Osteoarthritis Pathogenesis: A Review of Molecular Mechanisms

Calcified Tissue International

Volumn 95, Issue 6, 2014, Pages 495-505

  Xia, Bingjiang ^a,b   Di Chen, ^b,c   Zhang, Jushi ^a,b   Hu, Songfeng ^a,b   Jin, Hongting ^b,d   Tong, Peijian ^b,d  

^a Traditional Chinese Medicine Hospital of Zhejiang Shaoxing   (China)

^b ZHEJIANG CHINESE MEDICAL UNIVERSITY   (China)

^c RUSH UNIVERSITY MEDICAL CENTER   (United States)

^d Institute of Orthopaedics and Traumatology of Zhejiang Province   (China)

Author keywords

Molecular mechanisms; Osteoarthritis; Potential therapeutic approches

Indexed keywords

AGGRECANASE 1; AGGRECANASE 2; BETA CATENIN; COLLAGENASE 3; FIBROBLAST GROWTH FACTOR 18; FIBROBLAST GROWTH FACTOR 2; GROWTH DIFFERENTIATION FACTOR 5; HYPOXIA INDUCIBLE FACTOR 2ALPHA; PARATHYROID HORMONE RELATED PROTEIN; SONIC HEDGEHOG PROTEIN; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEIN;

ARTICULAR CARTILAGE; CARTILAGE CELL; CARTILAGE DEGENERATION; CARTILAGE MATRIX; CELL DIFFERENTIATION; CELL MATURATION; DISEASE COURSE; ENCHONDRAL OSSIFICATION; HUMAN; JOINT PROSTHESIS; MOLECULAR PATHOLOGY; OSTEOARTHRITIS; PREVALENCE; REGULATORY MECHANISM; REVIEW; AGED; ANIMAL; PATHOLOGY; PATHOPHYSIOLOGY;

AGED; ANIMALS; HUMANS; OSTEOARTHRITIS;

EID: 84919448436     PISSN: 0171967X     EISSN: 14320827     Source Type: Journal    
DOI: 10.1007/s00223-014-9917-9     Document Type: Review

References (157)

