have been utilized to retain normal activity of BMP


Gorham-Stout disease

Largely unknown but may include proliferation of multinucleated cells

with increase in IL-6


Inhibition of IL-6 activity with drugs like tocilizumab bisphosphonates

like pamidronate targeting markers such as CD 105endoglin


Figure 4 Pathogenesis of GD and potential therapeutic interventions

Alk2

Alk6

ActRIIBMPRII

Alk3

Smad1Smad5Smad8

P

Smad4P

Smad4R-SmadP

TF

Co-Act

R-SmadP

BMPs

BMPRI

Intracellular

Extracellular

Nucleus

OB differentiationMatrix mineralizationBone formation

Figure 5 Schematic diagram of the pathogenesis of FOB mutation of the Alk2 subunit (blue arrow) of BMP receptor I leads to constitutivephosphorylation of the downstream regulated-smad1 -5 and -8 that associate with smad4 Multimeric smad complex translocates to thenucleus and positively regulates several transcription factors responsible for osteoblast differentiation and bone formation

[37 38] Kaplan et al [38] demonstrated selective suppressionof mutated ACVR1 by utilizing ASP-RNAi (allele-specificRNA interference) techniques This study showed a promis-ing glimpse of the possibility of shutting down ACVR1 activ-ity Yet furtherwork is needed to develop an effective regimenof ACVR1 suppression in humans Figure 6 summarizes thepathogenesis and possible therapeutic strategies that maytarget FOP

5 Melorheostosis

Melorheostosis is a rare genetic bone disease of unknownetiology in which patients exhibit bone dysplasia markedwith benign sclerosis [39] The disease has no predilectionfor gender and occurs sporadically Scleroderma of the skinoverlying the affected bone vascular malformations and softtissue masses have also been reported [40] Spinal sensorynerves are commonly involved [41] and the sclerosis is usuallyunilateral The disease can be monostotic and polyostotic oronly involve one limb (monomelic) [42] Involvement of thelower limbs is more commonly seen whereas skull involve-ment is rare [42] Histological analysis reveals thickening

of the cortical bone that is comprised of mature lamellarand woven bone with adjacent fibrocartilage surroundingcoronoid islands [43 44]

The classic radiologic appearance of melorheostosis isldquoflowing hyperostosisrdquo similar to hardened wax dripped onthe side of a candle [41] As such upon classic presentation ofthe disease diagnosis can be made by X-ray studies followedby increased uptake of radionuclide [41 45] The diagnosiscan be confirmed by MRI and CT by detecting hyperostosisFurthermore MRI can also be used to determine the degreeof soft tissue involvement [41] However Hollick et al [45]noted that a milder presentation of melorheostosis may bemore challenging to diagnose due to periosteal osteosarcomaand myositis ossificans competing as viable differentials

There is no treatment for melorheostosis although sev-eral potential therapeutic modalities have been suggested(Figure 7) Current management is highly individualized andis based on the severity of the disease areas of skeletal involve-ment and symptoms experienced by the patient Surgicaltreatment is undertaken when an adverse or life threateningcomplication needs to be avoided Zeiller et al [41] performedcervicothoracic decompressive laminectomy to alleviate the


Fibrousdysplasia ossificans progressiva

Mutation in the ACVR1ALK2 gene (substitution of histidine in place of arginine on codon 206)


Development of kinase inhibitors that can block ACVR1 or disrupt activity of ACVR1ALK2 pathway Inhibitors of ALK2 include LDN-193189 and dorsomorphin

Causes overactivity of ACVR1 (the receptor is active in absence of signal from BMP) resulting in bone formation


Figure 6 Summary of the pathogenesis of FOP and potential therapeutic interventions

Melorheostosis

Unknown potentially involves downregulation of TGF120573


Inhibition of fibroblast proliferation


Figure 7 Pathogenesis and potential therapeutic interventions of melorheostosis

worsening neurologic condition in their patients A follow-upexamination conducted six months after the surgery revealedsymptomatic improvement of the disease In another caseMoulder and Marsh [46] were successfully able to treatmelorheostosis by total knee arthroplasty Recently Hollicket al [45] were able to achieve a significant reduction of thelesions in melorheostosis with the associated symptoms bya single 5mg infusion of zoledronic acid administered overa duration of 30 minutes A follow-up conducted eighteenmonths after the initial therapy revealed an asymptomaticpatient with no further need for treatment

Hellemans et al [47] initially linked the etiology ofmelorheostosis (along with osteopoikilosis and Buschke-Ollendorff syndrome) to mutations in the LEMD3 geneHowever in a later study conducted by Hellemans et al [48]no LEMD3 mutations were identified in patients presentingsolely with sporadic melorheostosis Due to this discoverythe etiology of melorheostosis remains unknown

Kim et al [49] found that downregulation of adhe-sion proteins that regulate osteoblasts particularly TGF-120573 induced gene product occurs in melorheostosis Theyhypothesized that this may be the cause of the presentinghyperostosis and soft tissue abnormalities Examining theTGF-120573 pathway may provide some clues of the mechanismof melorheostosis Endo et al [50] displayed the fact that softtissue and skin changes occurred due to increased secretionof collagen from fibroblasts In addition they proposed thathyperostosis may be responsible for stimulation of fibroblas-tic secretion Therefore inhibition of fibroblast proliferationmay lead to an improvement in the soft tissue and skinmanifestations of the disease

6 Multiple Hereditary Exostosis

Multiple hereditary exostosis (MHE) is a genetic disordermarked by multiple cartilage-capped boney protuberances(osteochondromas) of the axial skeleton presenting usuallybefore twelve years of age The usual presentation is unequallimb lengths reduced range of motion and osteoarthritis[51] Joints of the upper and lower limb are commonlyaffected particularly the humerus distal femur and tibiahowever any bone might also be affected [52]

Diagnosis is made as outlined by Wuyts and Van Hul[53] primarily using radiologic studies The characteris-tic radiographic presentation of MHE is an uninterruptedcontinuation of the bone cortex into the osteochondromaAdditionally a family history remarkable for MHE also aidsin diagnosis [53]

Pathogenesis of MHE The genetic basis of MHE has beenidentified due to mutations in the exostosin-1 EXT1 andEXT2 genes These genes are involved in heparan sulfate(HS) chain elongation in the Golgi apparatus [54] Multiplestudies have found a more severe disease presentation inindividuals with EXT1 mutations versus those with EXT2mutations [55 56] Recent study showed that inactivation ofEXT1 in mouse chondrocytes leads to the development ofosteochondroma with characteristic bone deformities that isalmost identical to human MHE [57] It has been reportedthat EXT1 function is required for maintenance of normallevels of bone morphogenetic protein (BMP) and Wnt aswell as their target genes [58] Another study indicated thatloss of 120573-catenin expression (downstream target of BMP)


Multiple hereditary exostosis

Unknown potentially involves EXT1 and EXT2 genes


Targeting pathways of EXT1 and EXT2 genes to ensure lack of genetic disruptions


Figure 8 Pathogenesis of MHE and potential therapeutic interventions

in chondrocytes induces periosteal chondroma-like massesresulting in the cartilage cap in osteochondromas [59]

Since the mutation is known genetic testing is alsocurrently available for diagnosis of MHE [53] A novelmethod of diagnosing MHE has been proposed by Anower-E-Khuda et al [60] In their study they compared HS andchondroitin sulfate (CS) from the serum of MHE patientsand healthy individualsThey found that HS was significantlyless in the serum of MHE patients and the HSCS ratioswere nearly half those of healthy individuals Therefore itwas suggested that the HSCS ratios may be utilized as adiagnostic predictor of MHE

After diagnosis of MHE the locations of the lesionsassociated symptoms and any structural deformities andfunctional limitations need to be documented If the condi-tion is asymptomatic no therapy is indicated [53] Surgerieswhen performed are usually done to limit the presentingsymptoms or correct bone defects [61] Due to undergrowthof the fibula valgus deformities of the knee and ankleare usually seen [62] In the upper extremity the ulna isusually involved in causing radial deformities such as radialhead dislocation and radial bowing to occur [63] Surgicalintervention is used in all of these cases

A serious complication ofMHE is malignant transforma-tion into chondrosarcoma [64]The risk for malignant trans-formation was previously reported to be 06 to 28 [65] Incontrast to this Kivioja et al [51] determined higher risk fortransformation to chondrosarcoma at 83 in six generationsof a family with prevalent MHE Other literatures howeverreported the risk of malignant transformation as very low[66] A relatively rare and unique complication that Khanet al [67] reported in MHE patients was lower extremityischemia due to popliteal artery occlusion

Currently there is no cure forMHE Although the geneticmutations have been identified the genetic pathogenesis andparticular signaling pathways that lead to the manifestationof the disease remain unknown (Figure 8) If the signalingpathways of EXT1 and EXT2 can be understood molecularbiology can potentially be utilized to alleviate the geneticdisturbances due to lack of functional EXT1 and EXT2 genes

7 Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a rare genetic bone diseasecharacterized by the high incidence of fractures with orwithoutminor trauma [68] Hearing loss is amore commonlyobserved symptom of OI in older patients Other classicfeatures seen in patients with OI include blue sclerae andtriangular facies

