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Published in: Calcified Tissue International 6/2014

01-12-2014 | Review

Osteoarthritis Pathogenesis: A Review of Molecular Mechanisms

Authors: Bingjiang Xia, Di Chen, Jushi Zhang, Songfeng Hu, Hongting Jin, Peijian Tong

Published in: Calcified Tissue International | Issue 6/2014

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Abstract

Osteoarthritis (OA), the most prevalent chronic joint disease, increases in prevalence with age, and affects majority of individuals over the age of 65 and is a leading musculoskeletal cause of impaired mobility in the elderly. Because the precise molecular mechanisms which are involved in the degradation of cartilage matrix and development of OA are poorly understood and there are currently no effective interventions to decelerate the progression of OA or retard the irreversible degradation of cartilage except for total joint replacement surgery. In this paper, the important molecular mechanisms related to OA pathogenesis will be summarized and new insights into potential molecular targets for the prevention and treatment of OA will be provided.
Literature
1.
go back to reference 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 64:682–687PubMedCentralPubMed 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 64:682–687PubMedCentralPubMed
2.
go back to reference 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 38:1134–1141PubMed 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 38:1134–1141PubMed
3.
go back to reference 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 33:2271–2279PubMed 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 33:2271–2279PubMed
4.
go back to reference Felson DT (1988) Epidemiology of hip and knee osteoarthritis. Epidemiol Rev 10:1–28PubMed Felson DT (1988) Epidemiology of hip and knee osteoarthritis. Epidemiol Rev 10:1–28PubMed
5.
go back to reference March LM, Bachmeier CJ (1997) Economics of osteoarthritis: a global perspective. Baillieres Clin Rheumatol 11:817–834PubMed March LM, Bachmeier CJ (1997) Economics of osteoarthritis: a global perspective. Baillieres Clin Rheumatol 11:817–834PubMed
6.
go back to reference Rai MF, Sandell LJ (2011) Inflammatory mediators: tracing links between obesity and osteoarthritis. Crit Rev Eukaryot Gene Expr 21:131–142PubMed Rai MF, Sandell LJ (2011) Inflammatory mediators: tracing links between obesity and osteoarthritis. Crit Rev Eukaryot Gene Expr 21:131–142PubMed
7.
go back to reference Mobasheri A (2012) Osteoarthritis year 2012 in review: biomarkers. Osteoarthr Cartil 20(12):1451–1464PubMed Mobasheri A (2012) Osteoarthritis year 2012 in review: biomarkers. Osteoarthr Cartil 20(12):1451–1464PubMed
8.
9.
go back to reference Goldring MB, Goldring SR (2007) Osteoarthritis. J Cel Physiol 213:626–634 Goldring MB, Goldring SR (2007) Osteoarthritis. J Cel Physiol 213:626–634
10.
go back to reference 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 277:25–31PubMed 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 277:25–31PubMed
11.
go back to reference 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 50:1501–1510PubMed 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 50:1501–1510PubMed
12.
go back to reference 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 141:901–910PubMed 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 141:901–910PubMed
13.
go back to reference Bottegoni C, Muzzarelli RA, Giovannini F et al (2014) Oral chondroprotection with nutraceuticals made of chondroitin sulphate plus glucosamine sulphate in osteoarthritis. Carbohydr Polym 109:126–138PubMed Bottegoni C, Muzzarelli RA, Giovannini F et al (2014) Oral chondroprotection with nutraceuticals made of chondroitin sulphate plus glucosamine sulphate in osteoarthritis. Carbohydr Polym 109:126–138PubMed
14.
go back to reference Leopold SS (2009) Minimally invasive total knee arthroplasty for osteoarthritis. N Engl J Med 360:1749–1758PubMed Leopold SS (2009) Minimally invasive total knee arthroplasty for osteoarthritis. N Engl J Med 360:1749–1758PubMed
15.
go back to reference Krasonkutsky S, Samuels J, Abramson SB (2007) Osteoarthritis in 2007. Bull NYU Hosp Jt Dis 65:222–228 Krasonkutsky S, Samuels J, Abramson SB (2007) Osteoarthritis in 2007. Bull NYU Hosp Jt Dis 65:222–228
16.
go back to reference Buckwalter JA, Saltzman C, Brown T (2004) The impact of osteoarthritis: implications for research. Clin Orthop Relat Res 427:S6–S15PubMed Buckwalter JA, Saltzman C, Brown T (2004) The impact of osteoarthritis: implications for research. Clin Orthop Relat Res 427:S6–S15PubMed
18.
go back to reference 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 30:893–899PubMed 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 30:893–899PubMed
19.
go back to reference Knudson CB, Knudson W (2001) Cartilage proteoglycans. Semin Cell Dev Biol 12:69–78PubMed Knudson CB, Knudson W (2001) Cartilage proteoglycans. Semin Cell Dev Biol 12:69–78PubMed
20.
go back to reference Woods A, Wang G, Beier F (2007) Regulation of chondrocyte differentiation by the actin cytoskeleton and adhesive interactions. J Cell Physiol 213:1–8PubMed Woods A, Wang G, Beier F (2007) Regulation of chondrocyte differentiation by the actin cytoskeleton and adhesive interactions. J Cell Physiol 213:1–8PubMed
21.
22.
go back to reference Kannu P, Bateman JF, Belluoccio D (2009) Employing molecular genetics of chondrodysplasias to inform the study of osteoarthritis. Arthritis Rheum 60:325–334PubMed Kannu P, Bateman JF, Belluoccio D (2009) Employing molecular genetics of chondrodysplasias to inform the study of osteoarthritis. Arthritis Rheum 60:325–334PubMed
23.
