The development of the skeleton and osteoarthritis

Authors

  • David Garciadiego Cázares Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación.

Keywords:

Articular cartilage, osteoarthritis, chondrocyte differentiation, integrins, Indian hedgehog, GDF-5

Abstract

Articular cartilage unlike the growth plate cartilage, is a specialized tissue to keep uncalcified.
However, the mineralization of articular cartilage is a common process in the osteoarthritis
(OA) and aging complications. Some studies shows similarities in the mechanisms of growth

plate differentiation and articular cartilage degeneration. These include chondrocyte prolifera-
tion, hypertrophy, extracellular matrix (ECM) mineralization and apoptosis. The growth plate

development is regulated by certain growth factors signaling and interactions of chondrocytes
with extracellular matrix molecules. Related Protein Parathyroid Hormone (PthrP) and Indian
hedgehog (Ihh) are central mediators of endochondral bone development, PthrP is abundant in
the synovial fluid of OA patients but decreased the expression of Ihh in the cartilage with OA .
Furthermore, PthrP is known to induce the proliferation of chondrocytes, while the Fibroblast
Growth Factor 18 (Fgf-18) negative regulates it and their application intra-synovial in OA rats
results in the generation of cartilage. Wnt signaling plays an important role in the differentiation
of chondrocyte growth plate, Wnt-5a promotes chondrocyte prehipertrofia but simultaneously
inhibits cartilage hypertrophy, on the contrary Wnt-4 induces chondrocyte hypertrophy and
from the early stages of OA increases its expression in the articular cartilage.

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References

Gardner DL. The nature and causes of osteoarthrosis.

Br Med J 1983; 286: 418-424.

Hedbom E, Häuselmann HJ. Molecular aspects of patho-

genesis in osteoarthritis: the role of infl ammation. Cell

Mol Life Sci 2002; 59: 45-53.

Vincent TL, Saklatvala J. Is the response of cartilage to

injury relevant to osteoarthritis? Arthritis Rheum 2008;

: 1207-1210.

Bos SD, Slagboom PE, Meulenbelt I. New insights into

osteoarthritis: early developmental features of an ageing-

related disease. Curr Opin Rheumatol 2008; 20: 553-559.

Ala-Kokko L, Baldwin CT, Moskowitz RW, Prockop DJ.

Single base mutation in the type II procollagen gene (CO-

L2A1) as a cause of primary osteoarthritis associated with

a mild chondrodysplasia. PNAS USA 1990; 87: 6565-6568.

Vikkula M, Olsen BR. Unravelling the molecular genetics

of osteoarthrosis. Ann Med 1996; 28: 301-304.

Eerola I, Salminen H, Lammi P, Lammi M, Von Der Mark

K, Vuorio E, Säämänen AM. Type X collagen, a natural

component of mouse articular cartilage. Association with

growth, aging, and osteoarthritis. Arthritis Rheum 1998;

: 1287-1295.

Aigner T, Zhu Y, Chansky HH, Matsen FA, Maloney WJ,

Sandell LJ. Reexpression of type IIA procollagen by

adult articular chondrocytes in osteoarthritic cartilage.

Arthritis Rheum 1999; 42: 1443-1450.

Pfander D, Cramer T, Deuerling D, Weseloh G, Swobo-

da B. Expression of thrombospondin-1 and its receptor

CD36 in human osteoarthritic cartilage. Ann Rheum Dis

; 59: 448-454.

Garnero P, Ayral X, Rousseau JC, Christgau S, Sandell

LJ, Dougados M et al. Uncoupling of type II collagen

synthesis and degradation predicts progression of joint

damage in patients with knee osteoarthritis. Arthritis

Rheum 2002; 46: 2613-2624.

Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho

AM, Doherty M et al. Mutations in ANKH cause chon-

drocalcinosis. Am J Hum Genet 2002; 71: 933-940.

Xu L, Peng H, Glasson S, Lee PL, Hu K, Ijiri K et al.

Increased expression of the collagen receptor discoidin

domain receptor 2 in articular cartilage as a key event in

the pathogenesis of osteoarthritis. Arthritis Rheum 2007;

: 2663-2673.

Klatt AR, Becker A-KA, Neacsu CD, Paulsson M, Wage-

ner R. The matrilins: Modulators of extracellular matrix

assembly. Int J Biochem Cell Biol 2011; 43: 320-330.