Pathogenesis of OI Type I collagen is an extracellular matrixprotein mainly found in bone and skin [69] Two importantsteps of posttranslational modifications occur first hydroxy-lation of lysine and proline residues that occurs and conveysstability of the collagen triple helix second 3-hydroxylationof a proline residue that occurs in the 120572-one chain of type 1collagen (COL1A1) at position 986 (P986) [69] In autosomaldominant OI mutations occur in COL1A1 and COL1A2 thatpreclude the right folding of type I collagen into propertriple helical structure [69] Autosomal recessive lethal OI iscaused by mutations in cartilage-associated protein CRTAPand prolyl-3-hydroxylase-1 (P3H1 encoded by LEPRE1 gene)which lead to decreased 3-hydroxylation of P986 in type Icollagenrsquos 120572-one chain In both cases overmodification oftype I collagen is noted [69]

A knock-in mouse model for moderately sever OI hasbeen generated [67 70] Characterization of the cellularcontribution into the brittle bone disease showed a decreaseof the cortical and trabecular bone before and after pubertyresulting in 50 reduction of the bone mass compared tothe wild type [70] Although osteoblasts matrix productionwas greatly diminished osteoclast number and activity wereincreased in the OI mouse compared to the wild type [70]The study concluded uncoupling between osteoblasts andosteoclasts in brittle bone disease perhaps due to higherexpression of RANK receptors on osteoclast precursors [70]This cellular imbalance results in decreased bone formationwith aging Interruption of the stimulus that increases osteo-clast precursors may leads to new therapeutic modalities forOI Interestingly separate study reported the therapeutic ben-efits of RANKL inhibitors (RANK-Fc) and bisphosphonatesin treatment of OI via increased number of bone trabeculaethat reduce the incidence of fracture risks [71]

Diagnosis of OI is made based on a history of fracturesfamily history remarkable for OI radiographic studies thatreveal multiple fractures at different stages of healing andgenetic testing for mutations in COL1A1 and COL1A2Additionally biochemical testing of type I collagen may alsobe conducted The biochemical testing consists of culturingdermal fibroblasts and analyzing the structure and quantityof the type I collagen produced Four types of COL1A1and COL1A2 related OI have been identified (I II IIIand IV) and biochemical testing has a high sensitivity fordetecting these four types of OI [68] Although the sensitivityof biochemical analysis and genetic testing is comparablegenetic testing is still the recommended first line test forconfirmation of OI [72]

Management of the disease is based on the degree ofdisease progression Caregivers and parents are advised to


Osteogenesis imperfecta

Overmodification of type I collagen by hydroxylation of lysine and proline residues


Cell therapies entailing transplant of mesenchymal stem cells and mesenchymal stromal cells into OI patients Potential benefits of bisphosphonate polytherapy and human growth hormone (HGH)

Mutations in COL1A1 and COL1A2 preventing timely folding of the triple helical structure of type I collagen


Figure 9 OI pathogenesis and potential therapeutic interventions

handle OI patients safely since they are susceptible to frac-tures As such management is primarily supportive [73]Symptomatic surgical interventions include bracing of limbsstabilization of joints and reduction of boney deformities[73]

Cases have been reported in which bisphosphonates havebeen used in an attempt to alter the disease course Phillipi etal [74] elaborated the use of bisphosphonates to treat OIThestudy indicated that although bone mineral density (BMD)and adult height of patients increased with bisphosphonatetherapy fracture incidence did not decline This was furtherconfirmed in the study conducted by Sakkers et al [75] inwhich the researchers were unable to determine whether theuse of olpadronate was able to alter the progression of OI

Though there is no cure for OI several therapies are beinginvestigated (Figure 9) A study conducted by Antoniazzi etal [76] investigated the effects of human growth hormone(HGH) and bisphosphonate polytherapy The use of growthhormone was correlated with increased BMD and lineargrowth Marini et al [77] conducted a study that yieldedsimilar results Recently Otsuru et al [78] transplantedmesenchymal stem cells and mesenchymal stromal cells intopatients with OIThe cell therapies proved to be very effectivein this pilot clinical trial This holds promise for a potentialcure for OI in the near future

8 Craniometaphyseal Dysplasia

Craniometaphyseal dysplasia (CMD) is an extremely raregenetic bone disorder characterized by overgrowth and pro-gressive sclerosis of the craniofacial bones (cranium) andflaring of the metaphyseal plates of femurs (metaphysealdysplasia) [79 80] The lifespan of patients diagnosed withcraniometaphyseal dysplasia is normal except in the mostsevere cases [81]

The characteristic bone outgrowth in the skull causesmany of the symptoms and signs seen in patients sufferingfrom craniometaphyseal dysplasia Affected individuals willtypically have distinguishing facial features such as thick-ening of the cranial bones prominent forehead paranasalbossing wide nasal bridge wide-set eyes (hypertelorism)and a prominent jaw [82] Infants affected by CMD will haveexcessive new bone formation (hyperostosis) in their jawresulting in delayed teething (dentition) or failure of teetheruption [83 84] These infants with CMD may also havebreathing or feeding problems due to narrow nasal passages

In the most severe cases abnormal bone outgrowth cancompress the cranial nerves emerging from the brain leadingto paralyzed facial muscles (facial nerve palsy) blindness ordeafness [82 84]

Craniometaphyseal dysplasia has twoways of inheritancethe autosomal dominant CMD that is typically more severethan the autosomal recessive form In most cases this con-dition is inherited in an autosomal dominant pattern whichmeans a mutation in one gene copy in each cell is sufficientto cause the CMD disorder [81 85 86] As craniometa-physeal dysplasia runs in families patients with autosomaldominant CMD typically have one parent who also has thecondition Less often cases result from new mutations in thegene and occur in people with no history of the disorder intheir family Rarely craniometaphyseal dysplasia is suspectedto have autosomal recessive inheritance when unaffected par-ents have more than one child with the condition Autosomalrecessive disorders are caused by mutations in both copiesof a gene in each cell The parents of an individual withan autosomal recessive condition each carry one copy ofa mutated gene but they typically do not show signs andsymptoms of the disorder [87]

Pathogenesis of CMD All CMD cases with known moleculardiagnosis have so far been linked to ankh nonsensemutationson chromosome 6 that underlie increased intracellular anddecreased extracellular pyrophosphates (PPi) [82 86 88 89]Recent studies of CMD also point to the role of PPi in theregulation of the bone modelingremodeling process TheANKH protein is type II transmembrane with 10ndash12 helicesspanning the outer cell membrane and is associated with PPiefflux (Figure 10) Most of the ankh mutations are located incytoplasmic domains close to the C-terminus [82 86] PPi is amajor inhibitor of physiologic pathologic tissue calcificationand bone mineralization Intracellular PPi is generated andstored largely in mitochondria but it is also detected inendoplasmic reticulum and Golgi [90ndash94] The extracellularPPi concentration in the skeletal tissue is determined byseveral types of cell membrane proteins ectoenzyme PC1which generates PPi from ATP tissue nonspecific alkalinephosphatase (TNAP) which hydrolyzes PPi into two inor-ganic phosphates (Pi) and ANKH which is involved in PPiefflux (Figure 11) While the functional role of intracellularPPi in mammalian cells remains elusive extracellular PPihas been extensively studied for its inhibitory role in tissuecalcification Extracellular PPi directly binds to the surface


Extracellular

IntracellularCMD

(BCP)

Ankank

Ank mouse

COOHNH2

(a)

4

Extracellular

IntracellularN C

CN

PPi 1

1

2

2

3

3

4

4

5

6

78 9

10

(b)

Figure 10 Schematic diagram of the structure of ANK protein ANK protein is a type II transmembrane protein that spans the cell membranewith 10 helices Most of the mutations responsible for CMD in humans fall in the intracellular sequence between 7 and 9 helix Nonsensenatural mutation in ANKmice locates toward the C-terminus on the 10th helix (a) The ANK protein works as a transporter that exports PPifrom inside out of the cell (b)

ATP

ATP

Intracellular

NTP-PPH

ANK

ALKPase

Pi + Pi

PPiPPi

AMP + PPi

Mito

(a)

Loss of function mutation

HA (BCP)deposition

CMD

HA (BCP)depositionank mouse

PPi homeostasisinhibits HA (BCP)

PPiPPiPPi

PPi PPi PPi

(b)

Figure 11 Schematic diagram of the pathogenesis of CMD PPi is generated from ATP hydrolysis intracellular by the mitochondria (Mito)or extracellular by the transmembrane enzyme nucleoside triphosphate pyrophosphohydrolase (NTP-PPH) PPi generated intracellular isexported by ANK transporter to the extracellular one and is hydrolysed into two Pi by alkaline phosphatase (ALP) (a) Loss of functionmutation in ANK leads to accumulation of PPi intracellular Absence of extracellular PPi results in excessive bone formation due to increaseddeposition of bone minerals hydroxyapatite (HA) crystals made of basic calcium phosphate (BCP) responsible for CMD phenotype inhumans (b)

of basic calcium phosphate hydroxyapatites and interfereswith propagation of crystal formation contributing to theformation of poorly ordered bone crystal structure [95 96]In addition exogenous PPi at micromolar concentrationsstimulates the expression of osteopontin which is a nega-tive regulator of mineralization and inhibits the enzymaticactivity of tissue nonspecific alkaline phosphatase (ALP) inosteoblast cultures [96 97] Thus a decrease in extracellularPPi may hinder normal bone remodeling for instance byinhibiting osteoclast differentiation or activity In support

of this notion bone marrow-derived monocytes (BMMs)from a CMD knock-in mouse (pPhe377del in ank) poorlydifferentiated to osteoclasts in cultures compared to thosefrom wild type mice [98] Consistent with the mouse datathe number of bone marrow-derived osteoclast-like cellsfrom a CMD patient was only 40 of a normal indi-vidual and they lacked osteoclast-specific vacuolar protonpump and the ability to absorb a dentin slice [99] TheANKH protein may have also other unknown functions(Figure 12)