1. Dahaghin S, Bierma-Zeinstra SM, Ginai AZ et al (2005) Prevalence and pattern of radiographic hand osteoarthritis and association with pain and disability. Ann Rheum Dis 64:682–687
2. Oliveria SA, Felson DT, Reed JI et al (1995) Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization. Arthritis Rheum 38:1134–1141
3. Dillon CF, Rasch EK, Gu Q et al (2006) Prevalence of knee osteoarthritis in the United States: arthritis data from the Third National Health and Nutrition Examination Surgery 1991–94. J Rheumatol 33:2271–2279
4. Felson DT (1988) Epidemiology of hip and knee osteoarthritis. Epidemiol Rev 10:1–28
5. March LM, Bachmeier CJ (1997) Economics of osteoarthritis: a global perspective. Baillieres Clin Rheumatol 11:817–834
6. Rai MF, Sandell LJ (2011) Inflammatory mediators: tracing links between obesity and osteoarthritis. Crit Rev Eukaryot Gene Expr 21:131–142
7. Mobasheri A (2012) Osteoarthritis year 2012 in review: biomarkers. Osteoarthr Cartil 20(12):1451–1464
8. Felson DT (2006) Osteoarthritis of the knee. NEJM 354:841–848
9. Goldring MB, Goldring SR (2007) Osteoarthritis. J Cel Physiol 213:626–634
10. Ettinger WH Jr, Burns R, Messier SP et al (1997) A randomized trial comparing aerobic exercise and resistance exercise with a health education program in older adults with knee osteoarthritis: the fitness arthritis and seniors trial (FAST). JAMA 277:25–31
11. Messier SP, Loeser RF, Miller GD et al (2004) Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the arthritis, diet, and activity promotion trial. Arthritis Rheum 50:1501–1510
12. Berman BM, Lao L, Langenberg P et al (2004) Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial. Ann Intern Med 141:901–910
13. Bottegoni C, Muzzarelli RA, Giovannini F et al (2014) Oral chondroprotection with nutraceuticals made of chondroitin sulphate plus glucosamine sulphate in osteoarthritis. Carbohydr Polym 109:126–138
14. Leopold SS (2009) Minimally invasive total knee arthroplasty for osteoarthritis. N Engl J Med 360:1749–1758
15. Krasonkutsky S, Samuels J, Abramson SB (2007) Osteoarthritis in 2007. Bull NYU Hosp Jt Dis 65:222–228
16. Buckwalter JA, Saltzman C, Brown T (2004) The impact of osteoarthritis: implications for research. Clin Orthop Relat Res 427:S6–S15
17. Jackson A, Gu W (2009) Transport properties of cartilaginous tissues. Curr Rheumatol Rev 5:40
18. Eyre DR, Wu JJ, Fermandes RJ et al (2002) Recent developments in cartilage research: matrix biology of the collagen II/IX/XI heterofibril network. Biochem Soc Trans 30:893–899
19. Knudson CB, Knudson W (2001) Cartilage proteoglycans. Semin Cell Dev Biol 12:69–78
20. Woods A, Wang G, Beier F (2007) Regulation of chondrocyte differentiation by the actin cytoskeleton and adhesive interactions. J Cell Physiol 213:1–8
21. Goldring MB, Marcu KB (2009) Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther 11:224
22. Kannu P, Bateman JF, Belluoccio D (2009) Employing molecular genetics of chondrodysplasias to inform the study of osteoarthritis. Arthritis Rheum 60:325–334
23. Iozzo RV (2000) Proteoglycans: structure, biology and molecular interactions, 1st edn. Thomas Jefferson University, Jefferson Medical College, Philadelphia
24. Verzijl N, DeGroot J, Thorpe SR (2000) Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 275:39027–39031
25. Pacifici M, Koyama E, Iwamoto M (2005) Mechanisms of synovial joint and articular cartilage formation: recent advances, but many lingering mysteries. Birth Defects Res 75:237–248
26. Goldring MB, Goldring SR (2010) Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann NY Acad Sci 1192:230–237
27. Mort JS, Billington CJ (2001) Articular cartilage and changes in arthritis matrix degradation. Arthritis Res 3:337–341
28. Ding CH, Martel-Pelletier J, Pelletier JP et al (2007) Meniscal tear as an osteoarthritis risk factor in a largely non-osteoarthritic cohort: a cross-sectional study. J Rheumatol 34:776–784
