224 THE JOURNAL OF PROSTHETIC DENTISTRY VOLUME 80 NUMBER 2 R esidual ridge is a term used to describe the shape of the clinical alveolar ridge after healing of bone and soft tissues after tooth extractions. After tooth extrac- tion, a cascade of inflammatory reactions is immediate- ly activated, and the extraction socket is temporarily closed by the blood clotting. Epithelial tissue begins its proliferation and migration within the first week and the disrupted tissue integrity is quickly restored. Histo- logic evidence of active bone formation in the bottom of the socket is seen as early as 2 weeks after the extrac- tion and the socket is progressively filled with newly formed bone in about 6 months. 1,2 The most striking feature of the extraction wound healing is that even Current perspectives in residual ridge remodeling and its clinical implications: A review Leila Jahangiri, BDS, MMSc, a Hugh Devlin, BDS, PhD, b Kang Ting, DMD, DMSc, c and Ichiro Nishimura, DDS, DMSc, DMD d Harvard School of Dental Medicine, Boston, Mass.; University Dental Hospital of Manchester, Manchester, United Kingdom; and UCLA School of Dentistry, Los Angeles, Calif. Purpose. This article reviews the current understanding of the biology of tooth extraction wound healing and residual ridge remodeling. Methods. The review of the biology of tooth extraction wound healing involves a discussion of the differ- ent cells populating the tooth extraction wound, the matrix formation, and the control of the repair process in the short-term. Defects in socket matrix formation or cellular activity will lead to stalled healing. The review of residual ridge remodeling describes the long-term result of tooth extraction and formation of residual ridges, in which the quantity of bone tissue continuously decreases. This may suggest that any potential regulatory factors of residual ridge resorption should have an adverse effect either on the increased catabolic activity by osteoclasts or on the decreased anabolic activity by osteoblasts. Both short-term tooth extraction healing and long-term residual ridge remodeling processes are interdependent. Furthermore, any potential genetic and environmental regulatory factors can affect the quality and quantity of bone by alter- ing the gene expression events taking place in bone cells. Results. The intent of this article was to review the current progress of biologic research on residual ridge remodeling and to relate the changes at molecular, cellular, and tissue levels. The understanding of residual ridge remodeling may provide a sound scientific basis for improved restorative and therapeutic treatments of the edentulous population. (J Prosthet Dent 1998;80:224-37.) Presented in part before the Academy of Prosthodontics, Tucson, Arizona, May 1995. This review was partly based on investigations supported by Proc- ter & Gamble Fellowship Award (L. Jahangiri), British Diabetic Association (H. Devlin), and NIH grants, EY08219, and DE10870 (I. Nishimura). a Instructor of Restorative Dentistry (Prosthodontics), Harvard School of Dental Medicine. b Senior Lecturer in Restorative Dentistry, University Dental Hospital of Manchester, University of Manchester. c Assistant Professor of Orthodontics, UCLA School of Dentistry. d Associate Professor Section of Advanced Prosthodontics, UCLA School of Dentistry and Director, Center for Reconstructive Biotechnology. CLINICAL IMPLICATIONS This review addressed the cellular and extracellular matrix component of alveolar bone regeneration. The cellular component is sensitively responding to the mechanical and biologic environments such as removable partial denture and osteoporosis. Uncov- ering these regulatory mechanisms may lead to a new therapeutic modality in main- taining and further regeneration of the residual ridge alveolar bone. The heteroge- neous reaction by osteoblasts to a newly characterized extracellular matrix containing type II and type IX collagens has provided a puzzling but exciting result, which seems to postulate two independent remodeling processes that regulate cortical bone and tra- becular bone separately. The proposed distinct remodeling processes may be directly applied to osseointegration phenomenon in which cortical and trabecular bones may provide different consequences.
Transcript
224 THE JOURNAL OF PROSTHETIC DENTISTRY VOLUME 80 NUMBER 2
Residual ridge is a term used to describe the shapeof the clinical alveolar ridge after healing of bone andsoft tissues after tooth extractions. After tooth extrac-tion, a cascade of inflammatory reactions is immediate-ly activated, and the extraction socket is temporarilyclosed by the blood clotting. Epithelial tissue begins itsproliferation and migration within the first week andthe disrupted tissue integrity is quickly restored. Histo-logic evidence of active bone formation in the bottomof the socket is seen as early as 2 weeks after the extrac-tion and the socket is progressively filled with newlyformed bone in about 6 months.1,2 The most strikingfeature of the extraction wound healing is that even
Current perspectives in residual ridge remodeling and its clinicalimplications: A review
Leila Jahangiri, BDS, MMSc,a Hugh Devlin, BDS, PhD,b Kang Ting, DMD, DMSc,c and IchiroNishimura, DDS, DMSc, DMDd
Harvard School of Dental Medicine, Boston, Mass.; University Dental Hospital of Manchester,Manchester, United Kingdom; and UCLA School of Dentistry, Los Angeles, Calif.
Purpose. This article reviews the current understanding of the biology of tooth extraction wound healingand residual ridge remodeling. Methods. The review of the biology of tooth extraction wound healing involves a discussion of the differ-ent cells populating the tooth extraction wound, the matrix formation, and the control of the repair processin the short-term. Defects in socket matrix formation or cellular activity will lead to stalled healing. Thereview of residual ridge remodeling describes the long-term result of tooth extraction and formation ofresidual ridges, in which the quantity of bone tissue continuously decreases. This may suggest that anypotential regulatory factors of residual ridge resorption should have an adverse effect either on the increasedcatabolic activity by osteoclasts or on the decreased anabolic activity by osteoblasts. Both short-term toothextraction healing and long-term residual ridge remodeling processes are interdependent. Furthermore, anypotential genetic and environmental regulatory factors can affect the quality and quantity of bone by alter-ing the gene expression events taking place in bone cells.Results. The intent of this article was to review the current progress of biologic research on residual ridgeremodeling and to relate the changes at molecular, cellular, and tissue levels. The understanding of residualridge remodeling may provide a sound scientific basis for improved restorative and therapeutic treatments ofthe edentulous population. (J Prosthet Dent 1998;80:224-37.)
Presented in part before the Academy of Prosthodontics, Tucson,Arizona, May 1995.
This review was partly based on investigations supported by Proc-ter & Gamble Fellowship Award (L. Jahangiri), British DiabeticAssociation (H. Devlin), and NIH grants, EY08219, andDE10870 (I. Nishimura).
aInstructor of Restorative Dentistry (Prosthodontics), Harvard Schoolof Dental Medicine.
bSenior Lecturer in Restorative Dentistry, University Dental Hospitalof Manchester, University of Manchester.
cAssistant Professor of Orthodontics, UCLA School of Dentistry.dAssociate Professor Section of Advanced Prosthodontics, UCLA
School of Dentistry and Director, Center for ReconstructiveBiotechnology.