Craniometaphyseal dysplasia

Loss of function nonsense mutation of transmembrane ANK

regulator of bone mineralization) extracellular and accumulation of


Surgical interventionCalcitriolCalcitoninSurveillance of complications


PPi intracellular

with absence of PPi (negative

Figure 12 CMD pathogenesis and potential therapeutic interventions

Treatment Therapeutic intervention consists primarily ofsurgery aiming to decompress the nerve canal andor nar-rowed foramenmagnum Excessive bony overgrowth of facialbone forehead and cranial regions can be contoured how-ever bone regrowth is common For severe complicationssurgery is conservative to relieve severe symptoms caused bycranial nerve compression Surveillance of patients is crucialas bone growth continues throughout life and the patientswill require regular neurologic evaluation hearing assess-ment and ophthalmologic examination for early diagnosisand management of complications Therapeutic trial withcalcitriol that stimulate bone resorption with low calciumdiet has been reported to improve facial paralysis but has noeffect on metaphyseal deformity [100] Trial with calcitoninhas been thought to be effective due to its inhibitory effect onbone turnover which is inefficient in treating hyperplasia ofcraniofacial bones in persons with CMD [101]

9 Achondroplasia

Achondroplasia (chondrodysplasias) is a human bone geneticdisorder of the growth plate and is the most common form ofdwarfism [102] Achondroplasia is caused byADmutations ofthe transmembrane receptor fibroblast growth factor receptor3 (FGFR3) an important regulator of linear bone growth [103104] Achondroplasia has an incidence rate of one in 20000live births and it results from a spontaneous heterogeneousmutation to nonachondroplastic parents in an estimated 80of cases [102 105]

Clinical Diagnosis Achondroplasia is most likely recognizedat birth because of its characteristic clinical and radio-graphic features Achondroplasia in newborn infants classi-cally presents with disproportionate shortening of the limbsa long and narrow trunk a large head with frontal bossingand a hypoplastic midface The hands are short and broadoften displaying a three-pronged (trident) configurationMoreover many joints show hyperextensibility and infantsare often hypotonic Skeletal x-rays of the newborn infantreveal characteristic abnormalities that include shortening ofthe long bones of the limbs particularly the proximal boneswith metaphyseal irregularities The pelvis is abnormal withsmall and square iliac wings The cranium is large with aprominent forehead with midface hypoplasia

Pathogenesis Achondroplasia is an AD genetic disorderwhere it is linked to mutations of FGFR3 on the distal shortarm of chromosome 4 [106 107] Patients with achondropla-sia have nonsense genetic mutation in FGFR3 with glycineto arginine substitution at position 380 (G380R) in thetransmembrane domain of the receptor [105] However addi-tional FGFR3 mutations have been detected in hypochon-droplasia achondroplasia with developmental delay andacanthosis nigricans Muenke craniosynostosis and Crouzonsyndrome with acanthosis nigricans [102 105 108] Howeverthe diagnosis can be established from DNA mutationalanalysis Mutational diagnosis can also be used for prenatalespecially in couples at risk of having baby with homozygousachondroplasia

FGFR3 mutations in mice have identified the function ofFGFR3 in skeletal development and postnatal bone forma-tion The global knockout of FGFR3 generated large micewith longer than normal limb bones [109 110] Howeverknocking in FGFR3 with achondroplasia mutation in carti-lage of transgenic mice produced a small mouse with shortbones a phenotype similar to those seen in human achon-droplasia [111] Collectively these observations establishedthe fact that FGFR3 is an important negative regulator ofendochondral bone formation and that the mutations cause aconstitutive activation of FGFR3 resulting in achondroplasiaand related dwarfing phenotype

Treatment A number of therapeutic approaches have beenattempted to reduce excessive activation of FGFR3 as possibletreatments to normalize bone growth in achondroplasiaThey include strategies to interfere with FGFR3 synthesisblock its activation inhibit its tyrosine kinase activity pro-mote its degradation and antagonize its downstream signalsThese treatment modalities include FGFR3 kinase inhibitorsand gamma-secretase that modulate FGFR3 cleavage andnuclear function Another valuable therapeutic candidatein the treatment of achondroplasia is CNP that works asan antagonist to FGFR3 signal A previous study revealedthat transgenic mice overexpressing brain natriuretic peptide(BNP) in the liver exhibited postnatal skeletal overgrowthwith elongation of long bone growth plates [112] Anotherstudy showed that CNP is more potent than BNP in stimu-lating bone growth by using tibial organ culture experimentssuggesting that CNP was the physiological ligand in growing


Achondroplasia

Mutation and constitutive activation of FGFR3 (negative regulator of linear bone growth) resulting in disproportionate limb development and dwarfism


FGFR3 kinase inhibitors

CNP (FGFR3 antagonist)


Gamma secretase

Figure 13 Achondroplasia pathogenesis and potential therapeutic interventions

bones [113] Global knockout of CNP in mice showed severepostnatal dwarfism that was rescued after crossing with miceoverexpressing CNP from a transgene driven by the cartilage-specific COL2A1 promoter [114] These results confirmed thestimulatory effects of CNP on endochondral ossification invivo To explore the beneficial effects of CNP in treatingachondroplasia mice overexpressing CNP in cartilage werecrossed with mice displaying an achondroplastic phenotypedue to overexpressionmutation of FGFR3 [115] Interestinglythe skeletal growth defect in the achondroplastic mice wascorrected by the local overexpression of CNP The resultssuggested that CNP antagonizes the active FGFR3 possibly byinhibition of MAPK-mediated FGFR3 signaling (Figure 13)

10 Hypophosphatasia

Hypophosphatasia (HPP) is an inherited metabolic bonedisorder [116] caused by genetic loss of function mutation(s)of tissue-nonspecific alkaline phosphatase (TNSALP) [117]Therefore the high extracellular inorganic pyrophosphate(PPi) a TNSALP substrate with inhibiting effects on min-eralization accumulates leads to subnormal extracellularconcentrations of calcium and Pi that result in rickets orosteomalacia [117] HPP is an exception where the circulatinglevels are usually normal or elevated [118] Despite the highlevels of TNSALP in bone cartilage liver and kidney inhealthy individuals HPP appears to disrupt only ALP inldquohard tissuesrdquo directly [118] HPP is characterized by a wide-ranging expressivity that ranges from death in utero withalmost an unmineralized skeleton to difficulties with adultteeth without skeletal disease Five major forms of HPPhave been identified based on clinical diagnosis The ageat diagnosis of skeletal disease determines the perinatalinfantile childhood and adult types of HPP [118] Individ-uals without skeletal findings but dental features only aresaid to have ldquoodonto-HPPrdquo [118] Autosomal recessive (AR)and autosomal dominant (AD) inheritance partially explainthe remarkable range of HPP severity [117] Perinatal andinfantile HPP cases are inherited as an AR trait whereasthe more mild forms may reflect AR or AD inheritance[117 119] To date 224 different defects in TNSALP (80missense mutation) have been identified in HPP that explainthe extreme range of severity of this disorder The prognosesfor these five major forms of HPP are determined by theskeletal complications Typically the earlier the signs andsymptoms the worse the outcome [118]

Pathogenesis of HPP The bone disease is due to missensemutation of TNSALP with structural defects Many TNSALPmutations responsible for HPP change a conserved aminoacid in the mammalian TNSALPs [120] Some mutationsdisturb the catalytic pocket or the structural binding sitefor metal ligand others compromise dimer formation [118120] Moreover some mutations impair the intracellularmovement of TNSALP [120] TNSALP deficient mice haveconfirmed insight from HPP patients and showed reducedlongitudinal growth and delayed epiphyseal ossificationaccompanied by disturbance in the mineralization patternIt is concluded that ablation of TNALP results in hypomin-eralization of the skeleton with sever disordered mineralizedmatrix architecture [121]

Prognosis Perinatal HPP is always fatal Infantile HPP oftenfeatures clinical and radiographic deterioration with approx-imately 50 of babies dying from respiratory compromise[122 123] Childhood HPP may get improved after fusion ofthe growth plates Skeletal problems are likely to return inadulthood [124] Adult HPP causes recurrent and long lastingorthopedic difficulties (Figure 14)

Treatment There is no established therapeutic protocol ofHPP although several approaches have been attemptedincluding intravenous infusions of soluble recombinant ALP[125] bone marrow transplantation [123] and teriparatideadministration [124] Bisphosphonates (derivatives of PPi)could be ineffective or pose further problems [118] It hasbeen reported that plasma and urine PPi decrease after pla-cental ALP correction of the hypophosphatasia in pregnantcarriers of HPP [118] and iv injection of purified placentalALP was used to correct hypophosphatasemia in a severelyaffected infant but there was no clinical or radiographicimprovement These negative results suggested the greatertissue need for ALP or perhapsALPmust be bound to plasmamembranes for therapeutic efficacy