29. Hunter DJ, Zhang YQ, Niu JB et al (2006) The association of meniscal pathologic changes with cartilage loss in symptomatic knee osteoarthritis. Arthritis Rheum 54:795–801
30. Clements KM, Price JS, Chambers MG et al (2003) Gene deletion of either interleukin-1beta, interleukin-1beta-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transaction of the medial collateral ligament and partial medial meniscectomy. Arthritis Rheum 48:3452–3463
31. Li Y, Xu L, Olsen BR (2007) Lessons from genetic forms of osteoarthritis for the pathogenesis of the disease. Osteoarthr Cartil 15:1101–1105
32. Kannu P, Bateman JF, Belluoccio D et al (2009) Employing molecular genetics of chondrodysplasias to inform the study of osteoarthritis. Arthritis Rheum 60:325–334
33. Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat Inflamm 2014:561459
34. van der Kraan PM, Goumans MJ, Blaney Davidson E et al (2012) Age-dependent alteration of TGF-β signalling in osteoarthritis. Cell Tissue Res 347:257–265
35. Kolpakova E, Olsen BR (2005) Wnt/beta-catenin-a canonical tale of cell-fate choice in the vertebrate skeleton. Dev Cell 8:626–627
36. Komori T (2003) Requisite roles of Runx2 and Cbfb in skeletal development. J Bone Miner Metab 21:193–197
37. Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423:332–336
38. Degnin CR, Laederich MB, Horton WA (2010) FGFs in endochondral skeletal development. J Cell Biochem 110:1046–1057
39. Schmidt MB, Chen EH, Lynch SE (2006) A review of the effects of insulin-like growth factor and platelet derived growth factor on in vivo cartilage healing and repair. Osteoarthr Cartil 14:403–412
40. Blaney Davidson EN, Vitters EL, van der Kraan PM et al (2006) Expression of transforming growth factor-β (TGF-β) and the TGF-β signalling molecule SMAD-2P in spontaneous and instability-induced osteoarthritis: role in cartilage degradation, chondrogenesis and osteophyte formation. Ann Rheum Dis 65:1414–1421
41. Miyazawa K, Shinozaka M, Hara T et al (2002) Two major Smad pathways in TFG-β superfamily signaling. Genes Cells 7:1191–1204
42. Nicole D, Kerstin K (2000) Targeted mutations of transforming growth factor-β genes reveal important roles in mouse development and adult homeostasis. Eur J Bioche 267:6982–6988
43. Serra R, Johnson M, Filvaroff EH et al (1997) Expression of a truncated, kinase-defective TGF-b type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol 139:541–552
44. Yang X, Chen L, Xu X et al (2001) TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 153:35–46
45. Chen M, Lichtler AC, Sheu T et al (2007) Generation of a transgenic mouse model with chondrocyte-specific and tamoxifen-inducible expression of Cre recombinase. Genesis 45:44–50
46. Zhu M, Chen M, Lichlter AC et al (2008) Tamoxifen-inducible Cre-recombination in articular chondrocytes of adult Col2a1-CreERT2 transgenic mice. Osteoarthr Cartil 16:129–130
47. Shen J, Li J, Wang B et al (2013) Deletion of the transforming growth factor β receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis Rheum 65:3107–3119
48. Valdes AM, Spector TD, Tamm A et al (2010) Genetic variation in the smad3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 62:2347–2352
49. Zhen G, Wen C, Jia X et al (2013) Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 19:704–712
50. Blaney Davidson EN, van der Kraan PM, van den Berg WB (2007) TGF-beta and osteoarthritis. Osteoarthritis Cartilage 15:597–604
51. Fortier LA, Barker JU, Strauss EJ et al (2011) The role of growth factors in cartilage repair. Clin Orthop Relat Res 469:2706–2715
52. Chia SL, Sawaji Y, Burleigh A et al (2009) Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis Rheum 60:2019–2027
53. Cucchiarini M, Terwilliger EF, Kohn D et al (2009) Remodelling of human osteoarthritic cartilage by FGF-2, alone or combined with Sox9 via rAAV gene transfer. J Cell Mol Med 13:2476–2488
54. Li X, Ellman MB, Kroin JS et al (2012) Species-specific biological effects of FGF-2 in articular cartilage: implication for distinct roles within the FGF receptor family. J Cell Biochem 113:2532–2542