CLINICAL IMPLICATIONS
This review addressed the cellular and extracellular matrix component of alveolarbone regeneration. The cellular component is sensitively responding to the mechanicaland biologic environments such as removable partial denture and osteoporosis. Uncov-ering these regulatory mechanisms may lead to a new therapeutic modality in main-taining and further regeneration of the residual ridge alveolar bone. The heteroge-neous reaction by osteoblasts to a newly characterized extracellular matrix containingtype II and type IX collagens has provided a puzzling but exciting result, which seemsto postulate two independent remodeling processes that regulate cortical bone and tra-becular bone separately. The proposed distinct remodeling processes may be directlyapplied to osseointegration phenomenon in which cortical and trabecular bones mayprovide different consequences.
after the healing of wounds, the residual ridge alveolarbone undergoes a life-long catabolic remodeling. Thesize of the residual ridge is reduced most rapidly in thefirst 6 months, but the bone resorption activity of resid-ual ridge continues throughout life at a slower rate,resulting in removal of a large amount of jaw structure(Fig. 1).3-10 This unique phenomenon has beendescribed as residual ridge reduction (RRR) (TableI).11 The rate of RRR is different among persons, andeven at different sites in the same person. Residualridge remodeling directly affects the function of remov-able prostheses, which rely greatly on the quantity andarchitecture of the jaw bones.12-17
The RRR phenomenon is easily observed clinicallyafter tooth extraction, but the sequence of biologicevents is not well-understood. Since the first reports ofsubstantial resorption of the edentulous residual ridge by
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Fig. 1. Longitudinal observations by standardized lateral cephalographs on continuousresorption of maxillary and mandibular residual ridge before tooth extraction (A), and 3months (B), 7 months (C), 17 years (D), and 25 years (E) after extraction. Superimposedcephalographs depict that large amount of bone structure was removed during this time (F).
Table I. Clinical features of reduction of residual ridges(RRR)
• DefinitionContinuous size reduction of the residual ridge, largely due to bone loss after tooth extraction.
• General featureRRR is chronic, progressive and irreversible.
• The rate is fastest in the first 6 months after extraction.• Rate is variable
–between different persons–within the same person at different times–within the same person at different sites
• Has a multifactorial cause–anatomic factor–prosthetic factor–metabolic and systemic factor–functional factor
Thompson,18 Atwood,19 and Tallgren,20 a number ofstudies have been conducted to describe the structure ofthe changing residual ridge using standardized measure-ments of lateral cephalographs,21-35 panoramic radi-ographs,36,37 or diagnostic casts.38-45 In 1979,Atwood46 postulated that there are four major etiologic
factors that cause RRR: anatomic, prosthetic, metabolic,and functional factors. The primary goal of thosedescriptive studies was therefore to elucidate a patholog-ic cause of the severe form of RRR. These observationsin edentulous patients are not conclusive and, to date,no single factor alone has been found to contribute to
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Table II. Etiologic factors of reduction of residual ridges (RRR)
Etiologic factor Correlation with RRR Source
Anatomic factorMandible 4 × more RRR than maxilla Tallgren23
Inconclusive Atwood and Coy31
Short and square face Increased RRR Tallgren23
Direct effect of masticatory force? Mercier and Lafontant113
Large alveolar process Increased RRR Wictorin25
No correlation with the jaw size Atwood and Coy31
Density of alveolar bone Classification postulated Wilson114
No correlation with bone density Atwood and Coy31
Labial alveoloplasty Increased RRR Gazabatt et al.40
Regular denture wearing No correlation with the rate of RRR Tallgren24
Nicol et al.119
Bergman and Carlsson120
(Statistically insignificant trend) Atwood and Coy31
Other factorBioelectric potential Decreased RRR by exogenous pulsed van der Kuij et al.121
electromagnetic fields in dogs Ortman et al.122
the severe form of RRR (Table II). However, there areseveral consistent observations that suggest that localmechanical stress often generated by removable prosthe-ses may affect the state of residual ridges. Other studiespointed out that postmenopausal osteoporosis hasattracted much attention in causal relation to RRR.
The first objective of this article was to review localmechanical stress and systemic osteoporosis as potentialfactors that influence the long-term sequelae of toothextraction and resorption of residual ridges, in whichbone tissue is adversely affected, either on the increasedcatabolic activity by osteoclasts or on the decreasedanabolic activity by osteoblasts.
The second objective was to review the currentunderstanding of the biology of extraction wound heal-ing, which involves a discussion of the different cellspopulating the extraction site, matrix formation, andshort-term control of the repair process. The residualridge is primarily composed of unique oral soft tissueand alveolar bone, both of which are formed as a resultof tooth extraction wound healing. Defects in socketmatrix formation or cellular activity will lead to stalledhealing, and any potential genetic and environmentalregulatory factors can affect the quality and quantity ofbone by altering the gene expression events. Thereforethis article reviewed current progress of biologicresearch on residual ridge remodeling, relating thechanges at molecular, cellular, and tissue levels.
In this article, all efforts were made to comprehen-sively list the dental literature that is thought to be rel-evant to RRR. The results from most of these studiesare summarized in Table II; however, it was not ourintent to verify the data and conclusions of all thesestudies. Thus, although in-depth analyses are providedfor the biologic data on tooth extraction socket healingand long-term residual ridge remodeling from selectedarticles, the list in Table II should serve only as an indexfor RRR studies.
LOCAL AND SYSTEMIC FACTORSINFLUENCING THE RESIDUAL RIDGEREMODELINGMechanical stress by prosthesis affecting boneresorption
It is observed that patients with combination syn-drome, as described by Kelly,47 exhibit severe RRR inthe anterior segment of maxillary residual ridge (Fig. 2).An exaggerated mechanical stress applied to the maxil-lary complete denture from the remaining mandibularanterior teeth has been postulated to cause this site spe-cific RRR. It was suspected that excessive mechanicalstresses were responsible for the less advantageousresidual ridges observed in the institutionalizedpatients who wore their complete dentures for longhours than the edentulous ridges of the patients in thesame institution who refused to wear their dentures.38
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Fig. 2. Panoramic radiograph (A) and intraoral photograph (B) of patients exhibiting severelocalized bone resorption at anterior segment of maxillary residual ridge. Hypotheticalscheme (C) has been postulated that mechanical stress may induce local synthesis of mes-senger signals such as prostaglandins, which then activate osteoclastic bone resorption (OC)at surface of residual ridge alveolar bone. Bar = 200 µm.
A prospective clinical study addressing the mechanicalfactors on RRR was conducted by Carlsson et al.4,29 inwhich partially edentulous patients (Kennedy class I)were divided into three experimental groups wearing(1) no mandibular denture, (2) partial denture withbilateral free-end denture bases, and (3) partial denturewith anterior alveolar bar. The longitudinal observationof the edentulous ridge of these patients revealed theincreased rate of RRR in the groups of wearingdentures.