Otten C, Hansen U, Talke A, Wagener R, Paulsson M,

Zaucke F. A matrilin-3 mutation associated with osteoar-

thritis does not affect collagen affi nity but promotes the

formation of wider cartilage collagen fi brils. Hum Mutat

; 31: 254-263.

Klatt AR, Klinger G, Paul-Klausch B, Kühn G, Renno JH,

Wagener R et al. Matrilin-3 activates the expression of

osteoarthritis-associated genes in primary human chon-

drocytes. FEBS lett 2009; 583: 3611-3617.

van der Weyden L, Wei L, Luo J, Yang X, Birk DE, Adams

DJ et al. Functional knockout of the matrilin-3 gene cau-

ses premature chondrocyte maturation to hypertrophy

and increases bone mineral density and osteoarthritis.

Am J Path 2006; 169: 515-527.

Majumdar MK, Askew R, Schelling S, Stedman N, Blan-

chet T, Hopkins B et al. Double-knockout of ADAMTS-4

and ADAMTS-5 in mice results in physiologically normal

animals and prevents the progression of osteoarthritis.

Arthritis Rheum 2007; 56: 3670-3674.

Huang K, Wu LD. Aggrecanase and aggrecan degrada-

tion in osteoarthritis: a review. J Int Med Res 2008; 36:

-1160.

Malfait A-M, Arner EC, Song R-H, Alston JT, Markosyan

S, Staten N et al. Proprotein convertase activation of

aggrecanases in cartilage in situ. Arch Biochem Biophys

; 478: 43-51.

Echtermeyer F, Bertrand J, Dreier R, Meinecke I,

Neugebauer K, Fuerst M et al. Syndecan-4 regulates

ADAMTS-5 activation and cartilage breakdown in os-

teoarthritis. Nature Medicine 2009; 15: 1072-1076.

Miwa HE, Gerken TA, Huynh TD, Duesler LR, Cotter

M, Hering TM. Conserved sequence in the aggrecan

interglobular domain modulates cleavage by ADAMTS-4

and ADAMTS-5. Biochim Biophys Acta 2009; 1790:

-172.

Xu L, Peng H, Glasson SS, Lee PL, Hu K, Ijiri K et al.

Increased expression of the collagen receptor discoidin

domain receptor 2 in articular cartilage as a key event in

the pathogenesis of osteoarthritis. Arthritis Rheum 2007;

: 2663-2673.

Reginato AM, Olsen BR. The role of structural genes in

the pathogenesis of osteoarthritic disorders. Arthritis Res

; 4: 337-345.

van der Kraan PM, Blaney Davidson EN, Blom A, van den

Berg WB. TGF-beta signaling in chondrocyte terminal

differentiation and osteoarthritis: modulation and inte-

gration of signaling pathways through receptor-Smads.

Osteoarthr Cartil 2009; 17: 1539-1545.

Wang M, Shen J, Jin H, Im H-J, Sandy J, Chen D. Re-

cent progress in understanding molecular mechanisms

of cartilage degeneration during osteoarthritis. Ann N Y

Acad Sci 2011; 1240: 61-69.

Scharstuhl A, Glansbeek HL, van Beuningen HM, Vitters

EL, van der Kraan PM, van den Berg WB. Inhibition of

endogenous TGF-beta during experimental osteoarthri-

tis prevents osteophyte formation and impairs cartilage

repair. J Immunol 2002; 169: 507-514.

Archer CW. Skeletal development and osteoarthritis. Ann

Rheum Dis 1994; 53: 624-630.

DeLise AM, Fischer L, Tuan RS. Cellular interactions

and signaling in cartilage development. Osteoarthr Cartil

; 8: 309-334.

Honsawek S, Tanavalee A, Yuktanandana P, Ngarmukos

S, Saetan N, Tantavisut S. Dickkopf-1 (Dkk-1) in plasma

and synovial fl uid is inversely correlated with radiographic

severity of knee osteoarthritis patients. BMC Musculos-

kelet Dis 2010; 11: 257.

Luyten FP, Tylzanowski P, Lories RJ. Wnt signaling and

osteoarthritis. Bone 2009; 44: 522-527.

Aigner T, Gerwin N. Growth plate cartilage as develop-

mental model in osteoarthritis research-potentials and

limitations. Curr Drug Targ 2007; 8: 377-385.

