Molecular Basisi of Growth / orthodontic courses by Indian dental academy

MOLECULAR BASIS OF GROWTH

INDIAN DENTAL ACADEMY

Leader in continuing dental education www.indiandentalacademy.com

www.indiandentalacademy.com

INDEX INTRODUCTION DEFINITION OF GROWTH GROWTH – EXTERNAL & MOLECULAR GFOWTH FACTORS MATRIXMETALLOPROTEINASES CYTOKINES BONE & TGF B(RECEPTORS & BIOLOGICAL

ACTIVITY) BMP – CLASSIFICATION PDGF,FGF, IGF CONCLUSION REFERENCES www.indiandentalacademy.com


Craniofacial development

Facial development in the embryo involves the origin of the facial mesenchyme which arises from neural crest cells.

Unusually, they disrupt the ectodermal-mesodermal junction and migrate into the underlying tissue as ectomesenchymal cells.


Among the derivatives of the cephalic neural crest cells are the maxilla, mandible, zygomatic, nasal bones, and bones of the cranial vault.

This process is presumed to be under the control of genes known as homeobox genes (1984), which endow neural crest cells (NCC) with a positional identity, which mediates aspects of craniofacial morphogenesis and patterning.


Role of Homeobox genes

genes which are highly conserved throughout evolution of diverse organisms

fundamental in evolution of the specialised body parts of many animal species


master genes of the head and face controlling patterning, induction, programmed cell death, and epithelial mesenchymal interaction during development of the craniofacial complex.

Those of particular interest in craniofacial development include the Hox group, Msx1 and Msx2 (muscle segment), Dlx (distalless), Otx (orthodontical), Gsc (goosecoid), and Shh (sonic hedgehog).


Proteins encoded by these homeobox genes are transcription factors, which can switch genes on and off by activating or repressing gene expression, and therefore control other genes producing a co-ordinated cascade of molecular events which, in turn, control patterning and morphogenesis .

(Thesleff, 1995).


At a cellular level this control is expressed through two main groups of regulatory proteins, the growth factor family and the steroid/ thyroid/retinoic acid super family (Evans, 1988), that regulate growth (Johnston and Bronsky, 1995).

These regulatory molecules in the mesenchyme are fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor alpha (TGF ), transforming growth factor beta (TGF ), and bone morphogenetic proteins (BMPs)www.indiandentalacademy.com

MSX genes

Homologous to drosophila msh (muscle segment homeobox)

Murine msx family – msx1, msx2, msx3

Msx1 & 2 – transcriptina; repressors in cellular differentiation.

Along with dlx genes (activator)- mutually modulate their own transcriptional activities www.indiandentalacademy.com

Mice studies

Msx1- targeted disruption – loss of palatal shelves & maxillary bones , slight shortening of maxilla &/or mandible, no tooth development beyond bud stage

Msx2-(less well defined role in lip & palate development) deficiency-skull ossification defects & persistent calvarial foramen; mutation- craniofacial malformation- mandibular hypoplasia, cleft palate medial facial palate.


DLX genes

Homologous to drosophila distal-less (Dll gene)

At least 6 members in mice- dlx1,2, 3, 5,6 &7 –encode transcription factors involved in orofacial patterning from neural crest cells


Dlx 1 & 2-development of maxi arch (development of palatine & pterygoid bones of palate)

Dlx 1, 2, 3, 5, 6 –development of mandible


LHX genes

(lim homeobox genes)

Tissue patterning/specification & differentiation of different cell types

Lhx 6 & 7- expressed prior to initiation of tooth formation in oral & odontogenic mesenchyme of maxi & mandi processes (mice)


Lhx 8(L3)-differentially expressed in maxilla, mandible & ventral forebrain; continuous expression in mesenchyme during diff stages of palatogenesis- candidate gene for isolated nonsyndromic form of cleft palate


PRRX gene

Paired related homeobox

Homologous to drosophila paired & gooseberry genes & to mouse pax3, 6 & 7 genes.

2 best studied prrx genes-prrx1(mhox/phox1/prx1/K2) & 2(S8/prx2)-similar expressions in cranium, branchial arches, body wall & limbs


Prrx 1- detected in most of the ectoderm including brain precursors- inactivation (mice)- microcephaly, low set ears, pointed snout, cleft palate & mild mandibular hypoplasia.

Prrx 2 – no expression in developing brain – inactivation is compensated by prrx 1 functionality


GOOSECOID genes

Involved in the final stages of formation of craniofacial structures like the ear, nose & mouth.

Disruption – lower mandible & associated musculature including tongue, nasal cavity, nasal pits, malleus & external auditory meatus, malformation of various bones of base of skull (e.g;palatine)


RYK gene

Related to tyrosine kinases (receptor proteins).

Rugulate diverse cellular functions-mitogenesis, differentiation & morphogenesis


Disruption (mice study– Halford 2000) – some limb abnormalities with slightly smaller & more rounded cranial vault, shorter snout premaxillary/maxillary hypoplasia(flattened midface) & reduced mandible with clefting of palate.


GROWTH FACTORS - FGF

FUNCTIONS – angiogenesis, wound healing, embryonic development & malignant transformation, regulate cell proliferation, differentiation & migration in different tissues

At least 7 members are expressed in the developing face – Fgf 1,2,4,5,8,9 & 12


Receptors – FGFRs – fgfrs 1,2 & 3- expressed in development of face & later associated with some regions of chondrogenesis

FGFR activating mutations – embryonic lethality & limb & craniofacial abnormalities such as CP & reduced maxillary bone (Apert, Crouzon syndromes)


PDGF & PDGFR 2 RECEPTORS – pdgfr-alpha & pdgfr-beta

Pdgfs & Pdgfrs –regulatory roles in development of CNS, vascular system, in maintenance of tissue homeostasis & in wound healing along with imp role in palate development

Homozygous knockout of Pdgfra – midline defects & underdevelopment of face with absence of some facial bones (Soriano 1997)


TGF TGF ALPHA & BETA-contribute to facial

development, especially palate formation.

Tgf A – some human studies indicate a positive association between tgfa & CL with/without CP(Ardinger 1989)

Rather than a necessary & sufficient determinant , it has been postulated that tgfa acts as a modifier gene.


TGF Beta superfamily

Tgf beta 1,2,3,4 & 5 and more distantly related bone morphogenetic proteins

Tgh beta 1,2, 3-expressed in early embryogenesis & are associated later with some regions of skeletal development


Depletion of tgf beta 3(Brunet 1995)-prevents in vitro fusion of palatal shelves.