Bone that receives constant mechanical stimulimaintain a coupled cellular activity between osteoclastsand osteoblasts. When the bone tissue is placed in astate of immobilization or a weightless environment, itbears less mechanical stress and cannot sustain the nor-mal coupled remodeling process and results in loss ofcalcified bone mass described as disuse atrophy.48,49
Conversely, applied mechanical force can stimulatebone apposition. For example, facial bone remodelingin mountain gorillas appears to closely correlate withtheir unique chewing habits. Mountain gorillas tend touse only one side of the jaw consistently until the teethare totally worn so that food is no longer effectivelyheld. The habitual chewing side of the facial bone, par-ticularly at the facial muscle attachment site, exhibits asignificant bone apposition to the extent that facialstructure is often altered.50
During mastication, swallowing, and any other func-tional jaw movements, masticatory muscles produceforce on the occlusal surface of artificial teeth, which istransmitted through the denture base and to the resid-ual ridge. Sharry et al.51 examined bone stress patternsin dry skulls and reported that stress resulting fromdentures may be transmitted over a rather wide area.However, in the patient’s mouth, dentures are seatedon the residual ridge mucosa overlying the bone direct-ly, which appears to primarily bear the mechanicalstress. This unique environment may differentiate RRRfrom the common disuse atrophy concept.
The keratinized edentulous mucosa can be deformedas a result of pressure from dentures15-17,52,53 and vas-cular alterations such as arteriosclerosis may result fromlong-term denture wear.5,6,54 However, the edentulousmucosa shows remarkable tolerance, and no substantialinflammatory reaction is observed.5,9,10,55-57 Themechanical stimulus applied to dentoalveolar tissue inorthodontic treatment is known to induce local boneremodeling. The synthesis of prostaglandins in peri-odontal tissues has been postulated to play the “mes-senger” role in linking the mechanical stimulus to theosteoclastic activity.58-60 Prostaglandins are a group offatty acid derivatives synthesized by many different cellsunder stress and exert various biologic actions in theneighboring tissues, including bone resorption. Thepossible involvement of prostaglandin in residual ridgeremodeling has been suggested. Yeh and Rodan61
reported that repetitive mechanical stresses applied toosteoblastic cells in vitro significantly increased theprostaglandin E2 synthesis. In a separate study thatused edentulous rats, the daily administration ofindomethacin, an inhibitor of cyclooxygenase (anenzyme required for the prostaglandin synthesis),reduced the rate of RRR to 50% within the experimen-tal period.62 Because the systemic delivery ofprostaglandin E2 successfully reverted the inhibitoryeffect of indomethacin, the local synthesis ofprostaglandins was postulated to mediate the residualridge bone resorption activity.62 The direct relationshipbetween mechanical stress and residual ridge andprostaglandin-mediated bone resorption causing severeform of RRR has not yet been fully elucidated.63 It isconceivable that biologic molecules locally synthesizedin the edentulous mucosa may induce the osteoclasticactivity on the surface of residual ridge alveolar bone(Fig. 2).
Osteoporosis and residual ridge remodeling
The clinical and pathophysiologic views of osteo-porosis has been refined recently to the concept ofTypes I and II osteoporosis.64 Type I osteoporosis isdefined as the specific consequence of menopausalestrogen deprivation, and characteristically presents thebone mass loss, notably in the trabecular bone. Type IIosteoporosis reflects a composite of age-relatedchanges in intestinal, renal, and hormonal function.Both cortical and trabecular bone are affected in TypeII osteoporosis. In either case, one of clinical manifes-tations of “osteoporosis” is observed as less radi-ographic bone density.
Numerous radiographs are taken in general dentalpractice for the screening and diagnosis of conditionsnot relevant to osteoporosis. However, dental radi-ographs might be used to screen for systemic osteo-porosis as there is much evidence that the mandiblereflects the quantity of bone elsewhere in the skele-ton.63 For example, the dentist might suspect osteo-porosis in a person with a thinned mandibular cor-tex.65,66 The microradiographic and histologic exami-nations of cadaveric mandibular bone samples from anelderly sample of edentulous persons have demonstrat-ed that the mandibular bone undergoes considerableremodeling.3,67,68 A general radiolucency of themandible might also be expected in those patients withsystemic osteoporosis. Relationships have been foundin cadaveric bone samples between the specific gravityof edentulous mandible slices and the radius.69 Densi-tometry of the mandible,70 dual photon absorptiome-try,71 and dual energy x-ray absorptiometry (DXA)72 alldemonstrated significant relationships between sys-temic and mandibular osteopenia.
The degree of residual ridge resorption is closelyrelated to the time since tooth extraction, and hence to
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the age of the patient.73 However, the rate of residualridge resorption has not been clearly shown to directlycorrelate with the bone density measured in the bodyof mandible and metacarpal bone.31,74-76 These studiesused the height of the mandibular edentulous ridge asthe measurement of residual ridge resorption. Becauseosteoclastic activity occurs on the surface of the resid-ual ridge, bone resorption can result in changes ofthree-dimensional bone structure. The maxillary resid-ual ridge was reported to be significantly smaller in
postmenopausal osteoporotic women while their eden-tulous mandible remained the same as the age-matchedcontrols.37 A knife-edged ridge is formed when boneresorption occurs at the labial and lingual surfaces ofthe residual ridge in preference to the occlusal surface.Postmenopausal women with lower bone densitometricscores exhibited a tendency to develop a knife-edgeridge in the mandible.35 These results suggested thatclinically less advantageous residual ridge conditions, acombination of a small maxillary ridge and a knife-edge
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Fig. 3. Combination of disadvantaged residual ridges (small maxillary residual ridge [Mx] andknife-edge mandibular residual ridge [Md]) is often presented in postmenopausal osteo-porotic patients (A). Knife-edge residual alveolar bone (A: Boxed, and B) has been reportedto associate with residual ridge mucosa with characteristic undercut (C, arrow).123
mandibular ridge, may be more prevalent in thosepatients with postmenopausal osteoporosis (Fig. 3).
Ovariectomized animals have been intensively char-acterized and used in many studies as a model forhuman Type I osteoporosis.77,78 In ovariectomizedmonkeys, there is a tendency to form a knife-edgemandibular ridge as seen in postmenopausal women.79
The detailed bone remodeling in the residual ridge wasexamined in ovariectomized rats. By using a bone vitalstaining method, Hsieh et al.80,81 observed a significantincrease in bone turnover and formation of immaturewoven bone in a trabecular area. Li and Nishimura82
reported a unique surface structure of the residualridge alveolar bone depicted in scanning electronmicrographs associated with ovariectomy pretreatment.As demonstrated in a recent study, this unique surfacetissue may be influenced by the systemic estrogen leveland exhibit different remodeling patterns.83 Becausethe residual ridge is composed of both cortical and tra-becular bones, the systemic condition of Type I osteo-porosis may contribute to the different remodelingrates for the cortical bone and trabecular bone. Thisuncoordinated remodeling pattern may result in theunique RRR pattern observed in postmenopausalfemale patients.
The causal relationship between Type II osteoporo-sis and RRR has not been addressed. Recently, a line oftransgenic mice was developed for the purpose of over-producing interleukin 4 (LCK-IL4 mice), which led towidespread effects on the immune system. In additionto this immunologic phenotype, characteristic bonedisease involving both cortical bone and trabecularbone was observed.84 Separately developed mutantmice, the Senesent Accelerated Mouse (SAM) strainalso presents “senile” osteoporotic bone features.85,86
The previously mentioned mouse models have greatpotential to be used for human Type II osteoporosisstudies and may provide a long-awaited opportunity toinvestigate the effect of “senile” osteoporosis on resid-ual ridge remodeling.