11 Conclusion

There is yet a large scale of work needed to be donetowards the discovery of new therapeutic methods of raregenetic bone disorders The elucidation of disease mecha-nisms will provide the first step Several potential therapeuticinterventions have been proposed however implementationof these therapeutic strategies will take time The disease


Hypophosphatasia

Mutation and loss of function of TNALP with increased

hypomineralized bone tissue


iv recombinant ALPiv placental ALPTeriparatideBisphosphonatesBone marrow transplantation


extracellular PPi and decreasedCa and Pi levels resulting in

Figure 14 Hypophosphatasia pathogenesis and potential therapeutic interventions

mechanism of Gorham-Stout disease melorheostosis andmultiple hereditary exostosis still needs to be fully elucidatedThe development of inhibitors of the ACVR1ALK2 pathwayseems to show promise as a possible therapeutic interventionfor FOPThe use of bisphosphonates and IL-6 inhibitors maybe useful in the treatment of fibrous dysplasia but furtherstudies are needed A viable cell therapy bisphosphonatepolytherapy and HGH may have potential to avert thepathology in osteogenesis imperfecta but more research isneeded to prove therapeutic benefit

The need for cures to these rare bone disorders has neverbeen more pressing given the increasing number of afflictedindividuals living across the globe Furthermore potentialcures for these rare bone disorders may also impact themanagement of more common bone diseases that display thesame basic mechanisms such as heterotrophic ossificationThus research in the upcoming years will show that viabletherapies of rare bone disorders might be in the horizons

Conflict of Interests

The authors declare that there is no conflict of interests

References

[1] R Rubin D S Strayer and E Rubin Rubinrsquos PathologyClinicopathologic Foundations of Medicine Wolters KluwerHealthLippincott Williams amp Wilkins Philadelphia Pa USA6th edition 2012

[2] BWNevilleOral andMaxillofacial Pathology SaundersElsev-ier St Louis Mo USA 3rd edition 2009

[3] S Yetiser E Gonul F Tosun M Tasar and Y Hidir ldquoMonos-totic craniofacial fibrous dysplasia the Turkish experiencerdquoJournal of Craniofacial Surgery vol 17 no 1 pp 62ndash67 2006

[4] R D Chapurlat and P Orcel ldquoFibrous dysplasia of bone andMcCune-Albright syndromerdquo Best Practice amp Research ClinicalRheumatology vol 22 no 1 pp 55ndash69 2008

[5] J B Regard N Cherman D Palmer et al ldquoWnt120573-catenin sig-naling is differentially regulated by G120572 proteins and contributesto fibrous dysplasiardquo Proceedings of the National Academy ofSciences of the United States of America vol 108 no 50 pp20101ndash20106 2011

[6] T G Kashima T Nishiyama K Shimazu et al ldquoPeriostina novel marker of intramembranous ossification is expressedin fibrous dysplasia and in c-Fos-overexpressing bone lesionsrdquoHuman Pathology vol 40 no 2 pp 226ndash237 2009

[7] I Saggio C Remoli E Spica et al ldquoConstitutive expression ofGs120572R201C in mice produces a heritable direct replica of humanfibrous dysplasia bone pathology and demonstrates its naturalhistoryrdquo Journal of Bone and Mineral Research 2014

[8] M G Su R Tian Q P Fan et al ldquoRecognition of fibrousdysplasia of bone mimicking skeletal metastasis on 18F-FDGPETCT imagingrdquo Skeletal Radiology vol 40 no 3 pp 295ndash302 2011

[9] F Tabareau-Delalande C Collin A Gomez-Brouchet et alldquoDiagnostic value of investigating GNAS mutations in fibro-osseous lesions a retrospective study of 91 cases of fibrous dys-plasia and 40 other fibro-osseous lesionsrdquo Modern Pathologyvol 26 no 7 pp 911ndash921 2013

[10] A A Makitie J Tornwall and O Makitie ldquoBisphosphonatetreatment in craniofacial fibrous dysplasiamdasha case report andreview of the literaturerdquo Clinical Rheumatology vol 27 no 6pp 809ndash812 2008

[11] R D Chapurlat D Gensburger J M Jimenez-Andrade J RGhilardi M Kelly and P Mantyh ldquoPathophysiology and med-ical treatment of pain in fibrous dysplasia of bonerdquo OrphanetJournal of Rare Diseases vol 7 no 1 article S3 2012

[12] P Garnero E Thompson T Woodworth and J S SmolenldquoRapid and sustained improvement in bone and cartilageturnover markers with the anti-interleukin-6 receptor inhibitortocilizumab plus methotrexate in rheumatoid arthritis patientswith an inadequate response to methotrexate results from asubstudy of the multicenter double-blind placebo-controlledtrial of tocilizumab in inadequate responders to methotrexatealonerdquo Arthritis and Rheumatism vol 62 no 1 pp 33ndash43 2010

[13] D P Minde Z Anvarian S G D Rudiger and M M MauriceldquoMessing up disorder how domissense mutations in the tumorsuppressor protein APC lead to cancerrdquoMolecular Cancer vol10 article 101 2011

[14] K Radhakrishnan and S G Rockson ldquoGorhamrsquos disease anosseous disease of lymphangiogenesisrdquo Annals of the New YorkAcademy of Sciences vol 1131 pp 203ndash205 2008

[15] W M Tsang A C Tong L T Chow and I O Ng ldquoMassiveosteolysis (Gorhamdisease) of themaxillofacial skeleton reportof 2 casesrdquo Journal of Oral andMaxillofacial Surgery vol 62 no2 pp 225ndash230 2004

[16] T Hirayama A Sabokbar I Itonaga S Watt-Smith and NA Athanasou ldquoCellular and humoral mechanisms of osteoclastformation and bone resorption in Gorham-Stout diseaserdquo TheJournal of Pathology vol 195 no 5 pp 624ndash630 2001

[17] R Venkatramani N S Ma P Pitukcheewanont M H Mal-ogolowkin and L Mascarenhas ldquoGorhamrsquos disease and dif-fuse lymphangiomatosis in children and adolescentsrdquo PediatricBlood and Cancer vol 56 no 4 pp 667ndash670 2011


[18] D Bruch-Gerharz C-D Gerharz H Stege et al ldquoCutaneouslymphatic malformations in disappearing bone (Gorham-Stout) disease a novel clue to the pathogenesis of a raresyndromerdquo Journal of the American Academy of Dermatologyvol 56 supplement 2 pp S21ndashS25 2007

[19] S Ray S Mukhopadhyay R Bandyopadhyay and S K SinhaldquoVanishing bone disease (Gorhamrsquo disease)mdasha rare occurrenceof unknown etiologyrdquo Indian Journal of Pathology and Microbi-ology vol 55 no 3 pp 399ndash401 2012

[20] MTDellingerNGarg andB ROlsen ldquoViewpoints on vesselsand vanishing bones in Gorham-Stout diseaserdquo Bone vol 63pp 47ndash52 2014

[21] T Mukai F Otsuka H Otani et al ldquoTNF-120572 inhibitsBMP-induced osteoblast differentiation through activatingSAPKJNK signalingrdquo Biochemical and Biophysical ResearchCommunications vol 356 no 4 pp 1004ndash1010 2007

[22] R D Devlin H G Bone III and G D Roodman ldquoInterleukin-6 a potential mediator of the massive osteolysis in patients withGorham-Stout diseaserdquo The Journal of Clinical Endocrinologyand Metabolism vol 81 no 5 pp 1893ndash1897 1996

[23] J Fontanesi ldquoRadiation therapy in the treatment of Gorhamdiseaserdquo Journal of Pediatric HematologyOncology vol 25 no10 pp 816ndash817 2003

[24] F Hammer W Kenn U Wesselmann et al ldquoGorham-Stoutdiseasemdashstabilization during bisphosphonate treatmentrdquo Jour-nal of Bone and Mineral Research vol 20 no 2 pp 350ndash3532005

[25] A Franchi F Bertoni P Bacchini V Mourmouras and CMiracco ldquoCD105endoglin expression in Gorham disease ofbonerdquo Journal of Clinical Pathology vol 62 no 2 pp 163ndash1672009

[26] F S Kaplan M Le Merrer D L Glaser et al ldquoFibrodysplasiaossificans progressivardquo Best Practice and Research ClinicalRheumatology vol 22 no 1 pp 191ndash205 2008

[27] J M Connor and D A P Evans ldquoGenetic aspects of fibrodys-plasia ossificans progressivardquo Journal of Medical Genetics vol19 no 1 pp 35ndash39 1982

[28] L S de La Pena P C Billings J L Fiori J Ahn F S Kaplanand E M Shore ldquoFibrodysplasia ossificans progressiva (FOP)a disorder of ectopic osteogenesis misregulates cell surfaceexpression and trafficking of BMPRIArdquo Journal of Bone andMineral Research vol 20 no 7 pp 1168ndash1176 2005

[29] DM RockeM Zasloff J Peeper R B Cohen and F S KaplanldquoAge- and joint-specific risk of initial heterotopic ossification inpatientswhohave fibrodysplasia ossificans progressivardquoClinicalOrthopaedics and Related Research no 301 pp 243ndash248 1994