Critical role of tgf beta2& 3 in molecular control of orofacial clefting (Lidral, 1998, Sanford 1997)


EGF & EGFR

Necessary for normal craniofacial development.

Increases matrix metalloproteinases(MMPs) secretion (downstream signal transduction effector)


Mice studies –(Miettinen 1999) egfr knockout-facial mediolateral defects like narrow & elongated snouts, underdeveloped lower jaws, CP & diminished secretion of MMPs in palatal shelf tissues


GABA

Major inhibitory neurotransmitter with many critical functions as an intercellular signaling molecule in the CNS

Receptors – gaba A,B & C. gaba A can be modulated by steroids, benzodiazepines.


Gaba- capable of promoting survival, differentiation & migration of embryonic neurons

Mice studies(Miller 1975, Homanics 1997) Abberations in gaba/gaba A – induces clefting of palate


Growth factors

This collective term originally referred to substances that promote cell growth.


The genes and mechanisms of our body are tirelessly operating day in, day out, and are part of a long interconnected chain of reactions that make our body work.

There are various factors involved that affect growth. It is the genetic coding of our bodies that determine the way we are and how we work, with the external environment either emphasizing or inhibiting the effectiveness of some of these genes.


Growth factors

Introduction Growth factors are proteins that bind to

receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation. Many growth factors are quite versatile, stimulating cellular division in numerous different cell types; while others are specific to a particular cell-type.


Growth factors comprises of molecules that function as growth stimulators but also as growth inhibitors (sometimes referred to as negative growth factors ), factors that stimulate cell migration or as chemotactic agents or inhibit cell migration or invasion of tumor cells, factors that modulate differentiated functions of cells, factors involved in apoptosis , factors involved in angiogenesis , or factors that promote survival of cells without influencing growth and differentiation.


Growth factors are polypeptides that belongs to a number of families.

Cell surface receptors capture them. Upon capturing receptor interacts with

membrane and cytoplasmic bound components to bring about alteration in gene expression of a cell.

Thus a growth factor is an inductive agent.


A growth factor produced by one cell and acting on another is described as paracrine regulation.

Whereas the process of a cell that recaptures its own product is known as autocrine regulation.

Few growth factors act during embryogenesis.


By contrast, the retinoic acid family freely enters a cell to complex with intracellular receptors, which eventually affect gene expression.

Both growth factors and the retinoids regulate the expression of the homeobox genes, which, in turn, regulate the expression of growth factors(role of regulatory loops in development).


Epidermal Growth Factor (EGF) Platelet-Derived Growth Factor (PDGF) Fibroblast Growth Factors (FGFs) Transforming Growth Factors-b (TGFs-b) Transforming Growth Factor-a (TGF-a) Erythropoietin (Epo) Insulin-Like Growth Factor-I (IGF-I) Insulin-Like Growth Factor-II (IGF-II) Interleukin-1 (IL-1) Interleukin-2 (IL-2) Interleukin-6 (IL-6) Interleukin-8 (IL-8) Tumor Necrosis Factor-a (TNF-a) Tumor Necrosis Factor-b (TNF-b) Interferon-g (INF-g) Colony Stimulating Factors (CSFs) www.indiandentalacademy.com

http://www.indstate.edu/thcme/mwking/growth-factors.html#egf

http://www.indstate.edu/thcme/mwking/growth-factors.html#pdgf

http://www.indstate.edu/thcme/mwking/growth-factors.html#fgf

http://www.indstate.edu/thcme/mwking/growth-factors.html#tgfb

http://www.indstate.edu/thcme/mwking/growth-factors.html#tgfa

http://www.indstate.edu/thcme/mwking/growth-factors.html#epo

http://www.indstate.edu/thcme/mwking/growth-factors.html#igf1

http://www.indstate.edu/thcme/mwking/growth-factors.html#igf2

http://www.indstate.edu/thcme/mwking/growth-factors.html#il1




http://www.indstate.edu/thcme/mwking/growth-factors.html#tnfa

http://www.indstate.edu/thcme/mwking/growth-factors.html#tnfb

http://www.indstate.edu/thcme/mwking/growth-factors.html#infg

http://www.indstate.edu/thcme/mwking/growth-factors.html#csfs

Osteoblasts synthesize and regulate the deposition and mineralization of the extracellular matrix of bone. Systemic and locally active hormones, growth factors, ions, lipid metabolites and steroids are regulators of osteoblastic activity and/or differentiation.


Members of the transforming growth factor beta (TGF-b) family, particularly TGF-b and the bone morphogenetic proteins (BMPs) are important to bone homeostasis. These factors modulate osteoblast proliferation and differentiation .


Matrixmetalloproteinases

Extracellular matrix degrading metallo enzymes are known collectively as Matrixmetalloproteinases(MMPs).

Tissue inhibitors of metalloproteinases(TIMPs).

Depend on Zn²+ and Ca²+ for activity.


Matrixmetalloproteinases

Rather than being primarily involved in matrix degradation MMPs have equally or more important roles as efficient processing enzymes of many bioactive mediators such as cytokines, chemokines, growth factors, their receptors and specific matrix protein anchors for these molecules.


Cytokines

Includes a family of molecules which are small proteins with either paracrine or endocrine functions which are involved in local inflammation or immunoregulation.

Within this definition growth factors could be included.


Cytokines.

Cytokines are a unique family of growth factors.

Secreted primarily from leukocytes, cytokines stimulate both the humoral and cellular immune responses, as well as the activation of phagocytic cells.

Lymphokines Monokines.


Cytokines

A large family of cytokines are produced by various cells of the body.

Many of the lymphokines are also known as interleukins (ILs), since they are not only secreted by leukocytes but also able to affect the cellular responses of leukocytes.


Cytokines

Specifically, interleukins are growth factors targeted to cells of hematopoietic origin.

The list of identified interleukins grows continuously with the total number of individual activities now at 22.