TOOTH EXTRACTION, WOUNDHEALING, AND FORMATION OF THERESIDUAL RIDGE
A specific feature of residual ridge formation is thatits essential components are formed as the consequenceto healing of a significant bony and mucosal woundcreated by tooth extraction. Histologic studies of resid-ual ridges indicate that extraction sockets heal withactive synthesis of trabecular bone.87-89 Trabecularbone formation reaches the edge of extraction socket,whereas the osteoclastic bone resorption takes place onthe surface of the residual ridge, a combination ofwhich results in a distinct porosity on the crest of theresidual ridge alveolar bone (Fig. 4).90
Aaron and Skerry91 described trabecular bone
regeneration in the sheep after localized ablation. Theradial arrangement of the developing bone trabeculaeobserved in their defects resembled the radial trabecu-lar pattern observed on radiographs of healing toothsockets. Coarse, birefringent collagen fibers formed apreliminary framework along which the trabeculaewere oriented and were fabricated by fibroblasts, mar-row reticular cells, and osteoblasts. Trabeculae wereabsent where this preliminary collagenous frameworkfailed to form. Subsequent remodeling of the small pri-mary trabeculae produced secondary trabeculae thatresembled the original cancellous bone pattern. Thedelayed tooth socket healing often observed in poorlycontrolled diabetes inevitably causes a poor alveolarridge contour. A dense network of collagen fibers nor-mally fills the socket soon after tooth extraction, andthe defect in diabetes mellitus may be due to a reducedcollagen production and an absence of these fibers.92
Precursor “template” collagens for bonewound healing
The collagenous extraction socket matrix formsbefore bone formation, and it has been hypothesizedthat this matrix serves as a template or framework thatorientates the forming bone trabeculae. Controversysurrounds the nature of the collagen molecules thatprovide this template function. However, because of itspotentials in guiding bone wound healing, the majoremphasis of current biologic studies of residual ridgeremodeling is directed toward the characterization ofthis “template” stage of bone remodeling.
A two-stage process of bone formation is evident inendochondral ossification, in which cartilage tissue isinitially present. Chondrocytes undergo sequential his-todifferentiation, which result in cellular hypertrophyand apoptosis. The remnant hypertrophic cartilagematrix is believed to provide the template scaffold forosteoblasts to precipitate bone extracellular matrix. Thetemplate cartilage matrix is eventually resorbed. Endo-chondral ossification is commonly seen at the growthplate of long bone, synchondrosis of the skull base, andmandibular condyle.
One of the most obvious features of the healing oftooth extraction sockets is the absence of precursor car-tilaginous tissue. This unique feature has beendescribed by a general hypothesis that the tissue regen-eration is considered to be a reiterated process of tissueembryogenesis. In embryos, maxillofacial bones,including tooth bearing alveolar process, is formedthrough intramembranous bone formation, which isdifferent from endochondral ossification. In intramem-branous bone formation examined in calvaria, the ini-tial ectomesenchymal cells directly differentiate intoosteoblasts,93 bypassing the deposition and resorptionof hypertrophic cartilage matrix; osteoblasts can direct-ly deposit osteoid tissue, which is then calcified.
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It is of particular interest that recent investigationsreported the transient expression of cartilaginous pro-collagen type II mRNA during intramembranous boneformation.94-96 Type II collagen is a major collagentype of hyaline cartilage and thus has been long con-sidered to contribute to the structural integrity of car-tilage tissue and provide a template during endochon-
dral ossification. The involvement of type II procolla-gen mRNA in different tissues other than cartilage maysuggest some as yet undefined function of type II col-lagen, unrelated to chondrogenesis.97
In recent years, type II collagen has been furtherinvestigated and its two alternative splicing variants oftype IIA and type IIB are found to have differing cell
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Fig. 4. Occlusal radiographic observations of extraction socket healing in monkey suggestthat active trabecular bone formation takes place at bottom of socket, while cortical bone issubjected to bone resorption (A, 1 week after extraction of mandibular central and lateralincisors; B, 3 weeks; C, 6 weeks; D, 9 weeks; E, 12 weeks). Histology of cadaveric mandibu-lar specimen depicting porosity at top of residual ridge alveolar bone resulted from uniquebone wound healing in socket mostly with trabecular bone formation (F, Goldner’s trichromestaining; bar = 50 µm).
origins.98,99 Type IIA is found in noncartilaginous tis-sues, whereas type IIB has a strong association withchondrocytes and cartilage tissue formation (Fig. 5).100
The expression of type II procollagen mRNA has beenidentified in the healing extraction sockets in experi-mental animals by the method of RNA transfer blotanalysis and in situ hybridization.89,101
Analysis of studies on the uncomplicated healing ofextraction wounds have shown that after the clot for-mation, granulation tissue is gradually replaced by con-nective tissues and later by intramembranous bone,without cartilage formation. A cluster of cells that areassociated with the early socket wound healing havebeen shown to express type II collagen mRNA.89,101 Apuzzling finding is that investigators have failed todetect the presence of protein collagen type II by wayof immunohistochemical studies in actively healingextraction sockets.101 This may be suggestive of eitherlack of collagen type II translation or difficulties in
detecting this protein in the healing socket. Some ofthe questions that need to be answered include: Whichsplicing variant of type II collagen is expressed in theextraction socket? What are the role of these cells in thesocket healing if type II collagen protein is synthesized?Do systemic or local factors influence the gene expres-sion pattern during socket healing?
Two-stage process of bone formation
Cartilage collagen fibrils are composed of a group ofdifferent types of collagens including type II. The sur-face of this fibril is associated with small collagen typeIX. Because of the exposed perifibril location and theinteractive peptide structure of type IX collagen, it hasbeen postulated that type IX collagen plays a molecularbridging role in the extracellular matrix and contributesto formation of a cartilage tissue architecture.102 It hasbeen reported that collagen type IX mRNA is alsoexpressed in early healing stages of extraction sockets.89
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Fig. 5. Diagram of alternative expression of α1(II) collagen and α1(IX) collagen genes gener-ating tissue specific forms of collagen molecules. In type II collagen gene, exons 2 and 3 arealternatively spliced. Type IIA and IIB collagen isoforms are synthesized as result. In type IXcollagen gene, two separate promoter/transcriptional start sites are found. Use of upstreampromoter results in synthesis of long form type IX collagen containing amino-terminal NC4globule, whereas activation of downstream promoter generates short form type IX collagen,which misses NC4. These alternative gene expression mechanisms appear to be used in tis-sue specific fashion. Cartilage tissue predominantly synthesizes combination of type IIB andlong type IX collagens. During alveolar bone wound healing, it has been postulated that com-bination of type IIA and short type IX collagens may be synthesized.