[30] F S Kaplan M A Zasloff J A Kitterman E M Shore C CHong and D M Rocke ldquoEarly mortality and cardiorespiratoryfailure in patients with fibrodysplasia ossificans progressivardquoThe Journal of Bone and Joint Surgery American Volume A vol92 no 3 pp 686ndash691 2010

[31] J A Kitterman S Kantanie D M Rocke and F S KaplanldquoIatrogenic harm caused by diagnostic errors in fibrodysplasiaossificans progressivardquo Pediatrics vol 116 no 5 pp e654ndashe6612005

[32] S A Chakkalakal D Zhang A L Culbert et al ldquoAn Acvr1R206H knock-in mouse has fibrodysplasia ossificans progres-sivardquo Journal of Bone and Mineral Research vol 27 no 8 pp1746ndash1756 2012

[33] L Mao M Yano N Kawao Y Tamura K Okada and H KajildquoRole of matrix metalloproteinase-10 in the BMP-2 inducing

osteoblastic differentiationrdquo Endocrine Journal vol 60 no 12pp 1309ndash1319 2013

[34] F Giacopelli S Cappato L Tonachini et al ldquoIdentificationand characterization of regulatory elements in the promoterof ACVR1 the gene mutated in Fibrodysplasia OssificansProgressivardquo Orphanet Journal of Rare Diseases vol 8 no 1article 145 2013

[35] M Mura S Cappato F Giacopelli R Ravazzolo and RBocciardi ldquoThe role of the 3rsquoUTR region in the regulation of theacvr1alk-2 gene expressionrdquo PLoSONE vol 7 no 12 Article IDe50958 2012

[36] H Song Q Wang J Wen et al ldquoACVR1 a therapeutic target offibrodysplasia ossificans progressiva is negatively regulated bymiR-148ardquo International Journal of Molecular Sciences vol 13no 2 pp 2063ndash2077 2012

[37] S Shi J Cai D J de Gorter and et al ldquoAntisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2 inhibiting the receptor that is overactive infibrodysplasia ossificans progressivardquo PLoS ONE vol 8 no 7Article ID e69096 2013

[38] J Kaplan F S Kaplan and E M Shore ldquoRestoration ofnormal BMP signaling levels and osteogenic differentiation inFOP mesenchymal progenitor cells by mutant allele-specifictargetingrdquo Gene Therapy vol 19 no 7 pp 786ndash790 2012

[39] AMMotimaya and S PMeyers ldquoMelorheostosis involving thecervical and upper thoracic spine radiographic CT and MRimaging findingsrdquoTheAmerican Journal of Neuroradiology vol27 no 6 pp 1198ndash1200 2006

[40] A M Judkiewicz M D Murphey C S Resnik A H New-berg H T Temple and W S Smith ldquoAdvanced imaging ofmelorheostosis with emphasis on MRIrdquo Skeletal Radiology vol30 no 8 pp 447ndash453 2001

[41] S C Zeiller A R Vaccaro D W Wimberley T J Albert J SHarrop and A S Hilibrand ldquoSevere myelopathy resulting frommelorheostosis of the cervicothoracic spine A case reportrdquoJournal of Bone and Joint SurgerymdashSeries A vol 87 no 12 I pp2759ndash2762 2005

[42] N T Kalbermatten P Vock D Rufenacht and S E AndersonldquoProgressivemelorheostasis in the peripheral and axial skeletonwith associated vascular malformations imaging findings overthree decadesrdquo Skeletal Radiology vol 30 no 1 pp 48ndash52 2001

[43] M McCarthy H Mehdian K J Fairbairn and A StevensldquoMelorheostosis of the tenth and eleventh thoracic vertebraecrossing the facet joint a rare cause of back painrdquo SkeletalRadiology vol 33 no 5 pp 283ndash286 2004

[44] P A Robertson A S Don and M V Miller ldquoPainful lum-bosacral melorheostosis treated by fusionrdquo Spine vol 28 no 12pp E234ndashE238 2003

[45] R J Hollick A Black and D Reid ldquoMelorheostosis and itstreatment with intravenous zoledronic acidrdquo BMJ Case Reports2010

[46] E Moulder and C Marsh ldquoSoft tissue knee contracture of theknee due to melorheostosis treated by total knee arthroplastyrdquoThe Knee vol 13 no 5 pp 395ndash396 2006

[47] J Hellemans O Preobrazhenska A Willaert et al ldquoLoss-of-function mutations in LEMD3 result in osteopoikilosisBuschke-Ollendorff syndrome and melorheostosisrdquo NatureGenetics vol 36 no 11 pp 1213ndash1218 2004

[48] J Hellemans P Debeer M Wright et al ldquoGermline LEMD3mutations are rare in sporadic patients with isolated melorheo-stosisrdquo Human mutation vol 27 no 3 p 290 2006


[49] J E Kim E H Kim E H Han et al ldquoA TGF-beta-inducible cell adhesion molecule betaig-h3 is downregulatedin melorheostosis and involved in osteogenesisrdquo Journal ofCellular Biochemistry vol 77 no 2 pp 169ndash178 2000

[50] H Endo A Katsumi K Kuroda A Utani H Moriya andH Shinkai ldquoIncreased procollagen 1205721(I) mRNA expression bydermal fibroblasts in melorheostosisrdquo The British Journal ofDermatology vol 148 no 4 pp 799ndash803 2003

[51] A Kivioja H Ervasti J Kinnunen I Kaitila M Wolf and TBohling ldquoChondrosarcoma in a family withmultiple hereditaryexostosesrdquo Journal of Bone and Joint SurgerymdashSeries B vol 82no 2 pp 261ndash266 2000

[52] G A Schmale E U Conrad III and W H Raskind ldquoThenatural history of hereditary multiple exostosesrdquoThe Journal ofBone and Joint SurgerymdashSeries A vol 76 no 7 pp 986ndash9921994

[53] W Wuyts and W Van Hul ldquoMolecular basis of multipleexostoses mutations in the EXT1 and EXT2 genesrdquo HumanMutation vol 15 no 3 pp 220ndash227 2000

[54] M Busse A Feta J Presto et al ldquoContribution of EXT1 EXT2and EXTL3 to heparan sulfate chain elongationrdquo Journal ofBiological Chemistry vol 282 no 45 pp 32802ndash32810 2007

[55] C Francannet A Cohen-Tanugi M Le Merrer A MunnichJ Bonaventure and L Legeai-Mallet ldquoGenotype-phenotypecorrelation in hereditary multiple exostosesrdquo Journal of MedicalGenetics vol 38 no 7 pp 430ndash434 2001

[56] D E Porter L Lonie M Fraser et al ldquoSeverity of diseaseand risk of malignant change in hereditary multiple exostosesrdquoJournal of Bone and Joint SurgerymdashSeries B vol 86 no 7 pp1041ndash1046 2004

[57] K Matsumoto F Irie S Mackem and Y Yamaguchi ldquoA mousemodel of chondrocyte-specific somatic mutation reveals a rolefor Ext1 loss of heterozygosity in multiple hereditary exostosesrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 107 no 24 pp 10932ndash10937 2010

[58] Y-E Shieh D E Wells and A K Sater ldquoZygotic expression ofexostosin1 (Ext1) is required for BMP signaling and establish-ment of dorsal-ventral pattern in Xenopusrdquo The InternationalJournal of Developmental Biology vol 58 no 1 pp 27ndash34 2014

[59] L Cantley C Saunders M Guttenberg et al ldquoLoss of 120573-catenininduces multifocal periosteal chondroma-like masses in micerdquoThe American Journal of Pathology vol 182 no 3 pp 917ndash9272013

[60] M F Anower-E-Khuda K Matsumoto H Habuchi et al ldquoGly-cosaminoglycans in the blood of hereditary multiple exostosespatients Half reduction of heparan sulfate to chondroitin sul-fate ratio and the possible diagnostic applicationrdquo Glycobiologyvol 23 no 7 pp 865ndash876 2013

[61] J R Stieber and J P Dormans ldquoManifestations of hereditarymultiple exostosesrdquo The Journal of the American Academy ofOrthopaedic Surgeons vol 13 no 2 pp 110ndash120 2005

[62] K B Jones ldquoGlycobiology and the growth plate currentconcepts in multiple hereditary exostosesrdquo Journal of PediatricOrthopaedics vol 31 no 5 pp 577ndash586 2011

[63] S H Kozin ldquoCongenital differences about the elbowrdquo HandClinics vol 25 no 2 pp 277ndash291 2009

[64] I Solomon ldquoChondrosarcoma in hereditarymultiple exostosisrdquoSouth AfricanMedical Journal vol 48 no 16 pp 671ndash676 1974

[65] R C M Hennekam ldquoHereditary multiple exostosesrdquo Journal ofMedical Genetics vol 28 no 4 pp 262ndash266 1991

[66] J V M G Bovee ldquoMultiple osteochondromasrdquo OrphanetJournal of Rare Diseases vol 3 no 1 article 3 2008

[67] I Khan C A West Jr G P Sangster M Heldmann LDoucet and M Olmedo ldquoMultiple hereditary exostoses asa rare nonatherosclerotic etiology of chronic lower extremityischemiardquo Journal of Vascular Surgery vol 51 no 4 pp 1003ndash1005 2010