Factor Principal Source Primary Activity

Comments

PDGF platelets, endothelial cells, placenta

promotes proliferation of connective tissue, glial and smooth muscle cells

two different protein chains form 3 distinct dimer forms; AA, AB and BB



EGF submaxillary gland, Brunners gland

promotes proliferation of mesenchymal, glial and epithelial cells



Comments

TGF-a common in transformed cells

may be important for normal wound healing

related to EGF


Factor Principal Source

Primary Activity Comments

FGF wide range of cells; protein is associated with the ECM

promotes proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos

at least 19 family members, 4 distinct receptors




NGF promotes neurite (axites & dendrites) outgrowth and neural cell survival

several related proteins first identified as proto-oncogenes; trkA (trackA), trkB, trkC




Erythropoietin kidney promotes proliferation and differentiation of erythrocytes




TGF-b activated TH1 cells (T-helper) and natural killer (NK) cells

anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation

at least 100 different family members



Comments

IGF-I primarily liver promotes proliferation of many cell types

related to IGF-II and proinsulin, also called Somatomedin C



Comments

IGF-II variety of cells promotes proliferation of many cell types primarily of fetal origin

related to IGF-I and proinsulin


Factors modulating growth, chemotactic behavior and/or functional activities of smooth muscle cells include Activin A , Adrenomedullin , aFGF, ANF , Angiogenin , Angiotensin-2 , Betacellulin , bFGF , CLAF , ECDGF (endothelial cell-derived growth factor ), ET (Endothelins ), Factor X , Factor Xa , HB-EGF , Heart derived inhibitor of vascular cell proliferation , IFN-gamma , IL1 , LDGF (Leiomyoma-derived growth factor ), MDGF (macrophage-derived growth factor , monocyte-derived growth factor ), Oncostatin M , PD-ECGF , PDGF , Prolactin , Protein S , SDGF (smooth muscle cell-derived growth factor ), SDMF (Smooth muscle cell-derived migration factor ), Tachykinins , TGF-beta , Thrombospondin .


http://www.copewithcytokines.de/cope.cgi?000213




































Factors modulating growth, chemotactic behavior and/or functional activities of vascular endothelial cells include AcSDKP , aFGF , ANF , Angiogenin , angiomodulin , Angiotropin , AtT20-ECGF , B61 , bFGF , bFGF inducing activity , CAM-RF , ChDI , CLAF , ECGF , ECI , EDMF , EGF , EMAP-2 , Neurothelin , Endostatin , Endothelial cell growth inhibitor , Endothelial cell-viability maintaining factor , Epo , FGF-5 , IGF-2 , HBNF , HGF , HUAF , IFN-gamma , IL1 , K-FGF , LIF , MD-ECI , MECIF , NPY , Oncostatin M , PD-ECGF , PDGF , PF4 , PlGF , Prolactin , TNF-alpha , TNF-beta , Transferrin , VEGF .















































A mind once stretched by a new idea, never regains its original dimensions.


Bone – enormous reservoir

1.PDGF2.IGF – I IGF – II3.BMP (PART OF TGF-β FAMILY) Binding proteins to keep these factors within

bone itself.


Transforming Growth Factors-β (TGFs- β)

ALTERNATIVE NAMES CIF-B ( cartilage inducing factor B =

TGF-beta-2 ) DIF ( differentiation-inhibiting factor ) DSF ( decidual suppressor factor =

TGF-beta-2 ) EIF ( Epstein-Barr virus inducing factor ) EGI (epithelial growth inhibitor )














MDGF ( milk-derived growth factor ) MGF ( milk growth factor ) MGF-a ( milk growth factor =TGF-beta-2 ) MGF-b ( milk growth factor =TGF-beta-1 ) TCGF ( transformed cell growth factor ) TGI ( tissue-derived growth inhibitor ) TIF-1 ( tumor inducing factor-1 ).


















Sources of TGFs- β

Found predominantly in spleen and bone tissues. Platelets - milligrams of TGF-beta/ kg. other tissues - microgram TGF/kg. Human milk – MGF. Synthesized also by - macrophages(TGF-beta-1 ),

lymphocytes(TGF-beta-1 ), endothelial cells(TGF-beta-1 ), keratinocytes(TGF-beta-2 ), granulosa cells(TGF-beta-2 ), chondrocytes (TGF-beta-1 ), glioblastoma cells(TGF-beta-2 ), leukemia cells(TGF-beta-1 ).










Inducers of TGFs- β

secretion can be induced by a no. of different stimuli including: steroids, retinoids, EGF , NGF , activators of lymphocytes, vitamin D3 , and IL1 .






Inhibitors of TGFs- β

The synthesis of TGF-beta can be inhibited by: EGF , FGF , dexamethasone, calcium, retinoids and follicle stimulating hormone .

TGF-beta also influences the expression of its own gene and this may be important in Wound healing .






TGFs- β

With the extracellular matrix as a complex with betaglycan and decorin.

Stored in a biologically inactive form. The exact molecular mechanisms underlying

its release from these reservoirs is unknown.




PROTEIN CHARACTERISTICS Five isoforms TGF-beta-1 , TGF-beta-2 , TGF-beta-3 ,

TGF-beta-4 , TGF-beta-5 . They are not related to TGF-alpha . Their amino acid sequences display

homologies on the order of 70-80 percent. TGF-beta-1 - prevalent form.









PROTEIN CHARACTERISTICS The biologically active forms of all isoforms

are disulfide-linked homodimers. Sometimes hetrodimers. The isoforms of TGF-beta arise by proteolytic

cleavage of longer precursors.


PROTEIN CHARACTERISTICS Isoforms isolated from different species are

evolutionarily closely conserved and have sequence identities on the order of 98 percent.

Mature human, porcine, simian and bovine TGF-beta-1 are identical and differ from murine TGF-beta-1 in a single amino acid position.

Carboxy terminal end and Amino terminal end of precursor.




Biosynthesis and processing of mature Biosynthesis and processing of mature TGF-betaTGF-beta (dark blue) (dark blue)


L - TGF Almost all forms of TGF-β are released as

biologically inactive forms that are known also as L-TGF ( latent TGF ).

Latent forms are complexes of TGF-β, an aminoterminal portion of the TGF-beta precursor, designatedTGF-LAP ( TGF-latency associated peptide ), and a specific binding protein, known as LT-BP ( latent TGF binding protein).








L-TGF

L-TGF - localized at the cell surface by binding to the mannose-6-phosphate/IGF-2 receptor.

Biologically active TGF-beta results after dissociation from the LAP complex.

The nature of the activation mechanism of L-TGF in vivo is unclear.

Direct cell-to-cell contacts, proteases, specifically plasmin, transglutaminases Thrombospondin .








Alpha2M/TGF-beta complexes The main fraction of the factor in the serum is

covalently attached to one of the acute phase proteins , Alpha-2-Macroglobulin (Alpha2M).