Sandell LJ, Adler P. Developmental patterns of cartilage.

Front Biosci 1999; 4: 731-742.

Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro

A, Karperien M et al. PTH/PTHrP receptor in early de-

velopment and Indian hedgehog-regulated bone growth.

Science 1996; 273: 663-666.

Minina E, Wenzel HM, Kreschel C, Karp S, Gaffi eld W,

McMahon AP et al. BMP and Ihh/PTHrP signaling interact

to coordinate chondrocyte proliferation and differentia-

tion. Development 2001; 128: 4523-4534.

St-Jacques B, Hammerschmidt M, McMahon AP. In-

dian hedgehog signaling regulates proliferation and

differentiation of chondrocytes and is essential for bone

formation. Genes Dev 1999; 13: 2072-2086.

Mak KK, Kronenberg HM, Chuang P-T, Mackem S, Yang

Y. Indian hedgehog signals independently of PTHrP to

promote chondrocyte hypertrophy. Development 2008;

: 1947-1956.

Naski MC, Colvin JS, Coffi n JD, Ornitz DM. Repression

of hedgehog signaling and BMP4 expression in growth

plate cartilage by fi broblast growth factor receptor 3.

Development 1998; 125: 4977-4988.

Decker E, Durand C, Bender S, Rödelsperger C, Glaser

A, Hecht J et al. FGFR3 is a target of the homeobox

transcription factor SHOX in limb development. Hum

Mol Genet 2011; 20: 1524-1535.

Ohbayashi N, Shibayama M, Kurotaki Y, Imanishi M,

Fujimori T, Itoh N et al. FGF18 is required for normal cell

proliferation and differentiation during osteogenesis and

chondrogenesis. Genes Dev 2002; 16: 870-879.

Wang Y, Spatz MK, Kannan K, Hayk H, Avivi A, Gorivod-

sky M et al. A mouse model for achondroplasia produced

by targeting fi broblast growth factor receptor 3. PNAS

USA 1999; 96: 4455-4460.

Wang Q, Green RP, Zhao G, Ornitz DM. Differential

regulation of endochondral bone growth and joint deve-

lopment by FGFR1 and FGFR3 tyrosine kinase domains.

Development 2001; 128: 3867-3876.

Duprez D, Bell EJ, Richardson MK, Archer CW, Wol-

pert L, Brickell PM et al. Overexpression of BMP-2

and BMP-4 alters the size and shape of developing

skeletal elements in the chick limb. Mech Dev 1996;

: 145-157.

Haaijman A, Karperien M, Lanske B, Hendriks J, Löwik

CW, Bronckers AL et al. Inhibition of terminal chondro-

cyte differentiation by bone morphogenetic protein 7

(OP-1) in vitro depends on the periarticular region but

is independent of parathyroid hormone-related peptide.

Bone 1999; 25: 397-404.

Minina E, Wenzel HM, Kreschel C, Karp S, Gaffi eld W,

McMahon AP et al. BMP and Ihh/PTHrP signaling interact

to coordinate chondrocyte proliferation and differentia-

tion. Development 2001; 128: 4523-4534.

Mukherjee A, Rotwein P. Akt promotes BMP2-mediated

osteoblast differentiation and bone development. J Cell

Sci 2009; 122: 716-726.

Sears KE, Behringer RR, Rasweiler JJ, Niswander LA.

Development of bat fl ight: morphologic and molecular

evolution of bat wing digits. PNAS USA 2006; 103: 6581-

Koyama E, Yasuda T, Minugh-Purvis N, Kinumatsu T,

Yallowitz AR, Wellik DM et al. Hox11 genes establish

synovial joint organization and phylogenetic characteris-

tics in developing mouse zeugopod skeletal elements.

Development 2010; 137: 3795-3800.

Salsi V, Vigano MA, Cocchiarella F, Mantovani R, Za-

ppavigna V. Hoxd13 binds in vivo and regulates the

expression of genes acting in key pathways for early limb

and skeletal patterning. Dev Biol 2008; 317: 497-507.

Hérault Y, Beckers J, Gérard M, Duboule D. Hox gene

expression in limbs: colinearity by opposite regulatory

controls Dev Biol 1999; 208: 157-165.