55. Im HJ, Muddasani P, Natarajan V et al (2007) Basic fibroblast growth factor stimulates matrix metalloproteinase-13 via the molecular cross-talk between the mitogen-activated protein kinases and protein kinase c pathways in human adult articular chondrocytes. J Biol Chem 282:11110–11121
56. Ellman MB, An HS, Muddasani P et al (2008) Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis. Gene 420:82–89
57. Ellman M, Kim J, An H et al (2011) The pathophysiological role of the PKCδ pathway in the intervertebral disc: in vitro, ex vivo and in vivo studies. Arthritis Rheum 64:1950–1959
58. Yan D, Chen D, Im HJ (2012) Fibroblast growth factor-2 promotes catabolism via FGFR1–Ras–Raf–MEK1/2–ERK1/2 axis that coordinates with the PKCδ pathway in human articular chondrocytes. J Cell Biochem 113:2856–2865
59. Andrew SL, Michael BE, Dongyao Y et al (2013) A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 527:440–447
60. Maruoka Y, Ohbayashi N, Hoshikawa M et al (1998) Comparison of the expression of three highly related genes, Fgf8, Fgf17 and Fgf18, in the mouse embryo. Mech Dev 74:175–177
61. Usui H, Shibayama M, Ohbayashi N et al (2004) FGF18 is required for embryonic lung alveolar development. Biochem Biophys Res Comm 322:887–892
62. Davidson D, Blanc A, Filion D (2005) Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J Biol Chem 280:20509–20515
63. Liu Z, Lavine KJ, Hung IH et al (2007) FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev Biol 302:80–91
64. Carli A, Gao C, Khayyat-Kholghi M et al (2012) FGF 18 augments osseointegration of intra-medullary implants in osteopenic FGFR3(−/−) mice. Eur Cell Mater 24:116–117
65. Moore EE, Bendele AM, Thompson DL et al (2005) Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 13:623–631
66. Power J, Hernandez P, Guehring H et al (2014) Intraarticular injection of rhFGF-18 improves the healing in microfracture treated chondral defects in an ovine model. J Orthop Res 32:669–676
67. Barr L, Getgood A, Guehring H et al (2014) The effect of recombinant human fibroblast growth factor-18 on articular cartilage following single impact load. J Orthop Res 32:923–927
68. Geetha-Loganathan P, Nimmagadda S, Scaal M (2008) Wnt signaling in limb organogenesis. Organogenesis 4:109–115
69. Loughlin J, Mustafa Z, Smith A et al (2000) Linkage analysis of chromosome 2q in osteoarthritis. Rheumatology 39:377–381
70. Loughlin J, Dowling B, Chapman K et al (2004) Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci USA 101:9757–9762
71. Valdes AM, Doherty S, Muir KR et al (2012) Genetic contribution to radiographic severity in osteoarthritis of the knee. Ann Rheum Dis 71:1537–1540
72. Min JL, Meulenbelt I, Riyazi N et al (2005) Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis Rheum 52:1077–1080
73. Lories RJ, Peeters J, Bakker A et al (2007) Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 56:4095–4103
74. Lodewyckx L, Cailotto F, Thysen S et al (2012) Tight regulation of wingless-type signaling in the articular cartilage subchondral bone biomechanical unit: transcriptomics in Frzb-knockout mice. Arthritis Res Ther 14:R16
75. Zhu M, Tang D, Wu Q et al (2009) Activation of β-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult β-catenin conditional activation mice. J Bone Miner Res 24:12–21
76. Wu Q, Huang JH, Sampson ER et al (2009) Smurf2 induces degradation of GSK-3β and upregulates β-catenin in chondrocytes: a potential mechanism for Smurf2-induced degeneration of articular cartilage. Exp Cell Res 315:2386–2398
77. Blom AB, Brockbank SM, van Lent PL et al (2009) Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum 60:501–512
78. Zhu M, Chen M, Zuscik M et al (2008) Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum 58:2053–2064
79. Alcaraz MJ, Megías J, García-Arnandis I et al (2010) New molecular targets for the treatment of osteoarthritis. Biochem Pharmacol 80:13–21