Alpha2M/TGF-beta complexes are believed to represent TGF-beta molecules released by platelets after tissue injuries and destined to degradation.




Mutant TGF- β

Mutant forms of TGF- β have been created. They form wild-type/mutant heterodimers

deficient in assembly or processing. Such mutants behave as dominant negative

mutants and are useful in investigation of the role of TGF- β in normal and pathological conditions.


GENE STRUCTURE

The different isoforms of TGF-β are encoded by different genes.

All genes have a length of more than 100 kb and contain seven exons.

The genes map to different chromosomes.


GENE STRUCTURE The TGF-beta-1 gene maps to human chromosome

19q13. The TGF-beta-2 gene maps to human chromosome 1q41. The TGF-beta-3 gene maps to human chromosome

14q24. These genes are expressed differentially. The TGF-beta-3 gene is expressed strongly in embryonic

heart and lung tissues but only marginally in liver, spleen, and kidney tissues. TGF-beta-1 is expressed strongly in spleen tissues.







RELATED FACTORS

TGF-beta is the prototype of a protein family known as the TGF-beta superfamily.

This family includes Inhibins , Activin A , MIS (Müllerian inhibiting substance ), BMP (bone morphogenetic proteins ), dpp (decapentaplegic ) and Vg-1 .












RECEPTORS

An entire family of glycoprotein receptors for TGF-beta has emerged.

Some of these proteins do not bind TGFbeta-related factors belonging to the TGF-beta family.

Type-1 receptors (hematopoietic progenitor cells) and type-2 receptors.



RECEPTOR AFFINITY

Individual TGF-b isotypes - varying affinities. E.g., TGF-beta-1 binds approximately tenfold

better than TGF-beta-2. Expression of the TGF-beta receptors is

decreased by EGF (Receptor transmodulation).

In endothelial cells the expression of the TGF-beta receptor is decreased by bFGF .






RECEPTORS

Almost all types of cells express, type-3 receptor.

This receptor type is not expressed in primary epithelial, endothelial, and lymphoid cells .

The type-3 receptor is a proteoglycan (Betaglycan), binds TGF-beta-1 and TGF-beta-2 equally well.






BIOLOGICAL ACTIVITIES

Not species-specific. TGF-beta-2 is the only variant that does not

inhibit the growth of endothelial cells. Most pronounced differences in the TGF-beta

isoforms is their spatially and temporally distinct expression of both the mRNAs and proteins in developing tissues, regenerating tissues, and in pathologic responses.




TGF-beta is the most potent known growth inhibitor for normal and transformed epithelial cells, endothelial cells, fibroblasts, neuronal cells, lymphoid cells and other hematopoietic cell types (CFU-S ), hepatocytes, and keratinocytes.





Inhibits the proliferation of T-lymphocytes. Inhibits the growth of natural killer cells in

vivo. Deactivates macrophages. Blocks the antitumor activity mediated in vivo

by IL2 and transferred lymphokine-activated or tumor infiltrating lymphocytes .





Inhibits the growth of immature hematopoietic progenitor cells .

In particular growth of CFU-GEMM . Inhibits megakaryocytopoiesis. Antagonizes the biological activities of EGF ,

PDGF , aFGF and bFGF . Latent form of TGF-beta is a strong inhibitor

of erythroleukemia cell lines.









The extent of growth inhibition induced by TGF-beta depends on the cell type, on the concentration of TGF-beta, and on the presence of other factors.

The growth-inhibitory activities of TGF-beta can be abolished by HGF (hepatocyte growth factor ).




BIOLOGICAL ACTIVITIES At concentrations of 1-2 fg/cell - growth inhibition for

smooth muscle cells, fibroblasts, and chondrocytes. At higher concentrations - stimulation. This bimodal activity is mediated in part by PDGF . Low concentrations of TGF-beta - synthesis and

secretion of PDGF. Higher concentrations – lower expression of the

PDGF receptors and hence diminish the biological effects of PDGF .






Overproduction of TGF-beta-1 by tumor cells - neovascularization and may help promote tumor development in vivo.

TGF-beta is an autocrine growth modulator for malignant gliomas.

It stimulates the growth of fibroblasts and osteoblasts in vivo and in vitro.

TGF-beta induces the synthesis of bone matrix proteins in osteoblasts.






Factors that promote bone resorption (IL1 , vitamin D3 , parathormone) induce the synthesis of TGF-beta in bone cells.

While calcitonin, an inhibitor of bone resorption, reduces the synthesis of TGF-beta.

It suppresses the expression of class II MHC antigens .

Microglial cells.




TGF-beta stimulates the synthesis of the major matrix proteins including collagen, proteoglycans , glycosaminoglycans, fibronectin , integrins, Thrombospondin , osteonectin, osteopontin .

It inhibits degradation mainly by inhibiting the synthesis of neutral metalloproteinases and by increasing the synthesis of proteinase inhibitors.



Involved in metastatic processes. It is responsible for the transformation of

epithelial cells into mesenchymal cells. Suppressive effects on the immune system . TGF-beta-1 is the most potent known

chemoattractant for neutrophils .


CLINICAL USE AND SIGNIFICANCE It may be a potent regulator of Wound

healing and of bone fracture healing. Local application of TGF-beta has been

shown to accelerate wound repair. In combination with bone morphogenetic

protein-2 it causes development of ossification of the posterior longitudinal ligament of the cervical spine.


CLINICAL USE AND SIGNIFICANCE The factor may be helpful in the treatment of

traumatic tissue injuries. Treatment of osteoporosis. Reverses age- or glucocorticoid-impaired

Wound healing even if given 24 hours before wounding.


Bone morphogenetic protein (BMP) Responsible for osteoinductive activity in

bone matrix. Non-collagenous. Water soluble.


Bone morphogenetic protein (BMP) The cellular and molecular events governing

bone formation in the embryo, healing of a fractured bone, and induced bone fusion follow a similar pattern.

Bone is unique of all the tissues. When injured, it heals by formation of new

bone.


BMP-Introduction

The molecular and cellular processes that lead to the development of the skeletal structures within the embryo are very similar to the cascades that occur in the healing process in an injured bone.

Thus, there is a common theme in the development of bone from primitive mesenchymal tissues to a well-structured, well-organized mature bone.


BMP-Introduction

The ongoing remodeling process in an adult organism, which is exposed to external physical and hormonal influences, is also modulated through a similar molecular mechanism.