Further analyses of residual ridge remodeling in ratshave revealed that the α1(IX) collagen mRNA, whichwas expressed in the extraction socket, was differentand markedly shorter than that of cartilage.89 Theshort form of type IX collagen omits the multipleexons, that encode the amino-terminal globulardomain (Fig. 5).103 Therefore this alternative expres-sion of the short form of type IX collagen, which lacksthe interactive peptide structure, may explain why car-tilage tissue is not assembled in the extraction socket.However, the function of the short form of type IX col-lagen in residual ridge remodeling remains to be clari-fied.
Recent immunohistochemical data suggest that typeIX collagen is present only in the early bone formationstages of extraction socket healing and seems to disap-pear during the maturation stages.104 It has been char-acterized in the similar transient expression of the shortform of type IX collagens along with type II collagen inembryonic chicken cornea,105,106 in which the princi-ple orthogonal fiber architecture of the mature corneais organized according to the template tissue, primarycornea stroma.107 Both cornea and bone possess thesimilar orthogonal pattern of collagen fibrils. Thedetailed molecular assembly of type II and the short
form of type IX collagen in bone remodeling is not elu-cidated. However, it is tempting to speculate that thetransient matrix containing short type IX collagen maybe involved in a tissue guiding role in alveolar bonerepair, as used in avian eye formation.
Transgenic and inactive gene allelicmanipulation in experimental animals
To understand the role of a specific molecule, onecan generate animals harboring an experimentallyintroduced mutation to the molecule or inactivate thecorresponding gene (Fig. 6). Such transgenic animalscan provide a powerful tool to investigate the conse-quences to the missing biologic role of a specific mole-cule. Several transgenic mice have been generated withdefective type II collagen.108,109 The introducedmutated pro α1(II) collagen chain appears to beincluded in a procollagen molecule and prevents fold-ing into a stable triple helix. Transgenic mice with func-tionally impaired type II collagen result in chondrodys-plasia with dwarfism, short and thick limbs, a shortsnout, a cranial bulge, a cleft palate, delayed mineral-ization of bone, and a severe retardation of growth forpractically all bones. Because type II collagen compris-es the major constituent of cartilage, the principal con-
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Fig. 6. Diagram of transgenic mouse generation. Target gene that has been manipulated invitro to introduce mutation is introduced into mouse embryonic stem cells. After introducedmutant gene is incorporated into mouse chromosomes, embryonic stem cells are implantedin pseudopregnant mothers. Thus, F1 chimera population is established, which provides nextgeneration of transgenic mice for various evaluations. In many situations, homozygousmutant mice carrying mutation in both pairs of chromosomes are used to examine effect ofintroduced mutation by comparison with wild type litter mates. Heterozygous mutant miceoften exhibit a milder phenotype, due to existence of unaffected chromosome.
sequence of this mutation is anticipated to cause disor-ganization of the growth plate. However, it is interest-ing to note that both endochondral bones andintramembranous bones are affected by the type II col-lagen mutation.
Nakata et al.110 reported the generation of trans-genic mice harboring the minigene of α1(IX) collagenwith an inframe deletion of the central domain. Somehomozygous transgenic mice displayed mild propor-tionate dwarfism. The vertebral bodies were ovoid inshape as a result of a mild ossification defect, and theend plates in the mid-dorsal region were irregular; oth-erwise, the offspring of the transgenic mice survived totheir maturity. After reaching maturity, onset of
osteoarthritic changes became apparent particularly inthe anterior part of the weight bearing area of the tibia.They reported that even before the histologic onset ofosteoarthritis, a significant decrease in the intrinsiccompressive stiffness was found in the articular carti-lage of the transgenic mice. Furthermore, corneas ofthe transgenic offspring appeared opaque or irregularand were sometimes infiltrated by capillary vessels. Theophthalmopathy was found in about 15% of transgenicanimals. These results strongly indicate that type IXcollagen may play diverse biologic roles in various tis-sues, including localized bone remodeling.
Recently, α1(IX) collagen knock-out transgenicmice were developed.111 The Neo gene was inserted inthe exon 8 of the α1(IX) gene by homologous recom-bination, which resulted in the total inactivation ofα1(IX) alleles, including both promoters. Thereforethis animal model allows an investigation of the func-tional role of type IX collagen as a potent element foralveolar bone regeneration. Wild type and homozygousmutant mice were analyzed to elucidate the role of typeIX collagen in residual ridge remodeling.112 To evalu-ate alveolar bone repair, the specimens were obtained at7 days and 14 days after tooth extraction. The extrac-tion socket of mice with inactivated α1 (IX) alleles indi-cated that there was a considerable retardation in theformation of the trabecular bone pattern as comparedwith the healing socket of the control genotypicallynormal mice (Fig. 7). The results indicated that the tra-becular bone pattern was often disturbed in “knock-out” mice with some formation of cortical bone withinthe socket.
These data suggest that there may be two distinctbone remodeling processes. In the trabecular boneremodeling, the presence of type II and IX collagen
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Fig. 7. Different extraction socket wound healing found in wild type mouse (A; bar = 50 µm)and type IX collagen null transgenic mouse (B; bar = 20 µm). Bone healing in transgenicmouse was characterized by loss of trabecular bone formation at bottom of extraction sock-et (A, arrows). However, type IX collagen “knock-out” mice showed loss of trabecular bonerestoration pattern with relatively normal cortical bone at bottom of socket (B, arrows).(Hematoxylin and eosin staining.)
Fig. 8. Postulated bone remodeling processes that may regu-late trabecular bone and cortical bone separately. Trabecularbone remodeling is hypothesized to be dependent on priorexpression of type II and IX collagens, which may providenovel blueprint for trabecular bone pattern formation.
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precursors seems to be necessary. In the cortical boneremodeling, type II and IX collagen precursors may notbe prerequisite (Fig. 8). Successful socket healing mayuse the former process, which require the transientexpression of “template” collagens, including type IIand IX.
CONCLUSIONS
The current advances in the studies of oral and max-illofacial tissue reconstruction have led to significantunderstanding about tissue regeneration in terminallydifferentiated cells, such as osteoblasts and osteoclasts,and extracellular matrix substrata. The effect of each ofthese essential components on tooth socket healing hasbeen investigated extensively, but no effective thera-peutic regime allowing regeneration of the residualridge yet exists.
Further molecular biologic advancement in this fieldmay lead to the regeneration and maintenance of thealveolar bone of residual ridges, quicker osseointegra-tion of implants and structural, and functional healingof large craniofacial bone defects.
REFERENCES
1. Claflin RS. Healing of disturbed and undisturbed extraction wounds. JAm Dent Assoc 1936;23:945-59.
2. Guralnick WL. Text book of oral surgery. Boston: Little Brown Co.; 1968.p. 93-4.
3. Atwood DA. Postextraction changes in the adult mandible as illustratedby microradiographs of midsagittal sections and serial cephalometricroentgenograms. J Prosthet Dent 1963;13:810-24.
4. Carlsson GE, Ragnarson N, Astrand P. Changes in height of the alveolarprocess in edentulous segments. A longitudinal clinical and radiograph-ic study of full upper denture cases with residual lower anteriors. OdontTidskrift 1967;75:193-208.