[68] R D Steiner J Adsit and D Basel ldquoCOL1A12-related osteoge-nesis imperfectardquo in GeneReviews R A Pagon M P Adam HH Ardinger et al Eds 1993

[69] J C Marini W A Cabral A M Barnes and W ChangldquoComponents of the collagen prolyl 3-hydroxylation complexare crucial for normal bone developmentrdquo Cell Cycle vol 6 no14 pp 1675ndash1681 2007

[70] T E Uveges P Collin-Osdoby W A Cabral et al ldquoCellularmechanism of decreased bone in Brtl mouse model of OIimbalance of decreased osteoblast function and increasedosteoclasts and their precursorsrdquo Journal of Bone and MineralResearch vol 23 no 12 pp 1983ndash1994 2008

[71] R Bargman R Posham A L Boskey E Dicarlo C Raggioand N Pleshko ldquoComparable outcomes in fracture reductionand bone properties with RANKL inhibition and alendronatetreatment in a mouse model of osteogenesis imperfectardquoOsteo-porosis International vol 23 no 3 pp 1141ndash1150 2012

[72] F S vanDijk JM Cobben A Kariminejad et al ldquoOsteogenesisimperfecta a review with clinical examplesrdquoMolecular Syndro-mology vol 2 no 1 pp 1ndash20 2011

[73] J C Marini and N L Gerber ldquoOsteogenesis imperfectarehabilitation and prospects for gene therapyrdquoThe Journal of theAmericanMedical Association vol 277 no 9 pp 746ndash750 1997

[74] C A Phillipi T Remmington and R D Steiner ldquoBisphospho-nate therapy for osteogenesis imperfectardquoCochrane Database ofSystematic Reviews no 4 Article ID CD005088 2008

[75] R Sakkers D Kok R Engelbert et al ldquoSkeletal effects and func-tional outcome with olpadronate in children with osteogenesisimperfecta a 2-year randomised placebo-controlled studyrdquoTheLancet vol 363 no 9419 pp 1427ndash1431 2004

[76] F Antoniazzi E Monti G Venturi et al ldquoGH in combinationwith bisphosphonate treatment in osteogenesis imperfectardquoEuropean Journal of Endocrinology vol 163 no 3 pp 479ndash4872010

[77] J C Marini E Hopkins F H Glorieux et al ldquoPositive lineargrowth and bone responses to growth hormone treatment inchildren with types III and IV osteogenesis imperfecta highpredictive value of the carboxyterminal propeptide of type Iprocollagenrdquo Journal of Bone and Mineral Research vol 18 no2 pp 237ndash243 2003

[78] S Otsuru P L Gordon K Shimono et al ldquoTransplanted bonemarrow mononuclear cells and MSCs impart clinical benefitto children with osteogenesis imperfecta through differentmechanismsrdquo Blood vol 120 no 9 pp 1933ndash1941 2012

[79] D B Kirkpatrick ldquoCraniometaphyseal dysplasiardquo Surgical Neu-rology vol 28 no 3 p 231 1987

[80] D E Cole andM M Cohen Jr ldquoA new look at craniometaphy-seal dysplasiardquo Journal of Pediatrics vol 112 no 4 pp 577ndash5781988

[81] P Beighton ldquoCraniometaphyseal dysplasia (CMD) autosomaldominant formrdquo Journal of Medical Genetics vol 32 no 5 pp370ndash374 1995

[82] P Nurnberg HThiele D Chandler et al ldquoHeterozygousmuta-tions in ANKH the human ortholog of the mouse progressive


ankylosis gene result in craniometaphyseal dysplasiardquo NatureGenetics vol 28 no 1 pp 37ndash41 2001

[83] T Kato H Matsumoto A Chida H Wakamatsu and SNonoyama ldquoMaternal mosaicism of an ANKH mutation in afamily with craniometaphyseal dysplasiardquo Pediatrics Interna-tional vol 55 no 2 pp 254ndash256 2013

[84] G Baynam J Goldblatt and L Schofield ldquoCraniometaphysealdysplasia and chondrocalcinosis cosegregating in a family withan ANKHmutationrdquoTheAmerican Journal of Medical GeneticsPart A vol 149 no 6 pp 1331ndash1333 2009

[85] S Tinschert and H S Braun ldquoCraniometaphyseal dysplasiain six generations of a German kindredrdquo American Journal ofMedical Genetics vol 77 no 3 pp 175ndash181 1998

[86] E Reichenberger V Tiziani S Watanabe et al ldquoAutosomaldominant craniometaphyseal dysplasia is caused by mutationsin the transmembrane protein ANKrdquo The American Journal ofHuman Genetics vol 68 no 6 pp 1321ndash1326 2001

[87] Y Hu I-P Chen S de Almeida et al ldquoA novel autosomalrecessive GJA1missense mutation linked to Craniometaphysealdysplasiardquo PLoS ONE vol 8 no 8 Article ID e73576 2013

[88] K A Gurley R J Reimer andDMKingsley ldquoBiochemical andgenetic analysis of ANK in arthritis and bone diseaserdquoAmericanJournal of Human Genetics vol 79 no 6 pp 1017ndash1029 2006

[89] A M Ho M D Johnson and D M Kingsley ldquoRole of themouse ank gene in control of tissue calcification and arthritisrdquoScience vol 289 no 5477 pp 265ndash270 2000

[90] S E Mansurova ldquoInorganic pyrophosphate in mitochondrialmetabolismrdquo Biochimica et Biophysica Acta vol 977 no 3 pp237ndash247 1989

[91] A M Davidson and A P Halestrap ldquoInorganic pyrophosphateis located primarily in the mitochondria of the hepatocyteand increases in parallel with the decrease in light-scatteringinduced by gluconeogenic hormones butyrate and ionophoreA23187rdquo Biochemical Journal vol 254 no 2 pp 379ndash384 1988

[92] J W Rachow and L M Ryan ldquoInorganic pyrophosphatemetabolism in arthritisrdquo Rheumatic Disease Clinics of NorthAmerica vol 14 no 2 pp 289ndash302 1988

[93] J M Capasso T W Keenan C Abeijon and C B HirschbergldquoMechanism of phosphorylation in the lumen of the Golgiapparatus Translocation of adenosine 5 1015840-triphosphate intoGolgi vesicles from rat liver and mammary glandrdquo Journal ofBiological Chemistry vol 264 no 9 pp 5233ndash5240 1989

[94] K Johnson A Jung A Murphy A Andreyev J Dykens andR Terkeltaub ldquoMitochondrial oxidative phosphorylation is adownstream regulator of nitric oxide effects on chondrocytematrix synthesis and mineralizationrdquo Arthritis amp Rheumatol-ogy vol 43 no 7 pp 1560ndash1570 2000

[95] H Fleisch R G G Russell and F Straumann ldquoEffect ofpyrophosphate on hydroxyapatite and its implications in cal-cium homeostasisrdquoNature vol 212 no 5065 pp 901ndash903 1966

[96] W N Addison F Azari E S SoslashrensenM T Kaartinen andMDMcKee ldquoPyrophosphate inhibitsmineralization of osteoblastcultures by binding to mineral up-regulating osteopontin andinhibiting alkaline phosphatase activityrdquo Journal of BiologicalChemistry vol 282 no 21 pp 15872ndash15883 2007

[97] D Harmey L Hessle S Narisawa K A Johnson R Terkeltauband J L Millan ldquoConcerted regulation of inorganic pyrophos-phate and osteopontin by akp2 enpp1 and ank an integratedmodel of the pathogenesis of mineralization disordersrdquo TheAmerican Journal of Pathology vol 164 no 4 pp 1199ndash12092004

[98] I-P Chen C J Wang S Strecker B Koczon-Jaremko ABoskey and E J Reichenberger ldquoIntroduction of a Phe377delmutation in ANK creates amousemodel for craniometaphysealdysplasiardquo Journal of Bone and Mineral Research vol 24 no 7pp 1206ndash1215 2009

[99] T Yamamoto N Kurihara K Yamaoka et al ldquoBone marrow-derived osteoclast-like cells from a patient with craniometa-physeal dysplasia lack expression of osteoclast-reactive vacuolarproton pumprdquo Journal of Clinical Investigation vol 91 no 1 pp362ndash367 1993

[100] L Lyndon Key Jr F Volberg R Baron and C S AnastldquoTreatment of craniometaphyseal dysplasia with calcitriolrdquoTheJournal of Pediatrics vol 112 no 4 pp 583ndash587 1988

[101] S Fanconi J A Fischer P Wieland et al ldquoCraniometaphy-seal dysplasia with increased bone turnover and secondaryhyperparathyroidism therapeutic effect of calcitoninrdquo Journalof Pediatrics vol 112 no 4 pp 587ndash591 1988

[102] W A Horton J G Hall and J T Hecht ldquoAchondroplasiardquoTheLancet vol 370 no 9582 pp 162ndash172 2007

[103] R Shiang L M Thompson Y-Z Zhu et al ldquoMutations inthe transmembrane domain of FGFR3 cause the most commongenetic form of dwarfism achondroplasiardquo Cell vol 78 no 2pp 335ndash342 1994