Intracartilaginous process. Intramembranous process.


BMP-Introduction

Postfracture healing - intracartilaginous ossification process.

Very high concentration of BMP - intramembranous route may be taken.

It is unclear what factor(s) direct(s) one process as opposed to the other in the embryonic phase or during fracture healing.


Stages of bone healing and remodelingStages of bone healing and remodeling


GF and cytokines involved in generation of new bone


History

Senn(1889)-Decalcified ox bone promotes healing of osteomyelitic defects.

Lexer(1908)-Necrotic bone tissue released stimulating factors that affect osteoblasts.

Polettini(1922)-Substance released from graft tissue resulted in differentiation of fibroblasts into bone and cartilage forming cells.


History

Leriche(1928)-Ca materials contained in the graft tissue were the agents inducing new bone formation.

Levander(1934)-crude alcohol extracts of bone induce bone formation in muscle.

Sharrard and Collin(1961)-EDTA decalcified allograft induced spinal fusion in children.


History

Urist(1965)-acid-decalcified bone induced ectopic bone in rat model. He coined the term "bone morphogenetic protein" or "osteogenic protein" .

Reddi and Sampath(1983)-crude but reproducible bioassay for BMP; bone matrix when dissociated from BMP ineffective in bone induction; reconstituted matrix effective.


History

Johnson(1992)-first clinical study; purified human BMP successful clinically.

Creative biomolecules and genetic institute(1990s)-simultaneous gene sequencing for various BMP’s and related patent dispute.

Stryker Corp., Medtronic Sofamor Danek(2002)-FDA approval of OP-1 (BMP-7) for long bone defects and BMP-2 in a collagen carrier within a cage for anterior lumbar interbody fusions.


Classification of BMP

Bone morphogenic proteins are members of TGF superfamily.

The BMP subfamily comprises more than 10 proteins, and newer ones are being discovered.

Several structural homologies between BMPs and TGF growth factors.

The amino acid sequence of BMPs is considered to be as old as 600 million years.


Classification

Because of this conservation, human recombinant BMPs are highly effective in lower life forms, including fruit flies.

BMPs are synthesized as precursor proteins. The mature portion of the protein is located at

the carboxy terminal of the precursor molecule.



BMP

It is the only morphogen of all known growth factors that has the ability to transform connective tissue cell into osteoprogenitor cells.

Thus, it is not only a mitogen but can be a morphogen as well.

All other growth factors such as TGF, insulin-like growth factor, fibroblast growth factor, PDGF, and vascular endothelial growth factor all induce multiplication of cells but do not transform one cell type into the other.


Signaling Mechanism of BMP

BMP receptors - Type I and Type II serine/threonine kinase proteins.

The binding of the ligand to the Types I and II serine/threonine kinase transmembrane receptors results in the activation of the signaling cascade.

Type II receptor kinase phosphorylates the Type I receptor.


Signaling Mechanism of BMP

Type I receptor phosphorylates the intracytoplasmic signaling molecules Smads 1, 5, and 8.

Smads 1, 5, and 8 bind to Smad 4. Translocate into the cell nucleus. Activation of transcriptional factors for the

early BMP response genes.


Dosage

Normal bone contains approximately 0.002 mg of BMP per kilogram of pulverized bone.

At a fracture site, presumably the BMP is released at a higher concentration.


Dosage

The concentration required for ideal induced bone bridging in osseous defects depends on several factors.

- state of the organism in the evolutionary scale.

- type of defect. Bone induced under the influence of BMP

matures faster than natural healing of the bone.


Other uses

Brain protective agent. kidneys are their primary source in the

human adult. In chronic renal disease levels of BMP are lower. systemic administration of BMP may restore some of the renal functions.

Local application for dialysis patient in osteodystrophy.


BMP

Named because of their osteoinductive ability.

Role in embryonic and post embryonic development.

Signaling molecules in no. of tissues. Implicated in mesodermal patterning,

neurogenesis and organogenesis.


BMP

BMP signaling pathways ↔ other growth factors ↔ hormonal signaling pathways.

Cross talk between them must be evaluated to avoid side effects of BMP based therapies.


BMP

Mutations perturbing functions of BMP genes: BMP-5 gene mutation – short ear – abnormal

growth & patterning of skeletal structures and diminished repair of bone fracture.


BMP

GDF-5 gene mutation – brachypod phenotype in mice & in autosomal recessive syndromes Hunter – Thompson chondrodysplasia in humans – shortening of appendicular skeleton and loss or abnormal development of some joints.


BMP

BMP-2 & BMP-4 knock out mice die early in embryonic development, long before development of skeleton, because of defects in gastrulation.

BMP-7 knock out – eye and kidney defects, only mild skeletal defects.


BMP

Several extracellular proteins regulate activities of BMP.

Noggin (BMP-4 & BMP-2) Follistatin (BMP-4 & BMP-7) Protein chordin

Astacin family of metalloproteases – cleaves chordin.


Platelet-Derived Growth Factor (PDGF)ALTERNATIVE NAMES MDGF ( monocyte-derived growth factor ) ODGF ( osteosarcoma-derived growth factor ) SOURCES megakaryocytes stored in the alpha granules of

platelets(PDGF-BB/AB) released after cell activation of platelets for example

by thrombin .


Sources

Unstimulated cells of osteoblastic lineage – PDGF-AA.

Other cells - macrophages, endothelial cells, fibroblasts, glial cells, astrocytes, myoblasts, smooth muscle cells, and a number of tumor cell lines.

Synthesis of PDGF can be induced by IL1 , IL6 , TNF-alpha , TGF-beta and EGF .


Platelet-Derived Growth Factor (PDGF) PDGF is composed of two distinct

polypeptide chains, A and B, that form homodimers (AA or BB) or heterodimers (AB).

3 isoforms. PDGF receptors have intrinsic tyrosine

kinase activity.


PDGF

PDGF-BB – binds to receptor – activates extracellular signal regulated kinase 1&2 – cellular proliferation by accelerating cell recycle & inducing quiescent cells into the proliferation portion of the cell cycle.

This effect is mediated by protein kinase B, a serine-threonine protein kinase.

TGFb1 – inhibits receptor autophosphorylation – neutralizes mitogenic effect of PDGF.


PDGF

Proliferative responses to PDGF action are exerted on many mesenchymal cell types.

Two related receptors, called PDGFR alpha or PDGFR beta.