5. Nedelman C, Gamer S, Bernick S. The alveolar ridge mucosa in dentureand nondenture wearers. J Prosthet Dent 1970;23:265-73.
6. Nedelman CI, Bernick S. The significance of age changes in human alve-olar mucosa and bone. J Prosthet Dent 1978;39:495-501.
7. Wallenius K, Heyden G. Histochemical studies of flabby ridges. OdontRevy 1972;23:169-79.
9. Krajicek DD, Dooner J, Porter K. Observation on the histologic feature ofthe human edentulous ridge. Part I: mucosal epithelium. J Prosthet Dent1984;52:526-31.
10. Krajicek DD, Dooner J, Porter K. Observation on the histologic feature ofthe human edentulous ridge. Part II: connective tissue. J Prosthet Dent1984;52:682-7.
11. Atwood DA. Reduction of residual ridges: a major oral disease entity. JProsthet Dent 1971;26:266-79.
12. Cecconi BT, Asgar K, Dootz E. The effect of partial denture clasp designon abutment tooth movement. J Dent 1971;25:44-56.
13. Cecconi BT, Asgar K, Dootz E. Removable partial denture abutmenttooth movement as affected by inclination of residual ridges and type ofloading. J Dent 1971;25:375-81.
14. Cecconi BT, Asgar K, Dootz E. Clasp assembly modifications and theireffect on abutment tooth movement. J Dent 1972;27:160-7.
15. Jacobson TE, Krol AJ. A contemporary review of the factors involved incomplete denture retention, stability, and support. Part I: retention. JProsthet Dent 1983;49:5-15.
16. Jacobson TE, Krol AJ. A contemporary review of the factors involved incomplete dentures. Part II: stability. J Prosthet Dent 1983;49:165-72.
17. Jacobson TE, Krol AJ. A contemporary review of the factors involved incomplete dentures. Part III: support. J Prosthet Dent 1983;49:306-13.
18. Thompson JR. The rest position of the mandible and its significance todental science. J Am Dent Assoc 1946;33:151-80.
19. Atwood DA. A cephalometric study of the clinical rest position of themandible. Part II: the variability of the rate of bone loss following theremoval of occlusal contact. J Prosthet Dent 1957;7:544-52.
20. Tallgren A. Changes in adult face height due to aging, wear and loss ofteeth and prosthetic treatment. Acta Odontol Scand 1957;15(supp.24):7-122.
21. Atwood DA. Some clinical factors related to rate of resorption of resid-ual ridges. J Prosthet Dent 1962;12:441-50.
22. Tallgren A. The effect of denture wearing on facial morphology. A 7-yearlongitudinal study. Acta Odontol Scand 1967;25:563-92.
23. Tallgren A. Alveolar bone loss in denture wearers as related to facial mor-phology. Acta Odontol Scand 1970;28:251-70.
24. Tallgren A. The continuing reduction of the residual ridges in completedenture wearers: a mixed-longitudinal study covering 25 years. J ProsthetDent 1972;27:120-32.
25. Wictorin L. Bone resorption in cases with complete upper denture. ActaRadiol 1964;suppl 228:3-97.
26. Carlsson GE, Persson G. Morphologic changes of the mandible afterextraction and wearing of dentures. A longitudinal, clinical, and x-raycephalometric study covering 5 years. Odont Revy 1967;18:27-54.
27. Carlsson GE, Bergman B, Hedegard B. Changes in the contour of themaxillary alveolar process under immediate dentures. Acta OdontolScand 1967;25:1-31.
28. Carlsson GE, Thilader H, Hedegard B. Histologic changes in the upperalveolar process after extractions with or without insertion of an imme-diate full denture. Acta Odontol Scand 1967;25:21-43.
29. Carlsson GE, Ragnarson N, Astrand P. Changes in height of the alveolarprocess in edentulous segments II. A longitudinal clinical and radi-ographic study over 5 years of full upper denture patients with residualanteriors. STT 1969;62:125-36.
30. Hickey JC, Henderson D, Straus R. Patient response to variations in den-ture technique. I. Design of a study. J Prosthet Dent 1969;22:158-70.
31. Atwood DA, Coy WA. Clinical cephalometric and densitometric study ofreduction of residual ridges. J Dent 1971;26:280-95.
32. Winter CM, Woelfel JB, Igarashi T. Five year changes in the edentulousmandible as determined on oblique cephalometric radiographs. J DentRes 1974;53:1455-64.
33. Woelfel JB, Winter CM, Igarashi T. Five-year cephalometric study ofmandibular ridge resorption with different posterior occlusal forms. PartI. Denture construction and initial comparison. J Prosthet Dent1976;36:602-23.
34. Steen WH. Errors in oblique cephalometric radiographic projections ofthe edentulous mandible. Part I: geometric errors. J Prosthet Dent1984;51:411-8.
35. Nishimura I, Hosokawa R, Atwood DA. The knife-edge tendency in themandibular residual ridges in women. J Prosthet Dent 1992;67:820-6.
36. Wical KE, Brussee P. Effects of a calcium and vitamin D supplement onalveolar ridge resorption in immediate denture patients. J Prosthet Dent1979;41:4-11.
37. Von Wowern N, Kollerup G. Symptomatic osteoporosis: a risk factor forresidual ridge reduction of the jaws. J Prosthet Dent 1992;67:656-60.
38. Campbell RL. A comparative study of the resorption of the alveolar ridgesin denture-wearers and non-denture wearers. J Am Dent Assoc1960;60:143-53.
39. Lam RV. Contour changes of the alveolar processes following extrac-tions. J Prosthet Dent 1960;10:25-32.
40. Gazabatt CA, Parra NH, Meisser EV. A comparison of bone resorptionfollowing intraseptal alveolotomy and labial alveolotomy. J ProsthetDent 1965;15:435-43.
41. Carlsson GE. Measurements on casts of the edentulous maxilla. OdontolRevy 1966;17:386-402.
42. Johnson K. A three-year study of the dimensional changes occurring inthe maxilla following immediate denture treatment. Aust Dent J1967;12:152-9.
43. Johnson K. A study of the dimensional changes occurring in the maxillafollowing open face immediate denture treatment. Aust Dent J1977;22:451-4.
44. Likeman PR, Watt DM. Morphologic changes in the maxillary denturebearing area. A follow up 14 to 17 years after tooth extraction. Br DentJ 1974;136:500-3.
45. Michael CG, Barsoum WM. Comparing ridge resorption with various
THE JOURNAL OF PROSTHETIC DENTISTRY JAHANGIRI ET AL
236 VOLUME 80 NUMBER 2
surgical techniques in immediate dentures. J Prosthet Dent 1976;35:142-55.
46. Atwood DA. Bone loss of edentulous alveolar ridges. J Periodontol1979;50(Spec No):11-21.
47. Kelly E. Changes caused by a mandibular removable partial dentureopposing a maxillary complete denture. J Prosthet Dent 1972;27:140-50.