80. Huang SM, Mishina YM, Liu S et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461:614–620
81. Lane NE, Nevitt MC, Lui LY et al (2007) Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women. Arthritis Rheum 56:3319–3325
82. Diarra D, Stolina M, Polzer K et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163
83. Tamamura Y, Otani T, Kanatani N et al (2005) Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem 280:19185–19195
84. Lin AC, Seeto BL, Bartoszko JM et al (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15:1421–1426
85. Mak KK, Kronenberg HM, Chuang P-T et al (2008) Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 135:1947–1956
86. Beaupre GS, Stevens SS, Carter DR (2000) Mechanobiology in the development, maintenance, and degeneration of articular cartilage. J Rehabil Res Dev 37:145–151
87. Lin AC, Seeto BL, Bartoszko JM et al (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15:1421–1425
88. Ushijima Takahiro, Okazaki Ken, Tsushima Hidetoshi et al (2014) CCAAT/enhancer binding protein β regulates expression of Indian Hedgehog during chondrocytes differentiation. PLoS ONE 9:e104547
89. Zhou J, Wei X, Wei L (2014) Indian Hedgehog, a critical modulator in osteoarthritis, could be a potential therapeutic target for attenuating cartilage degeneration disease. Connect Tissue Res 55:257–261
90. Semenza GL (2011) Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb Symp Quant Biol 76:347–353
91. Lando D, Peet DJ, Whelan DA et al (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295:858–861
92. Bracken CP, Whitelaw ML, Peet DJ (2003) The hypoxia-inducible factors: key transcriptional regulators of hypoxic responses. Cell Mol Life Sci 60:1376–1393
93. Kiss J, Kirchberg J, Schneider M (2012) Molecular oxygen sensing: implications for visceral surgery. Langenbecks Arch Surg 397(4):603–610
94. Duval E, Leclercq S, Elissalde JM et al (2009) Hypoxia-inducible factor 1alpha inhibits the fibroblast-like markers type I and type III collagen during hypoxia-induced chondrocyte redifferentiation: hypoxia not only induces type II collagen and aggrecan, but it also inhibits type I and type III collagen in the hypoxia-inducible factor 1 alpha-dependent redifferentiation of chondrocytes. Arthritis Rheum 60:3038–3048
95. Pfander D, Cramer T, Schipani E et al (2003) HIF-1alpha controls extracellular matrix synthesis by epiphyseal chondrocytes. J Cell Sci 116:1819–1826
96. Saito T, Fukai A, Mabuchi A et al (2010) Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med 16:678–686
97. Yang S, Kim J, Ryu JH et al (2010) Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 16:687–693
98. Muraki S, Oka H, Akune T et al (2009) Prevalence of radiographic knee osteoarthritis and its association with knee pain in the elderly of Japanese population-based cohorts: the ROAD study. Osteoarthr Cartil 17:1137–1143
99. Lafont JE, Talma S, Murphy CL (2007) Hypoxia-inducible factor 2alpha is essential for hypoxic induction of the human articular chondrocyte phenotype. Arthritis Rheum 56:3297–3306
100. Lafont JE, Talma S, Hopfgarten C et al (2008) Hypoxia promotes the differentiated human articular chondrocyte phenotype through SOX9-dependent and -independent pathways. J Biol Chem 283:4778–4786
101. Domm C, Schunke M, Christesen K et al (2002) Redifferentiation of dedifferentiated bovine articular chondrocytes in alginate culture under low oxygen tension. Osteoarthr Cartil 10:13–22
102. Khan WS, Adesida AB, Hardingham TE (2007) Hypoxic conditions increase hypoxia-inducible transcription factor 2alpha and enhance chondrogenesis in stem cells from the infrapatellar fat pad of osteoarthritis patients. Arthritis Res Ther 9:R55
103. van den Berg WB (2011) Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthr Cartil 19:338–341
104. Wang M, Shen J, Jin H et al (2011) Recent progress in understanding molecular mechanisms of cartilage degeneration during osteoarthritis. Ann NY Acad Sci 1240:61–69