PDGF is not released into the circulation. The biological half-life is less than two

minutes after intravenous administration.


PDGF

In the adult organism PDGF is involved in Wound healing processes.

The dimeric form of PDGF is mainly mitogenic for cells of mesenchymal origin while monomeric forms of PDGF are mainly chemotactic.

Disruption of PDGF signaling – perinatal lethality > 50%.


PDGF

At low concentrations PDGF is a chemoattractant for fibroblasts.

PDGF is also chemotactic and activating for monocytes and neutrophils.

PDGF (alone and in combination) may be useful in promoting bone formation.

Promotes fracture healing. Doesn’t provides entire osteogenic properties

itself.


PDGF

Osteoblasts can specifically bind and proliferate in response to PDGF.

Enhanced proliferation of both osteoblasts and osteoclasts.

In tissue culture, PDGF alone has not yet been proved to be osteoinductive in vivo.

In osteosarcoma – positive feedback loop. Platelet gel.


PDGF

PDGF is chemotactic for both alkaline phosphatase positive and negative cells.

It may so contribute to recruitment of bone cells during remodeling and repair.

Used in implants and periodontal therapies. With or without IGF-I.


Fibroblast Growth Factors (FGFs) 19 distinct members FGF1 (acidic-FGF, aFGF) and FGF2 (basic-

FGF, bFGF). Studies of human disorders & gene knock-out

studies in mice show the prominent role for FGFs is in the development of the skeletal system in mammals.


aFGF

SOURCE Best sources of aFGF is brain tissue.

The mechanism underlying the release of aFGF is unknown.


bFGF

SOURCES Almost all tissues of mesodermal and

neuroectodermal origin. Also in tumors derived from these tissues. Endothelial cells.


FGF

potent inducers of mesodermal differentiation in early embryos.

Specific cell-surface receptors. 4 distinct receptor types identified as FGFR1

- FGFR4. Receptors has intrinsic tyrosine kinase

activity . autophosphorylation of the receptor is the

immediate response to FGF binding.


FGF

FGFs also bind to cell-surface heparan-sulfated proteoglycans with low affinity

The FGF receptors are widely expressed in developing bone.

Mutations in the FGFR genes-autosomal dominant disorders of bone growth e.g. achondroplasia(FGFR3).

FGFR3 is predominantly expressed in quiescent chondrocytes & it restricts chondrocyte proliferation and differentiation.


FGF

bFGF stimulates the growth of fibroblasts, myoblasts, osteoblasts, endothelial cells, chondrocytes, and many other cell types.

bFGF is not only a mitogen for chondrocytes but also inhibits their terminal differentiation.


FGF

Animals experiments with bFGF - promotes endosteal, but not periosteal, bone formation.

bFGF may thus be a potential agent for treatment of osteoporosis which may increase bone mass without causing outward deformation of the skeletal bones.


FGF

Craniosynostosis syndromes have been shown to result from mutations in FGFR1, FGFR2 and FGFR3.

Sometimes the same mutation can cause two or more different craniosynostosis syndromes.


Affected Receptor

Syndrome Phenotypes

FGFR1 Pfeiffer broad first digits, hypertelorism

FGFR2 Apert mid-face hypoplasia, fusion of digits

FGFR2 Beare-Stevenson

mid-face hypoplasia, corrugated skin


Affected Receptor

Syndrome Phenotypes

FGFR2 Crouzon mid-face hypoplasia

FGFR2 Jackson-Weiss

mid-face hypoplasia, foot anamolies

FGFR2 Pfeiffer same as for FGFR1 mutations


Affected Receptor

Syndrome Phenotypes

FGFR3 Crouzon mid-face hypoplasia, acanthosis nigricans

FGFR3 Non-syndromatic craniosynostosis

digit defects, hearing loss.


Insulin-Like Growth Factor IGFs are single chain peptides. 2 isoforms (IGF-I and IGF-II). 40-50% homology with insulin. Still all 3 have

unique binding site to their receptors. IGF also has general activity (metabolic &

growth promoting) in many tissue types.


IGF-I

SOURCE Mainly liver.

IGF – responsible for fetal and postnatal growth and development in general.


IGF-I

IGF-I receptor gene – deleted mice died at birth putatively due to poor muscular development.

IGF-I: pre + postnatal development. IGF-II: prenatal stages only. IGF-I/ IGF-II ratio increases with age in many

tissues. Role in skeletal development and skeletal mass

maintenance and development of teeth.


Insulin-Like Growth Factor-I (IGF-I) Called somatomedin C(considered as

circulating mediator of growth hormone). Primary protein involved in responses of cells

to growth hormone (GH) IGF-I is produced in response to GH and then

induces subsequent cellular activities, particularly on bone growth.


IGF-I

IGF-I has autocrine and paracrine activities in addition to endocrine activities on bone.

Family of transmembrane IGF-I(tyrosine kinase), IGF-II(mannose-6-phosphate receptor) & insulin receptor.

Receptor has intrinsic tyrosine kinase activity. Plays role in general growth and maintenance of

body skeleton.


Insulin-Like Growth Factor-II (IGF-II) Exclusively expressed in embryonic and

neonatal tissues. Following birth, the level of detectable IGF-II

protein falls significantly. The IGF-II receptor is identical to the

mannose-6-phosphate receptor.


IGF

Osteoblast aging is associated with impaired production of the stimulatory components of the IGF-system, that may contribute to age-related decline in osteoblast functions.

Of all IFG binding proteins, IGFBP-5 is abundant in bone matrix.


IGF

IGF-I & II are potent survival factors for fibroblasts, hematopoetic cells, cardiac muscle cells & pancreatic beta cell.

IGF-I has anti apoptotic activity in these cell types and in certain tumors.

Autocrine loop – tumor promoting effect. IGF-I has chemotactic effect on osteoblasts

in a dose dependent manner. IGF-II effects only at lowest conc.


IGF

It promotes expression of bone specific protein e.g. bone sialoprotein, and osteopontin.

In vivo, systemic application of IGF-I – rapidly activated bone turnover – increase in serum osteocalcin, increased collagen marker of bone formation, and an increased urinary ratio of Ca/creatinine.


IGF

In inflammatory tissue (e.g. fracture repair) – IL1 increases IGF-I production.

IGF-I activity can be suppressed by NSAIDs e.g. indomethacin.



Taken from the AJO-DO on CD-ROM (Copyright © 1997 AJO-DO), Volume 1993 Aug (121 - 131): Heritability of skeletodental relationships - King, Harris, and Tolley, Fig. 6.