49. Uebelhart D, Demiaux-Domenech B, Roth M, Chantraine A. Bonemetabolism in spinal cord injured individuals and in others who haveprolonged immobilisation. A review. Paraplegia 1995;33:669-73.
50. Walters MJ, O’Higgins P. Factors influencing craniofacial growth: a scan-ning electron microscope study of high resolution facial replicas. ProcAustralas Soc Hum Biol 1992;5:391-403.
51. Sharry JJ, Weber IJ, Parkel C. A study of the influence of occlusal planeson strains in the edentulous maxillae and mandible. J Prosthet Dent1956;6:768-74.
52. Kishi M. Experimental studies on the relation between area and dis-placement of loading surfaces in connection with displaceability in themucosa of edentulous alveolar ridge under pressure. Shikwa Gakuho1972;72:17-45.
53. Kydd WL, Daly CH, Nansen D. Variation in the response to mechanicalstress of human soft tissues as related to age. J Prosthet Dent1974;32:493-500.
54. Bradley JC. Age changes in the vascular supply of the mandible. Br DentJ 1972;132:142-4.
55. Ostlund SG. The effect of complete dentures on the gum tissues. ActaOdontol Scand 1958;16:1-41.
56. Turck D. A histologic comparison of the edentulous denture and non-denture bearing tissues. J Prosthet Dent 1965;15:419-34.
58. Yamasaki K, Miura F, Suda T. Prostaglandin as a mediator of bone resorp-tion induced by experimental tooth movement in rats. J Dent Res1980;59:1635-42.
59. Lilja E, Lindskog S, Hammarstorm L. Histochemistry of enzymes associ-ated with tissue degradation incident to orthodontic tooth movement.Am J Orthod 1983;83:62-75.
60. Davidovitch Z, Shanfeld JL, Montgomery PC, Lally E, Laster L, Furst L, etal. Biochemical mediators of the effects of mechanical forces and elec-tric currents on mineralized tissues. Calcif Tissue Int 1984;36 (Suppl1):S86-97.
62. Nishimura I, Szabo G, Flynn E, Atwood DA. A local pathophysiologicmechanism of the resorption of residual ridges: prostaglandin as a medi-ator of bone resorption. J Prosthet Dent 1988;60:381-8.
63. Devlin H, Ferguson MW. Alveolar ridge resorption and mandibular atro-phy. A review of the role of local and systemic factors. Br Dent J1991;170:101-4.
64. Marcus R, Feldman D, Kelsey J. Osteoporosis. New York: AcademicPress; 1996.
65. Kribbs PJ. Comparison of mandibular bone in normal and osteoporoticwomen. J Prosthet Dent 1990;63:218-22.
66. Kribbs PJ, Chesnut CH 3d, Ott SM, Kilcoyne RF. Relationships betweenmandibular and skeletal bone in a population of normal women. J Pros-thet Dent 1990;63:86-9.
67. Manson JD, Lucas RB. A microradiographic study of age changes in thehuman mandible. Arch Oral Biol 1962;7:761-9.
68. Devlin H, Sloan P, Luther F. Alveolar bone resorption: a histologicalstudy comparing bone turnover in the edentulous mandible and iliaccrest. J Prosthet Dent 1994;71:478-81.
69. Henrikson PA, Wallenius K. The mandible and osteoporosis. 1. A quali-tative comparison between the mandible and the radius. J Oral Rehabil1974;1:67-74.
70. Horner K, Devlin H. Clinical bone densitometric study of mandibularatrophy using dental panoramic tomography. J Dent 1992;20:33-7.
71. Von Wowern N. In vivo measurement of bone mineral content ofmandibles by dual-photon absorptiometry. Scand J Dent Res1985;93:162-8.
72. Ammann P, Rizzoli R, Slosman D, Bonjour JP. Sequential and precise invivo measurement of bone mineral density in rats using dual-energyx-ray absorptiometry. J Bone Miner Res 1992;7:311-6.
73. Humphries S, Devlin H, Worthington H. A radiographic investigationinto bone resorption of mandibular alveolar bone in elderly edentulousadults. J Dent 1989;17:94-6.
74. Ward VJ, Stephens AP, Harrison A, Lurie D. The relationship between themetacarpal index and the rate of mandibular ridge resorption. J OralRehabil 1977;4:83-9.
75. Mercier P, Inoue S. Bone density and serum minerals in cases of residualalveolar ridge atrophy. J Prosthet Dent 1981;46:250-5.
76. Kribbs PJ, Smith DE, Chesnut CH 3d. Oral findings in osteoporosis. PartII: relationship between residual ridge and alveolar bone resorption andgeneralized skeletal osteopenia. J Prosthet Dent 1983;50:719-24.
77. Kalu DN, Liu CC, Hardin RR, Hollis BW. The aged rat model of ovarianhormone deficiency bone loss. Endocrinol 1989;124:7-16.
78. Kalu DN, Liu CC, Salerno E, Hollis BW, Echon R, Ray M. Skeletalresponse of ovariectomized rats to low and high doses of 17 beta-estradiol. Bone Miner 1991;14:175-87.
79. Nishimura I, Hosokawa R, Kaplan ML, Atwood DA. Animal model forevaluating the effect of systemic estrogen deficiency on residual ridgeresorption. J Prosthet Dent 1995;73:304-10.
80. Hsieh YD, Devlin H, Roberts C. Early alveolar ridge osteogenesis fol-lowing tooth extraction in the rat. Arch Oral Biol 1994;39:425-8.
81. Hsieh YD, Devlin H, McCord F. The effect of ovariectomy on the healingtooth socket of the rat. Arch Oral Biol 1995;40:529-31.
82. Li X, Nishimura I. Altered bone remodeling pattern of the residual ridgein ovariectomized rats. J Prosthet Dent 1994;72:324-30.
83. Jahangiri L, Kim A, Nishimura I. Effect of ovariectomy on the local resid-ual ridge remodeling. J Prosthet Dent 1997;77:435-43.
84. Lewis DB, Liggitt HD, Effmann EL, Motley ST, Teitelbaum SL, Jaspen KJ,et al. Osteoporosis induced in mice by overproduction of interleukin 4.Proc Natl Acad Sci USA 1993;90:11618-22.
85. Matsushita M, Tsuboyama T, Kasai R, Okumura H, Yamamuro T, HiguchiK, et al. Age-related changes in bone mass in the senescence-accelerat-ed mouse (SAM): SAM-R/3 and SAM-P/6 as new murine models forsenile osteoporosis. Am J Pathol 1986;125:276-83.
86. Tsuboyama T, Takahashi K, Matsushita M, Okumura H, Yamamuro T,Umezawa M, et al. Decreased endosteal formation during cortical bonemodelling in SAM-P/6 mice with a low peak bone mass. Bone Min1989;7:1-12.
87. Todo H. Healing mechanism of tooth extraction wounds in rats. I. Initialcellular response to tooth extraction in rats studied with 3H-thymidine.Arch Oral Biol 1968;13:1421-7.
88. Todo H. Healing mechanism of tooth extraction wounds in rats. II. His-tochemical observations on hydrolytic and oxidative enzymes in toothextraction wounds in the rat. Arch Oral Biol 1968;13:1429-43.