[104] G A Bellus T W Hefferon R I de Ortiz Luna et alldquoAchondroplasia is defined by recurrent G380R mutations ofFGFR3rdquo The American Journal of Human Genetics vol 56 no2 pp 367ndash373 1995

[105] G A Bellus I McIntosh E A Smith et al ldquoA recurrentmutation in the tyrosine kinase domain of fibroblast growthfactor receptor 3 causes hypochondroplasiardquo Nature Geneticsvol 10 no 3 pp 357ndash359 1995

[106] F Rousseau J Bonaventure L Legeai-Mallet et al ldquoMutationsin the gene encoding fibroblast growth factor receptor-3 inachondroplasiardquo Nature vol 371 no 6494 pp 252ndash254 1994

[107] M Velinov S A Slaugenhaupt I Stoilov C I Scott Jr J FGusella and P Tsipouras ldquoThe gene for achondroplasiamaps tothe telomeric region of chromosome 4prdquo Nature Genetics vol6 no 3 pp 314ndash317 1994

[108] ZVajo CA Francomano andD JWilkin ldquoThemolecular andgenetic basis of fibroblast growth factor receptor 3 disordersthe achondroplasia family of skeletal dysplasias Muenke cran-iosynostosis and Crouzon syndrome with acanthosis nigri-cansrdquo Endocrine Reviews vol 21 no 1 pp 23ndash39 2000

[109] J S Colvin B A Bohne G W Harding D G McEwen and DM Ornitz ldquoSkeletal overgrowth and deafness in mice lackingfibroblast growth factor receptor 3rdquoNature Genetics vol 12 no4 pp 390ndash397 1996

[110] C Deng A Wynshaw-Boris F Zhou A Kuo and P LederldquoFibroblast growth factor receptor 3 is a negative regulator ofbone growthrdquo Cell vol 84 no 6 pp 911ndash921 1996

[111] M C Naski J S Colvin J Douglas Coffin and D M OrnitzldquoRepression of hedgehog signaling and BMP4 expression ingrowth plate cartilage by fibroblast growth factor receptor 3rdquoDevelopment vol 125 no 24 pp 4977ndash4988 1998

[112] M Suda Y Ogawa K Tanaka et al ldquoSkeletal overgrowthin transgenic mice that overexpress brain natriuretic peptiderdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 5 pp 2337ndash2342 1998

[113] A Yasoda Y Ogawa M Suda et al ldquoNatriuretic peptide regu-lation of endochondral ossification Evidence for possible rolesof the C-type natriuretic peptideguanylyl cyclase-B pathwayrdquo


Journal of Biological Chemistry vol 273 no 19 pp 11695ndash117001998

[114] H Chusho N Tamura Y Ogawa et al ldquoDwarfism and earlydeath inmice lacking C-type natriuretic peptiderdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 98 no 7 pp 4016ndash4021 2001

[115] A Yasoda Y Komatsu H Chusho et al ldquoOverexpressionof CNP in chondrocytes rescues achondroplasia through aMAPK-dependent pathwayrdquo Nature Medicine vol 10 no 1 pp80ndash86 2004

[116] P S Henthorn M Raducha K N Fedde M A Laffertyand M P Whyte ldquoDifferent missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal reces-sively inherited forms of mild and severe hypophosphatasiardquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 89 no 20 pp 9924ndash9928 1992

[117] D P Ramadza F Stipoljev V Sarnavka et al ldquoHypophosphata-sia phenotypic variability and possible Croatian origin of thec1402GgtA mutation of TNSALP generdquo Collegium Antropolog-icum vol 33 no 4 pp 1255ndash1258 2009

[118] M PWhyte M Landt L M Ryan et al ldquoAlkaline phosphataseplacental and tissue-nonspecific isoenzymes hydrolyze phos-phoethanolamine inorganic pyrophosphate and pyridoxal 51015840-phosphate Substrate accumulation in carriers of hypophos-phatasia corrects during pregnancyrdquo The Journal of ClinicalInvestigation vol 95 no 4 pp 1440ndash1445 1995

[119] S Mumm J Jones P Finnegan P S Henthorn M NPodgornik and M P Whyte ldquoDenaturing gradient gel elec-trophoresis analysis of the tissue nonspecific alkaline phos-phatase isoenzyme gene in hypophosphatasiardquo MolecularGenetics and Metabolism vol 75 no 2 pp 143ndash153 2002

[120] E Mornet A Taillandier S Peyramaure et al ldquoIdentificationof fifteen novel mutations in the tissue-nonspecific alkalinephosphatase (TNSALP) gene in European patients with severehypophosphatasiardquo European Journal of HumanGenetics vol 6no 4 pp 308ndash314 1998

[121] W Tesch T Vandenbos P Roschgr et al ldquoOrientation ofmineral crystallites and mineral density during skeletal devel-opment in mice deficient in tissue nonspecific alkaline phos-phataserdquo Journal of Bone andMineral Research vol 18 no 1 pp117ndash125 2003

[122] S Baumgartner-Sigl E Haberlandt S Mumm et alldquoPyridoxine-responsive seizures as the first symptom ofinfantile hypophosphatasia caused by two novel missensemutations (c677TgtC pM226T c1112CgtT pT371I) of thetissue-nonspecific alkaline phosphatase generdquo Bone vol 40no 6 pp 1655ndash1661 2007

[123] R A Cahill D Wenkert S A Perlman et al ldquoInfan-tile hypophosphatasia transplantation therapy trial usingbone fragments and cultured osteoblastsrdquo Journal of ClinicalEndocrinology and Metabolism vol 92 no 8 pp 2923ndash29302007

[124] M P Whyte S Mumm and C Deal ldquoAdult hypophosphatasiatreated with teriparatiderdquoThe Journal of Clinical Endocrinologyand Metabolism vol 92 no 4 pp 1203ndash1208 2007

[125] M P Whyte W H McAlister L S Patton et al ldquoEnzymereplacement therapy for infantile hypophosphatasia attemptedby intravenous infusions of alkaline phosphatase-rich Pagetplasma results in three additional patientsrdquo The Journal ofPediatrics vol 105 no 6 pp 926ndash933 1984


2 Fibrous Dysplasia

Fibrous dysplasia (FD) is a rare bone disease characterized byreplacement of the medullary cavity with fibrous tissue Anyregion of the skeleton can be affected by FD where the mostcommon areas involved include facial bones the tibia femurand the ribs [1] Several forms of FD exist The monostoticform of FD is limited to one bone whereas the polyostoticform is manifest in multiple bones [2] McCune-Albrightsyndrome is another variant of FD and in addition to boneinvolvement is associated with endocrine dysfunctions suchas Cushing syndrome hyperthyroidism and acromegaly [12] FD causes chronic pain in patients due to bone over-growth Other long term problems include bony deformitiesunequal limb lengths and diminished bone strength leadingto a high risk of fractures

FDdisplays no predilection for either genderThemonos-totic form is more prevalent than the polyostotic form withthe variants occurring at a ratio of 7 3 respectively [3] Themonostotic form classically occurs in individuals in their20s to 30s whereas the polyostotic form is usually seen inchildren Polyostotic FD usually enters dormancy at the onsetof puberty but pregnancy may result in reactivation of thedisease [1]

FD results of mutations in the guanine nucleotide bind-ing alpha stimulating (GNAS) complex locus located onchromosome 20 [4]Themutations occur postzygotically andlead to constitutive activation of G120572s resulting in stimulationof the Wnt120573-catenin signaling pathway [4 5] Mutationactivation of G120572s subunit leads to high levels of cyclicadenosine monophosphate (cAMP) levels that mediate thedownstream functions in the affected cells In particular thetranscription factors cFos and cJun and the cytokine IL-6are upregulated in osteoclasts resulting in excessive boneresorption and dysplastic fibrous growth [1 6]

Recent study showed that transgenic mice with consti-tutive expression of the G120572s subunit developed an inheritedpathologically replication of human FD The characteristicFD lesions in mice developed only in postnatal life as inhuman FD [6] In the affected bone the lesions developthrough a sequence of three consecutive stages a primarymodeling phase characterized by excess medullary boneformation a secondary phase with excess inappropriateremodeling and a tertiary phase of fibrous dysplastic in themarrow cavity that replicates the human bone pathology inmice of more than 1 year old [6 7]

X-ray diagnostic features of FD are a characteristic hazybone lesion (ground glass) For most parts this radiologicentity is sufficient for the initial diagnosis of the diseaseHow-ever in patients where metastasis may pose a viable concerna PETCT may be considered However Su et al concludedthat this alone may not be enough [8] They conducted F-fluoro-2-deoxy-glucose positron emission tomography (F-FDG PETCT) on a female patient in whom breast cancerrecurrence was suspected FD was an incidental findingon PETCT However they noted that the dysplastic lesionmimicked metastasis MRI proved to be a useful modality indifferentiating FD from metastasis Other novel approaches

of detecting the disease are also being pursued Tabareau-Delalande et al [9] demonstrated that GNAS mutationsare specific for fibrous dysplasia among other fibroossifyinglesions Thus DNA markers for the GNAS mutation mayprovide an alternate means of diagnosing the disease in morecomplicated cases of FD