-------------------------------- Fig. 6. The epigenetic

landscape (redrawn from Waddington82).


Taken from the AJO-DO on CD-ROM (Copyright © 1997 AJO-DO), Volume 1981 Oct (366 - 375): Genetics, epigenetics, and causation - Moss, Fig. 5.

-------------------------------- Fig. 5. This figure shows how boundaries

might be analogously demonstrated to operate in the epigenetic regulation. If the ball at the top of the figure is taken to represent a cell, or a tissue, capable of rolling down the convoluted surface shown, then the developmental pathway will be regulated by the convex ridges of that inclined surface. These epigenetic boundaries will effectively prevent the ball from passing into adjacent grooves, and thus determine the developmental pathway. (Adapted from Waddington: New Patterns in Genetics and Development, New York, 1962, Columbia University Press.)


The ball may be considered, for example, as a simple, totipotential cell with its complete, genomically encoded information regulatory of the full range of species-specific polypeptide synthesis. The subsequent history of this cell and its descendants is a function of which developmental pathway (or "Chreod") it moves along. Some initial epigenetic factor or process determines the initial path selected, at which time portions of the genome become, respectively, repressed and derepressed, so that initial cytodifferentiation occurs. This new state, or epigenetic environment, keeps the vital material moving along this particular pathway until another bifurcation point occurs (Fig. 5). Once again, the instantaneous epigenetic state regulates this decision, and a "catastrophic" event occurs; that is, a new structually higher-order state or path is evolved. These pathways become "deeper" (have higher "walls") as they progressively become hierarchically more complex. This represents, in such a model, the fact that there is an increasing ability to withstand lateral, homeostatic perturbations during "movement'' along the landscape. This movement is termed homeorrhesis. In this model, the selection of pathways is not genomically but epigenetically regulated. Yet the genomic information must be present to permit synthetic activity by the cell and is one type of intrinsic, necessary information needed for ontogenesis to occur. The constantly added epigenetic information is the other type of necessary causation required. There is no reason for conflict between the genomic and epigenetic hypotheses of ontogenetic regulation when it is perceived that they are interdependent, yet different, categories of necessary causes and that only their unity provides the sufficient condition for growth and development to occur.74


(1) all of the extrinsic (extraorganismal) factors impinging on vital structures, including importantly mechanical loadings and electroelectric states and (2) all of the intrinsic (intraorganismal) biophysical, biomechanical, biochemical, and bioelectric microenvironmental events occurring on, in, and between individual cells, extracellular materials, and cells and extracellular substances.

As previously noted,99 epigenetic factors include (1) all of the extrinsic, extraorganismal, macroenvironmental factors impinging on vital structures (for example, food, light, temperature), including mechanical loadings and electromagnetic fields, and (2) all of the intrinsic, intraorganismal, biophysical, biomechanical, biochemical, and bioelectric microenvironmental events occuring on, in, and between individual cells, extracellular materials, and cells and extracellular substances.





AJO-DO:1993 Mar - Sandy, Farndale, and Meikle Simplified diagram depicting

interactions of molecules at focal contacts. The model depicts how the cytoskeleton is linked through the membrane glycoprotein integrin to the extracellular matrix. Many of the extracellular matrix proteins which are responsible for cell adhesion contain common peptide sequences as cell recognition sites. These sites are recognized by integrins that are a family of glycoproteins, which span the cell membrane from the cytoplasm to the extracellular matrix. Integrin does not bind directly to microfilament structures, such as actin, but is dependent on associated proteins for this function. Integrin binds to fibronectin in the extracellular matrix and to talin on the cytoplasmic surface. Actin and vinculin then bind to this talin-integrin complex.



From macro to - micro


From macro to - micro



Terminology Cell – basic living, structural & functional unit of

body Chromosome – highly coiled & folded DNA molecule

combined with protein molecules, present in the nucleus of cell

Gene-The unit of heredity: one or more nucleic acid sequences incorporating information necessary for the generation of a particular peptide or RNA product

(AJODO-1997 : MOSS - Meier AE, editor. A is for . . . gene. Sci Med 1996;3:72.)

These are located on the chromosomeswww.indiandentalacademy.com

Terminology Apoptosis – physiological cell death occuring

in normal tissues/in diseased organs, not associated with inflammatory reactions

Chemotaxis – process of migration of cells towards an attractant

Ontogenesis - growth and development of the cell


Growth 3 possibilities : Hypertrophy – increase in the size of cells Hyperplasia – increase in the number of cells Secretion of extra cellular material MAINLY SEEN IN HARD TISSUES – BONE,

CARTILAGE, TEETH Atrophy – diminished size and number of cells due

to extreme failure of development Interstitial growth – occurring at all points within the

tissue; hyperplasia primarily & hypertrophy secondarily, with/without secretion of ECM

IN SOFT TISSUES & UNCALCIFIED CARTILAGE www.indiandentalacademy.com

Resolving synthesis (AJODO-1997 : MOSS) Morphogenesis is regulated (controlled, caused) by

the activity of both genomic and epigenetic processes and mechanisms. Both are necessary causes; neither alone are sufficient causes; and only their integrated activities provides the necessary and sufficient causes of growth and development. Genomic factors are considered as intrinsic and prior causes; epigenetic factors are considered as extrinsic and proximate causes.

It is probable that ontogeny involves nonlinear processes and is not fully predictable; that is, growth and development, to a significant extent, exhibit both random behaviors and frequent perturbations. www.indiandentalacademy.com

Resolving synthesis - Complexity and self-organization The highly ordered morphological properties of adult

complex biological systems (for example, functional matrices and skeletal units) result from the operation of a series of spontaneous and self-organized ontogenetic processes and mechanisms.

Environmental factors play a decisive role in all ontogenetic processes. But it is the organism itself that, as an integrated system, dictates the nature of each and every developmental response . . . the living organism self-organizes on the basis of its own internal structuring, in continuous interaction with the environment in which it finds itself.


Mechanotransduction (AJODO-1997 : MOSS) Occurs in single bone cells

All vital cells are "irritable" or perturbed by and respond to alterations in their external environment. Mechanosensing processes enable a cell to sense and to respond to extrinsic loadings by using the processes of mechanoreception and of mechanotransduction.