105. Buxton P, Edwards C, Archer CW et al (2001) Growth/differentiation factor-5 (GDF-5) and skeletal development. J Bone Joint Surg Am 83:23–30
106. Francis-West PH, Abdelfattah A, Chen P et al (1999) Mechanisms of GDF-5 action during skeletal development. Development 126:1305–1315
107. Nishitoh H, Ichijo H, Kimura M (1996) Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5. J Biol Chem 271:21345–21352
108. Mikic B, Battaglia TC, Taylor EA (2002) The effect of growth/differentiation factor-5 deficiency on femoral composition and mechanical behavior in mice. Bone 30:733–737
109. Masuya H, Nishida K, Furuichi T et al (2007) A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice. Hum Mol Genet 16:2366–2375
110. Chhabra A, Tsou D, Clark RT et al (2003) GDF-5 deficiency in mice delays Achilles tendon healing. J Orthop Res 21:826–835
111. Harada M, Takahara M, Zhe P et al (2007) Developmental failure of the intra-articular ligaments in mice with absence of growth differentiation factor 5. Osteoarthr Cartil 15:468–474
112. Nickel J, Kotzsch A, Sebald W (2005) A single residue of GDF-5 defines binding specificity to BMP receptor IB. J Mol Biol 349:933–947
113. Byrnes AM, Racacho L, Nikkel SM et al (2010) Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat 31:1155–1162
114. Miyamoto Y, Mabuchi A, Shi D et al (2007) A functional polymorphism in the 5′-UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat Genet 39:529–533
115. Byrnes AM, Racacho L, Nikkel SM et al (2010) Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat 31:1155–1162
116. Egli R, Southam L, Wilkins JM et al (2009) Functional analysis of the osteoarthritis susceptibility-associated GDF5 regulatory polymorphism. Arthritis Rheum 60:2055–2064
117. Tsezou A, Satra M, Oikonomou P et al (2008) The growth differentiation factor 5 (GDF5) core promoter polymorphism is not associated with knee osteoarthritis in the Greek population. J Orthop Res 26:136–140
118. Storm EE, Huynh TV, Copeland NG et al (1994) Limb alterations in brachypodism mice due to mutations in a new member of the TGFb-superfamily. Nature 368:639–643
119. Takahara M, Harada M, Guan D et al (2004) Developmental failure of phalanges in the absence of growth/differentiation factor 5. Bone 35:1069–1076
120. Daans M, Luyten FP, Lories RJ (2011) GDF5 deficiency in mice is associated with instability-driven joint damage, gait and subchondral bone changes. Ann Rheum Dis 70:208–213
121. Mikic B, Clark RT, Battaglia TC (2004) Altered hypertrophic chondrocyte kinetics in GDF-5 deficient murine tibial growth plates. J Orthop Res 22:552–556
122. Bobacz K, Gruber R, Soleiman A et al (2002) Cartilage-derived morphogenetic protein-1 and -2 are endogenously expressed in healthy and osteoarthritic human articular chondrocytes and stimulate matrix synthesis. Osteoarthr Cartil 10:394–401
123. Chubinskaya S, Segalite D, Pikovsky D et al (2008) Effects induced by BMPs in cultures of human articular chondrocytes: comparative studies. Growth Factors 26:275–283
124. Ratnayake M, Plöger F, Santibanez-Koref M et al (2014) Human chondrocytes respond discordantly to the protein encoded by the osteoarthritis susceptibility gene GDF5. PLoS ONE 9:e86590
125. Borden P, Heller RA (1997) Transcriptional control of matrix metalloproteinases and the tissue inhibitors of matrix metalloproteinases. Crit Rev Eukaryot Gene Expr 7:159–178
126. Mengshol JA, Vincenti MP, Coon CI (2000) Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor kappaB: differential regulation of collagenase 1 and collagenase 3. Arthritis Rheum 43:801–811
127. Vincenti MP, Coon CI, Mengshol JA et al (1998) Cloning of the gene for interstitial collagenase-3 (matrix metalloproteinase-13) from rabbit synovial fibroblasts: differential expression with collagenase-1 (matrix metalloproteinase-1). Biochem J 331:341–346
128. Vincenti MP (2001) The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol 151:121–148
129. Shiomi T, Lemaître V, D’Armiento J et al (2010) Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases. Pathol Int 60:477–496