Nowlan NC, Sharpe J, Roddy KA, Prendergast PJ, Mur-

phy P. Mechanobiology of embryonic skeletal develop-

ment: Insights from animal models. Birth Defect Res C

; 90: 203-213.

Montero JA, Hurle JM. Deconstructing digit chondroge-

nesis. Bioessays 2007; 29: 725-737.

Ehlen HWA, Buelens LA, Vortkamp A. Hedgehog signa-

ling in skeletal development. Birth Defect Res C 2006;

: 267-279.

Hartmann C, Tabin CJ. Wnt-14 plays a pivotal role

in inducing synovial joint formation in the developing

appendicular skeleton. Cell 2001; 104: 341-351.

Thomas JT, Lin K, Nandedkar M, Camargo M, Cervenka

J, Luyten FP. A human chondrodysplasia due to a muta-

tion in a TGF-beta superfamily member. Nature Genetics

; 12: 315-317.

Francis-West PH, Parish J, Lee K, Archer CW. BMP/

GDF-signalling interactions during synovial joint deve-

lopment. Cell Tiss Res 1999; 296: 111-119.

Bächner D, Ahrens M, Betat N, Schröder D, Gross G.

Developmental expression analysis of murine autotaxin

(ATX). Mech Dev 1999; 84: 121-125.

Nalin AM, Greenlee TK, Sandell LJ. Collagen gene

expression during development of avian synovial joints:

transient expression of types II and XI collagen genes

in the joint capsule. Dev Dyn 1995; 203: 352-362.

Dowthwaite GP, Edwards JC, Pitsillides AA. An es-

sential role for the interaction between hyaluronan and

hyaluronan binding proteins during joint development. J

Histochem Cytochem 1998; 46: 641-651.

Archer CW, Dowthwaite GP, Francis-West PH. Develo-

pment of synovial joints. Birth Defect Res C 2003; 69:

-155.

Ben-Ari E. Of Joints and Genes. HHMI Bulletin 2003:

-13.

Komori T. Runx2, a multifunctional transcription factor in

skeletal development. J Cell Biochem 2002; 87:1-8.

Stricker S, Fundele R, Vortkamp A, Mundlos S. Role of

Runx genes in chondrocyte differentiation. Dev Biol 2002;

: 95-108.

Yoshida CA, Yamamoto H, Fujita T, Furuichi T, Ito K,

Inoue KI et al. Runx2 and Runx3 are essential for chon-

drocyte maturation, and Runx2 regulates limb growth

through induction of Indian hedgehog. Genes Dev 2004;

: 952-963.

Kwan KM, Pang MK, Zhou S, Cowan SK, Kong RY,

Pfordte T et al. Abnormal compartmentalization of car-

tilage matrix components in mice lacking collagen X:

implications for function. J Cell Biol 1997; 136: 459-471.

Perumal S, Antipova O, Orgel JPRO. Collagen fi bril

architecture, domain organization, and triple-helical

conformation govern its proteolysis. PNAS USA 2008;

: 2824-2829.

Lefebvre V, Smits P. Transcriptional control of chondro-

cyte fate and differentiation. Birth Defects Res C 2005;

: 200-212.

Milz S, Boszczyk A, Putz R. Development and functional

structure of the epiphyseal plate. Der Orthopäde 2002;

:835-840.

Reddi AH. Cartilage morphogenetic proteins: role in joint

development, homoeostasis, and regeneration. Ann

Rheum Dis 2003; 62 (2): 73-78.

Guo X, Mak KK, Taketo MM, Yang Y. The Wnt/beta-

catenin pathway interacts differentially with PTHrP

signaling to control chondrocyte hypertrophy and fi nal

maturation. PLoS ONE 2009; 4: e6067.

Engsig MT, Chen QJ, Vu TH, Pedersen AC, Therkidsen

B, Lund LR et al. Matrix metalloproteinase 9 and vascu-

lar endothelial growth factor are essential for osteoclast

recruitment into developing long bones. J Cell Biol 2000;

: 879-889.

Shum L, Nuckolls G. The life cycle of chondrocytes in

the developing skeleton. Arthr Res 2002; 4: 94-106.

Boyle WJ, Simonet WS, Lacey DL. Osteoclast differen-

tiation and activation. Nature 2003; 423: 337-342.

Funaba M, Ogawa K, Abe M. Expression and localization

of activin receptors during endochondral bone develop-

ment. Eur J Endocrinol 2001; 144: 63-71.