The former transmits an extracellular physical stimulus into a receptor cell; the latter transduces or transforms the stimulus's energetic and/or informational content into an intracellular signalwww.indiandentalacademy.com

There are several mechanotransductive processes, for example, mechanoelectrical and mechanochemical. Whichever are used, bone adaptation requires the subsequent intercellular transmission of the transduced signals.

When an appropriate stimulus parameter exceeds threshold values, the loaded tissue responds by the triad of bone cell adaptation processes…..trio of possible osteoblastic responses to loading (deposition, resorption, or maintenance of bone tissue)


Osseous mechanotransduction is unique in four ways:

(1) Most other mechanosensory cells are cytologically specialized, but bone cells are not;

(2) one bone-loading stimulus can evoke three adaptational responses, whereas nonosseous processes generally evoke one;

(3) osseous signal transmission is aneural, whereas all other mechanosensational signals use some afferent neural pathways and,

(4) the evoked bone adaptational responses are confined within each "bone organ" independently, e.g., within a femur, so there is no necessary "interbone" or organismal involvement.


1. Electromechanical As in most cells, the osteocytic plasma membrane

contains voltage-activated ion channels, and transmembrane ion flow may be a significant osseous mechanotransductive process.

Stretch-activated channels - Several types of deformation may occur in strained bone tissue. One of these involves the plasma membrane stretch-activated (S-A) ion channels, a structure found in bone cells, in many other cell types and significantly in fibroblasts. When activated in strained osteocytes, they permit passage of a certain sized ion or set of ions, including K+, Ca2+, Na+. Such ionic flow may, in turn, initiate intracellular electrical events.


2. Electrokinetic Bound and unbound electric charges exist in

bone tissue, many associated with the bone fluid(s) in the several osseous spaces or compartments. Electrical effects in fluid-filled bone are not piezoelectric, but rather of electrokinetic, that is, streaming potential (SP) origin. The SP is a measure of the strain-generated potential (SGP) of convected electric charges in the fluid flow of deformed bone. The usually observed SPG of ±2 mV can initiate both osteogenesis and osteocytic action potentials.


3. Electric field strength

Bone responds to exogenous electrical fields. Although the extrinsic electrical parameter is unclear, field strength may play an important role. A significant parallel exists between the parameters of these exogenous electrical fields and the endogenous fields produced by muscle activity.


Gap junctions & Connected cellular network (CCN) Gap junctions are regions on the lateral surfaces of

cells where the gap between the adjoining plasma membranes is reduced from 20 nm to 2nm in width. Pits/holes may be present in these regions, permeable to small tracer particles

All bone cells, except osteoclasts, are extensively interconnected by gap junctions that form an osseous CCN. In these junctions, connexin is the major protein. Each osteocyte, enclosed within its mineralized lacuna, has many (n = ± 80) cytoplasmic (canalicular) processes, 15 mm long and arrayed three-dimensionally, that interconnect with similar processes of up to 12 neighboring cells. These processes lie within mineralized bone matrix channels (canaliculi). www.indiandentalacademy.com

Gap junctions are found where the plasma membranes of a pair of markedly overlapping canalicular processes meet. Gap junctions also connect superficial osteocytes to periosteal and endosteal osteoblasts. All osteoblasts are similarly interconnected laterally. Vertically, gap junctions connect periosteal osteoblasts with preosteoblastic cells, and these, in turn, are similarly interconnected.

In addition to permitting the intercellular transmission of ions and small molecules, gap junctions exhibit both electrical and fluorescent dye transmission. Gap junctions are electrical synapses, in contradistinction to interneuronal, chemical synapses, and, significantly, they permit bidirectional signal traffic, e.g., biochemical, ionic. www.indiandentalacademy.com

Mechanotransductively activated bone cells, e.g., osteocytes, can initiate membrane action potentials capable of transmission through interconnecting gap junctions.

The CCNs show oscillation, i.e.,reciprocal signaling (feedback) between layers. This attribute enables them to adjustively self-organize.

Gap junctions, permitting bidirectional flow of information, are the cytological basis for the oscillatory behavior of a CCN.


Integrins A family of membrane integral proteins that

span the cell membrane from the cytoplasm to the extracellular matrix.

Many of the extracellular matrix proteins which are responsible for cell adhesion contain common peptide sequences as cell recognition sites, these sites are recognized by integrins.

Changes in cell shape produce a range of effects mediated by integrins and the cytoskeleton, which may be important in transducing mechanical deformation into a meaningful biologic response.


Integrins A family of glycoproteins. These are

connected extracellularly with the macromolecular collagen of the organic matrix and intracellularly with the cytoskekeletal actin. The molecules of the latter, in turn, are connected to the nuclear membrane,

These aid in transmitting signals from the ECM directly to the intranuclear genome. This informational transfer between cells and ECM is dynamic, reciprocal, and continuous.


Osteoblasts (AJO-DO:1993 Mar - Sandy, Farndale, and Meikle) They are now recognized as the cells that

control both the resorptive and the formative phases of the remodeling cycle, and receptor studies have shown them to be the target cells for resorptive agents in bone.

The osteoblast is perceived as a pivotal cell, controlling many of the responses of bone to stimulation with hormones and mechanical forces.


Genes All somatic cells commonly share approximately

5000 different polypeptide chains, each specific cell type is characterized only by approximately 100 specific proteins. And it is claimed that "these quantitative (protein) differences are related to differences in cell size, shape and internal architecture”.

The encoding of the DNA exists in two families; the vastly preponderant "housekeeping" genes and the nonabundant "structural" genes. The former regulate the normal molecular synthesis of agents involved in (1) the common energetic (metabolic, respiratory) activities of all cells and, (2) the specific activities of special cell types (e.g., neurons, osteoblasts, ameloblasts etc.)www.indiandentalacademy.com

Prenatal craniofacial development is controlled by two interrelated, temporally sequential, processes: (1) initial regulatory (homeobox) gene activity and (2) subsequent activity of two regulatory molecular groups: growth factor families and steroid/thyroid/retinoic acid super-family. For example, "homeobox genes coordinate the development of complex craniofacial structures" and in "both normal and abnormal development, much of the regulation of the development of virtually all of the skeletal and connective tissue of the face is dependent on a cascade of overlapping activity of homeobox genes.“


It is claimed that regulatory molecules can (1) "alter the manner in which homeobox genes coordinate cell migration and subsequent cell interactions that regulate growth" and (2) be involved in the "genetic variations causing, or contributing to, the abnormal development of relatively common craniofacial malformations . . . perhaps modifying Hox gene activity."



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