130. Knäuper V, Lopez Otin C, Smith B, Knight G (1996) Biochemical characterization of human collagenase-3. J Biol Chem 271:1544–1550
131. Walling HW, Raggatt LJ, Irvine DW et al (2003) Impairment of the collagenase-3 endocytotic receptor system in cells from patients with osteoarthritis. Osteoarthr Cartil 11:854–863
132. Roach HI, Yamada N, Cheung KS et al (2005) Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions. Arthritis Rheum 52:3110–3124
133. Inada M, Wang Y, Byrne MH et al (2004) Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci USA 101:17192–17197
134. Stickens D, Behonick DJ, Ortega N et al (2004) Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131:5883–5895
135. Neuhold LA, Killar L, Zhao W et al (2001) Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Investig 107:35–44
136. Little CB, Barai A, Burkhardt D et al (2009) Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 60:3723–3733
137. Glasson SS, Askew R, Sheppard B et al (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644–648
138. Majumdar MK, Askew R, Schelling S et al (2007) Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis. Arthritis Rheum 56:3670–3674
139. Stanton H, Rogerson FM, East CJ et al (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434:648–652
140. Stetler Stevenson WG, Seo DW (2005) TIMP-2: an endogenous inhibitor of angiogenesis. Trends in molecular medicine 11:97–103
141. Wang M, Sampson ER, Jin H et al (2013) MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther 15:R5
142. Enomoto H, Enomoto Iwamoto M, Iwamoto M et al (2000) Cbfa1 is a positive regulatory factor in chondrocyte maturation. J Biol Chem 275:8695–8702
143. Inada M, Yasui T, Nomura S et al (1999) Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn 214:279–290
144. Komori T, Yagi H, Nomura S et al (1997) Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764
145. Kim HJ, Kim JH, Bae SC et al (2003) The protein kinase C pathway plays a central role in the fibroblast growth factorstimulated expression and transactivation activity of Runx2. J Biol Chem 278:319–326
146. Takamoto M, Tsuji K, Yamashita T et al (2003) Hedgehog signaling enhances core-binding factor a1 and receptor activator of nuclear factor-kappaB ligand (RANKL) gene expression in chondrocytes. J Endocrinol 177:413–421
147. Tou L, Quibria N, Alexander JM (2001) Regulation of human cbfa1 gene transcription in osteoblasts by selective estrogen receptor modulators (SERMs). Mol Cell Endocrinol 183:71–79
148. Zhou YX, Xu X, Chen L et al (2000) A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. Hum Mol Genet 9:2001–2008
149. Zhao M, Qiao M, Harris SE et al (2003) E3 ubiquitin ligase Smurf1 mediates core-binding factor alpha 1/Runx2 degradation and plays a specific role in osteoblast differentiation. J Biol Chem 278:27939–27944
150. Zhao M, Qiao M, Harris SE et al (2004) Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. J Biol Chem 279:12854–12859
151. Shen R, Chen M, Wang YJ et al (2006) Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. J Biol Chem 281:3569–3576
152. Shen R, Wang X, Drissi H et al (2006) Cyclin D1-cdk4 induce runx2 ubiquitination and degradation. J Biol Chem 281:16347–16353
153. Jeon EJ, Lee KY, Choi NS et al (2006) Bone morphogenetic protein-2 stimulates Runx2 acetylation. J Biol Chem 281:16502–16511
154. Jonason JH, Xiao G, Zhang M et al (2009) Post-transcriptional regulation of runx2 in bone and cartilage. J Dent Res 88:693–703
155. Akhtar N, Rasheed Z, Ramamurthy S et al (2010) MicroRNA-27b regulates the expression of MMP-13 in human osteoarthritis chondrocytes. Arthritis Rheum 62:1361–1371
156. Miyaki S, Nakasa T, Otsuki S et al (2009) MicroRNA-140 is expressed in differentiated human articular chondrocytes and modulates interleukin-1 responses. Arthritis Rheum 60:2723–2730
157. Yamasaki K, Nakasa T, Miyaki S et al (2009) Expression of microRNA-146a in osteoarthritis cartilage. Arthritis Rheum 60:1035–1041