McGlashan SR, Haycraft CJ, Jensen CG, Yoder BK,

Poole CA. Articular cartilage and growth plate defects are

associated with chondrocyte cytoskeletal abnormalities in

Tg737orpk mice lacking the primary cilia protein polaris.

Matrix Biol 2007; 26: 234-246.

Burdan F, Szumiło J, Korobowicz A, Farooquee R, Patel

S, Patel A et al. Morphology and physiology of the epi-

physeal growth plate. Folia Histochem Cytobiol 2009;

: 5-16.

Kobayashi T, Chung UI, Schipani E, Starbuck M, Kar-

senty G, Katagiri T et al. PTHrP and Indian hedgehog

control differentiation of growth plate chondrocytes at

multiple steps. Development 2002; 129: 2977-2986.

Swann DA, Silver FH, Slayter HS, Stafford W, Shore E.

The molecular structure and lubricating activity of lubricin

isolated from bovine and human synovial fl uids. Biochem

J 1985; 225: 195-201.

Jay GD, Torres JR, Warman ML, Laderer MC, Breuer

KS. The role of lubricin in the mechanical behavior of

synovial fl uid. PNAS USA 2007; 104: 6194-6199.

Koyama E, Shibukawa Y, Nagayama M, Sugito H,

Young B, Yuasa T et al. A distinct cohort of progenitor

cells participates in synovial joint and articular cartilage

formation during mouse limb skeletogenesis. Dev Biol

; 316:62-73.

Watanabe H, Yamada Y. Chondrodysplasia of gene

knockout mice for aggrecan and link protein. Glycoconj

J 2002; 19: 269-273.

Knudson W, Loeser RF. CD44 and integrin matrix recep-

tors participate in cartilage homeostasis. Cell Mol Life Sci

; 59: 36-44.

Surmann-Schmitt C, Dietz U, Kireva T, Adam N, Park

J, Tagariello A et al. UCMA, a novel secreted cartilage-

specifi c protein with implications in osteogenesis. J Biol

Chem 2008; 283: 7082-7093.

Eames BF, Schneider RA. The genesis of cartilage size

and shape during development and evolution. Develop-

ment 2008; 135: 3947-3958.

Brunet LJ, McMahon JA, McMahon AP, Harland RM.

Noggin, cartilage morphogenesis, and joint formation in

the mammalian skeleton. Science 1998; 280: 1455-1457.

Garciadiego-Cázares D, Rosales C, Katoh M, Chimal-

Monroy J. Coordination of chondrocyte differentiation and

joint formation by alpha5beta1 integrin in the developing

appendicular skeleton. Development 2004; 131: 4735-

Seemann P, Schwappacher R, Kjaer KW, Krakow D,

Lehmann K, Dawson K et al. Activating and deactivating

mutations in the receptor interaction site of GDF5 cause

symphalangism or brachydactyly type A2. J Clin Invest

; 115: 2373-2381.

van der Kraan PM, van den Berg WB. Chondrocyte

hypertrophy and osteoarthritis: Role in initiation and

progression of cartilage degeneration? Osteoarthr Cartil

; 20: 223-232.

Alliston T, Choy L, Ducy P, Karsenty G, Derynck R. TGF-

beta-induced repression of CBFA1 by Smad3 decreases

cbfa1 and osteocalcin expression and inhibits osteoblast

differentiation. EMBO J 2001; 20: 2254-2272.

Mateescu RG, Todhunter RJ, Lust G, Burton-Wurster

N. Increased MIG-6 mRNA transcripts in osteoarthritic

cartilage. Bioch Biophys Res Com 2005; 332: 482-486.

Zhang Y-W, Su Y, Lanning N, Swiatek PJ, Bronson RT,

Sigler R et al. Targeted disruption of Mig-6 in the mouse

genome leads to early onset degenerative joint disease.

PNAS USA 2005; 102: 11740-11745.

Published

2026-04-08

How to Cite

1.
Garciadiego Cázares D. The development of the skeleton and osteoarthritis. Invest. Discapacidad [Internet]. 2026 Apr. 8 [cited 2026 Apr. 8];1(1):7-17. Available from: https://dsm.inr.gob.mx/indiscap/index.php/INDISCAP/article/view/946

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Evidence synthesis and meta-research

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