89. Ting K, Petropulos LA, Iwatsuki M, Nishimura I. Altered cartilage pheno-type expressed during intramembranous bone formation. J Bone MinerRes 1993;8:1377-87.
90. Pietrokovski J. The bony residual ridge in man. J Prosthet Dent1975;34:456-62.
91. Aaron JE, Skerry TM. Intramembranous trabecular generation in normalbone. Bone Miner 1994;25:211-30.
92. Devlin H, Garland H, Sloan P. Healing of tooth extraction sockets inexperimental diabetes mellitus. J Oral Maxillofac Surg 1996;54:1087-91.
93. Hall BK, Horstadius S. The neural crest. London: Oxford University Press;1988. p. 84-95.
94. Cheah KS, Lau ET, Au PK, Tam PP. Expression of the mouse alpha 1(II)collagen gene is not restricted to cartilage during development. Devel-opment 1991;111:945-53.
95. Wood A, Ashhurst DE, Corbett A, Thorogood P. The transient expressionof type II collagen at tissue interfaces during mammalian craniofacialdevelopment. Development 1991;111:955-68.
96. Asahina I, Sampath TK, Nishimura I, Hauschka PV. Human osteogenicprotein-1 induces both chondroblastic and osteoblastic differentiation ofosteoprogenitor cells derived from newborn rat calvaria. J Cell Biol1993;123:921-33.
97. Kosher RA, Solursh M. Widespread distribution of type II collagen dur-ing embryonic chick development. Dev Biol 1989;131:558-66.
98. Nah HD, Upholt WB. Type II collagen mRNA containing an alternative-ly spliced exon predominates in chick limb prior to chondrogenesis. JBiol Chem 1991;266:23446-52.
99. Sandell LJ, Morris N, Robbins JR, Goldring RA. Alternatively spliced typeII procollagen mRNAs define distinct populations of cells during verte-bral development: differential expression of the amino-peptide. J CellBiol 1991;114:1307-19.
JAHANGIRI ET AL THE JOURNAL OF PROSTHETIC DENTISTRY
AUGUST 1998 237
100. Sandell LJ, Nanlin AM, Reife RA. Alternative splice form of type II pro-collagen mRNA (IIA) is predominant in skeletal precursors and non-cartilaginous tissues during early mouse development. Dev Dyn1994;199:129-40.
101. Devlin H, Hoyland J, Freemont AJ, Sloan P. Localization of procollagentype II mRNA and collagen type II in the healing tooth socket of the rat.Arch Oral Biol 1995;40:181-5.
102. Vasios G, Nishimura I, Konomi H, van der Rest M, Ninomiya Y, OlsenBR. Cartilage type IX collagen-proteoglycan contains a large amino-terminal globular domain encoded by multiple exons. J Biol Chem1988;263:2324-9.
103. Nishimura I, Muragaki Y, Olsen BR. Tissue specific form of type IXcollagen-proteoglycan arise from the use of two widely separatedpromoters. J Biol Chem 1989;264:20033-41.
104. Ting K, Nishimura I. Immunohistologic localization of type IX collagenduring intramembranous bone formation. J Dent Res 1994;73:2277[abstract].
105. Svoboda KK, Nishimura I, Sugrue SP, Ninomiya Y, Olsen BR. Embryonicchicken cornea and cartilage synthesize type IX collagen molecules withdifferent amino-terminal domains. Proc Natl Acad Sc USA 1988;85:7496-500.
106. Fitch JM, Mentzer A, Mayne R, Linsenmayer TF. Acquisition of type IXcollagen by the developing avian primary corneal stroma and vitreous.Devl Biol 1988;128:396-405.
107. Hay ED, Revel J-P. Fine structure of the developing avian cornea. In:Monographs in developmental biology. Vol. 1. New York: S. Karger;1969.
108. Vandenberg P, Khillan JS, Prockop DJ, Helminen H, Kontusaari S, Ala-Kokko L. Expression of a partially deleted gene of human type II procol-lagen (COL2A1) in transgenic mice produces a chondrodysplasia. ProcNatl Acad Sci USA 1991;88:7640-4.
109. Garofalo S, Vuorio E, Metsaranta M, Rosati R, Toman D, Vaughan J, et al.Reduced amounts of cartilage collagen fibrils and growth plate anom-alies in transgenic mice harboring a glycine-to-cycteine mutation in themouse type II procollagen alpha 1-chain gene. Proc Natl Acad Sci USA1991;88:9648-52.
110. Nakata K, Ono K, Miyazaki J, Olsen BR, Muragaki Y, Adachi E, et al.Osteoarthritis associated with mild chondrodysplasia in transgenic miceexpressing alpha 1(IX) collagen chains with a central deletion. Proc NatlAcad Sci USA 1993;90:2870-4.
111. Fassler R, Schnegelsberg PN, Dausman J, Shinya T, Muragaki Y, McCarthyMT, et al. Mice lacking alpha 1(IX) collagen develop noninflammatorydegenerative joint disease. Proc Natl Acad Sci USA 1994;91:5070-4.
112. Ting K, Olsen BR, Nishimura I. Alveolar bone repair examined in α1(IX)“knock-out” mice. J Dent Res 1995;74:1652 [abstract].
113. Mercier P, Inoue S. Bone density and serum minerals in cases of residualalveolar ridge atrophy. J Prosthet Dent 1981;46:250-5.
114. Wilson JH. Partial denture construction. Some aspects of diagnosis anddesign. Dent J Aust 1949;347-63.
115. Ortman LF, Hausmann E, Dunford RG. Skeletal osteopenia and residualridge resorption. J Prosthet Dent 1989;61:321-5.
116. Mesrobian AZ, Shklar G. The effect of dietary zinc sulfate supplementson the healing of experimental extraction wounds. J Oral Surg Oral MedOral Pathol 1969;28:259-65.
117. Olson HM, Hagen A. Inhibition of post-extraction alveolar ridge resorp-tion in rats by dichloromethane diphosphonate. J Periodont Res1982;17:669-74.
118. Fenton AH, El-Kassem M. The effect of fluoride on post-extraction alve-olar resorption in the rat. J Dent Res 1984;63:1427.
119. Nicol BR, Somes GW, Ellinger CW, Unger JW, Fuhrmann J. Patientresponse to variations in denture technique. Part II: five-year cephalo-metric evaluation. J Prosthet Dent 1979;41:368-72.
120. Bergman B, Carlsson GE. Clinical long-term study of complete denturewearers. J Prosthet Dent 1985;53:56-61.
121. van der Kuij P, Vingerling PA, Sillevis Smitt PA, de Groot K, de Graaff J.Reducing residual ridge reduction. Reconstr Surg Traumatol 1985;19:98-105.
122. Ortman LF, Casey DM, Deers M. Bioelectric stimulation and residualridge resorption. J Prosthet Dent 1992;67:61-71.
123. Nishimura I, Atwood DA. Knife-edge residual ridges: a clinical report. JProsthet Dent 1994;71:231-4.
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