In the present there is no cure for FD and the manage-ment is composed largely of reduction of pain preventingfurther degeneration of bone and surgical intervention toreshape and restore the functionality of the affected boneA current approach that aims at both strengthening boneand reducing pain is bisphosphonate therapy Makitie et al[10] administered bisphosphonates intravenously in a patientwith mandibular FD The therapeutic approach resulted inrapid reduction of pain stabilized turnover of bone andeven proved to be cosmetically beneficial In patients thatare nonresponsive to bisphosphonates Chapurlat et al [11]suggested the use of IL-6 inhibitors such as tocilizumab amonoclonal antibody used to treat rheumatoid arthritis (RA)A study investigating the effect of tocilizumab on systemicbone resorption through tracking serum cross-linked C-terminal telopeptide of type I collagen (CTX and ICTP)revealed a significant decrease in bone resorption with thetherapy [12] Therefore this approach could also be useful inpreventing the bone resorption seen in FD

Several potential therapeutic interventions may beemployed (Figure 1) A possible therapeutic strategy tobe pursued in the future could be targeting the Wnt120573-catenin pathway If the Wnt signaling pathway is halted120573-catenin will not accumulate within the cell since it ismarked for ubiquitination by casein kinase 1120572 (CK1120572)protein phosphatase 2A (PP2A) adenomatosis polyposis coli(APC) Axin and glycogen synthase kinase 3 (GSK3) [13]Ubiquitination of 120573-catenin would lead to its proteasomaldegradation thus preventing it from eliciting a cellularresponse contributing to FD Therefore if Wnt proteins canbe selectively bound by ligand analogs and inactivated thetumorigenic fibrous growth will be diminished (Figure 2)

3 Gorham-Stout Disease

Gorhamrsquos disease (GD) also known as vanishing bonedisease is a rare genetic disorder characterized by boneresorption and localized lymphangiogenic proliferation [14]This lymphatic and vascular proliferation within bone isthought to aid in osteolysis GD shows no preference forgender or race and occurs more often in children and youngadults Although GD manifests itself as a monostotic orpolyostotic disease it more commonly involves the flat bonesthat form by intermembranous ossification [15]

Diagnosis of GD is challenging it is often a diagnosisof exclusion Other differentials such as endocrinopathiesmalignancies and immunologic infectious and metabolicetiologies need to be ruled out before a diagnosis of GD canbe made [15 16]

A study conducted by Venkatramani et al [17] revealedinsights about GD manifestations Of the eight patients(median age at diagnosis was 115 years) who were part ofthe study seven presented with lymphangiomatous lesions in


ACReceptor

ATP

cAMP



Intracellular

ExtracellularLigand

120574120573 120572











Fibrous dysplasia






pathway (4 5)






Mac

OC

OB

LEC

BEC

IL-6

VEGF-A -C and -D

VEGF-C -D

VEGF-A

IL-6 TNF120572 TNF120572















Alk2

Alk6

ActRIIBMPRII

Alk3

Smad1Smad5Smad8

P

Smad4P

Smad4R-SmadP

TF

Co-Act

R-SmadP

BMPs

BMPRI

Intracellular

Extracellular

Nucleus




5 Melorheostosis













Melorheostosis

















































Extracellular

IntracellularCMD

(BCP)

Ankank

Ank mouse

COOHNH2

(a)

4

Extracellular

IntracellularN C

CN

PPi 1

1

2

2

3

3

4

4

5

6

78 9

10

(b)


ATP

ATP

Intracellular

NTP-PPH

ANK

ALKPase

Pi + Pi

PPiPPi

AMP + PPi

Mito

(a)


HA (BCP)deposition

CMD



PPiPPiPPi

PPi PPi PPi

(b)











PPi intracellular




9 Achondroplasia







Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References






































































































































ACReceptor

ATP

cAMP



Intracellular

ExtracellularLigand

120574120573 120572











Fibrous dysplasia






pathway (4 5)






Mac

OC

OB

LEC

BEC

IL-6

VEGF-A -C and -D

VEGF-C -D

VEGF-A

IL-6 TNF120572 TNF120572















Alk2

Alk6

ActRIIBMPRII

Alk3

Smad1Smad5Smad8

P

Smad4P

Smad4R-SmadP

TF

Co-Act

R-SmadP

BMPs

BMPRI

Intracellular

Extracellular

Nucleus




5 Melorheostosis













Melorheostosis

















































Extracellular

IntracellularCMD

(BCP)

Ankank

Ank mouse

COOHNH2

(a)

4

Extracellular

IntracellularN C

CN

PPi 1

1

2

2

3

3

4

4

5

6

78 9

10

(b)


ATP

ATP

Intracellular

NTP-PPH

ANK

ALKPase

Pi + Pi

PPiPPi

AMP + PPi

Mito

(a)


HA (BCP)deposition

CMD



PPiPPiPPi

PPi PPi PPi

(b)











PPi intracellular




9 Achondroplasia







Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References






































































































































Fibrous dysplasia






pathway (4 5)






Mac

OC

OB

LEC

BEC

IL-6

VEGF-A -C and -D

VEGF-C -D

VEGF-A

IL-6 TNF120572 TNF120572















Alk2

Alk6

ActRIIBMPRII

Alk3

Smad1Smad5Smad8

P

Smad4P

Smad4R-SmadP

TF

Co-Act

R-SmadP

BMPs

BMPRI

Intracellular

Extracellular

Nucleus




5 Melorheostosis













Melorheostosis

















































Extracellular

IntracellularCMD

(BCP)

Ankank

Ank mouse

COOHNH2

(a)

4

Extracellular

IntracellularN C

CN

PPi 1

1

2

2

3

3

4

4

5

6

78 9

10

(b)


ATP

ATP

Intracellular

NTP-PPH

ANK

ALKPase

Pi + Pi

PPiPPi

AMP + PPi

Mito

(a)


HA (BCP)deposition

CMD



PPiPPiPPi

PPi PPi PPi

(b)











PPi intracellular




9 Achondroplasia







Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References














































































































































Alk2

Alk6

ActRIIBMPRII

Alk3

Smad1Smad5Smad8

P

Smad4P

Smad4R-SmadP

TF

Co-Act

R-SmadP

BMPs

BMPRI

Intracellular

Extracellular

Nucleus




5 Melorheostosis













Melorheostosis

















































Extracellular

IntracellularCMD

(BCP)

Ankank

Ank mouse

COOHNH2

(a)

4

Extracellular

IntracellularN C

CN

PPi 1

1

2

2

3

3

4

4

5

6

78 9

10

(b)


ATP

ATP

Intracellular

NTP-PPH

ANK

ALKPase

Pi + Pi

PPiPPi

AMP + PPi

Mito

(a)


HA (BCP)deposition

CMD



PPiPPiPPi

PPi PPi PPi

(b)











PPi intracellular




9 Achondroplasia







Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References













































































































































Melorheostosis

















































Extracellular

IntracellularCMD

(BCP)

Ankank

Ank mouse

COOHNH2

(a)

4

Extracellular

IntracellularN C

CN

PPi 1

1

2

2

3

3

4

4

5

6

78 9

10

(b)


ATP

ATP

Intracellular

NTP-PPH

ANK

ALKPase

Pi + Pi

PPiPPi

AMP + PPi

Mito

(a)


HA (BCP)deposition

CMD



PPiPPiPPi

PPi PPi PPi

(b)











PPi intracellular




9 Achondroplasia







Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References









































































































































































Extracellular

IntracellularCMD

(BCP)

Ankank

Ank mouse

COOHNH2

(a)

4

Extracellular

IntracellularN C

CN

PPi 1

1

2

2

3

3

4

4

5

6

78 9

10

(b)


ATP

ATP

Intracellular

NTP-PPH

ANK

ALKPase

Pi + Pi

PPiPPi

AMP + PPi

Mito

(a)


HA (BCP)deposition

CMD



PPiPPiPPi

PPi PPi PPi

(b)











PPi intracellular




9 Achondroplasia







Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References























































































































































Extracellular

IntracellularCMD

(BCP)

Ankank

Ank mouse

COOHNH2

(a)

4

Extracellular

IntracellularN C

CN

PPi 1

1

2

2

3

3

4

4

5

6

78 9

10

(b)


ATP

ATP

Intracellular

NTP-PPH

ANK

ALKPase

Pi + Pi

PPiPPi

AMP + PPi

Mito

(a)


HA (BCP)deposition

CMD



PPiPPiPPi

PPi PPi PPi

(b)











PPi intracellular




9 Achondroplasia







Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References






































































































































Extracellular

IntracellularCMD

(BCP)

Ankank

Ank mouse

COOHNH2

(a)

4

Extracellular

IntracellularN C

CN

PPi 1

1

2

2

3

3

4

4

5

6

78 9

10

(b)


ATP

ATP

Intracellular

NTP-PPH

ANK

ALKPase

Pi + Pi

PPiPPi

AMP + PPi

Mito

(a)


HA (BCP)deposition

CMD



PPiPPiPPi

PPi PPi PPi

(b)











PPi intracellular




9 Achondroplasia







Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References












































































































































PPi intracellular




9 Achondroplasia







Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References






































































































































Achondroplasia






Gamma secretase



10 Hypophosphatasia





11 Conclusion



Hypophosphatasia












References






































































































































Hypophosphatasia












References







































































































































































































































































































































































































Date post:	14-Jul-2020
Category:	Documents
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ReviewArticle · Melorheostosis is a rare genetic bone disease of unknown etiology in which...

Documents