go back to reference Iozzo RV (2000) Proteoglycans: structure, biology and molecular interactions, 1st edn. Thomas Jefferson University, Jefferson Medical College, Philadelphia Iozzo RV (2000) Proteoglycans: structure, biology and molecular interactions, 1st edn. Thomas Jefferson University, Jefferson Medical College, Philadelphia
24.
go back to reference Verzijl N, DeGroot J, Thorpe SR (2000) Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 275:39027–39031PubMed Verzijl N, DeGroot J, Thorpe SR (2000) Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 275:39027–39031PubMed
25.
go back to reference 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 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.
go back to reference Goldring MB, Goldring SR (2010) Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann NY Acad Sci 1192:230–237PubMed Goldring MB, Goldring SR (2010) Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann NY Acad Sci 1192:230–237PubMed
27.
go back to reference Mort JS, Billington CJ (2001) Articular cartilage and changes in arthritis matrix degradation. Arthritis Res 3:337–341PubMedCentralPubMed Mort JS, Billington CJ (2001) Articular cartilage and changes in arthritis matrix degradation. Arthritis Res 3:337–341PubMedCentralPubMed
28.
go back to reference 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 34:776–784PubMed 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 34:776–784PubMed
29.
go back to reference Hunter DJ, Zhang YQ, Niu JB et al (2006) The association of meniscal pathologic changes with cartilage loss in symptomatic knee osteoarthritis. Arthritis Rheum 54:795–801PubMed Hunter DJ, Zhang YQ, Niu JB et al (2006) The association of meniscal pathologic changes with cartilage loss in symptomatic knee osteoarthritis. Arthritis Rheum 54:795–801PubMed
30.
go back to reference 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 48:3452–3463PubMed 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 48:3452–3463PubMed
31.
go back to reference Li Y, Xu L, Olsen BR (2007) Lessons from genetic forms of osteoarthritis for the pathogenesis of the disease. Osteoarthr Cartil 15:1101–1105PubMedCentralPubMed Li Y, Xu L, Olsen BR (2007) Lessons from genetic forms of osteoarthritis for the pathogenesis of the disease. Osteoarthr Cartil 15:1101–1105PubMedCentralPubMed
32.
go back to reference Kannu P, Bateman JF, Belluoccio D et al (2009) Employing molecular genetics of chondrodysplasias to inform the study of osteoarthritis. Arthritis Rheum 60:325–334PubMed Kannu P, Bateman JF, Belluoccio D et al (2009) Employing molecular genetics of chondrodysplasias to inform the study of osteoarthritis. Arthritis Rheum 60:325–334PubMed
33.
go back to reference Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat Inflamm 2014:561459 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.
go back to reference van der Kraan PM, Goumans MJ, Blaney Davidson E et al (2012) Age-dependent alteration of TGF-β signalling in osteoarthritis. Cell Tissue Res 347:257–265PubMedCentralPubMed van der Kraan PM, Goumans MJ, Blaney Davidson E et al (2012) Age-dependent alteration of TGF-β signalling in osteoarthritis. Cell Tissue Res 347:257–265PubMedCentralPubMed
35.
go back to reference Kolpakova E, Olsen BR (2005) Wnt/beta-catenin-a canonical tale of cell-fate choice in the vertebrate skeleton. Dev Cell 8:626–627PubMed Kolpakova E, Olsen BR (2005) Wnt/beta-catenin-a canonical tale of cell-fate choice in the vertebrate skeleton. Dev Cell 8:626–627PubMed
36.
go back to reference Komori T (2003) Requisite roles of Runx2 and Cbfb in skeletal development. J Bone Miner Metab 21:193–197PubMed Komori T (2003) Requisite roles of Runx2 and Cbfb in skeletal development. J Bone Miner Metab 21:193–197PubMed
37.
go back to reference Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423:332–336PubMed Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423:332–336PubMed
38.
go back to reference Degnin CR, Laederich MB, Horton WA (2010) FGFs in endochondral skeletal development. J Cell Biochem 110:1046–1057PubMed Degnin CR, Laederich MB, Horton WA (2010) FGFs in endochondral skeletal development. J Cell Biochem 110:1046–1057PubMed
39.
go back to reference 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 14:403–412PubMed 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 14:403–412PubMed
40.
go back to reference 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 65:1414–1421PubMed 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 65:1414–1421PubMed
41.
go back to reference Miyazawa K, Shinozaka M, Hara T et al (2002) Two major Smad pathways in TFG-β superfamily signaling. Genes Cells 7:1191–1204PubMed Miyazawa K, Shinozaka M, Hara T et al (2002) Two major Smad pathways in TFG-β superfamily signaling. Genes Cells 7:1191–1204PubMed
42.
go back to reference 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 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.
go back to reference 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 139:541–552PubMedCentralPubMed 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 139:541–552PubMedCentralPubMed
44.
go back to reference 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 153:35–46PubMedCentralPubMed 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 153:35–46PubMedCentralPubMed
45.
go back to reference 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 45:44–50PubMedCentralPubMed 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 45:44–50PubMedCentralPubMed
46.
go back to reference Zhu M, Chen M, Lichlter AC et al (2008) Tamoxifen-inducible Cre-recombination in articular chondrocytes of adult Col2a1-CreERT2 transgenic mice. Osteoarthr Cartil 16:129–130PubMedCentralPubMed Zhu M, Chen M, Lichlter AC et al (2008) Tamoxifen-inducible Cre-recombination in articular chondrocytes of adult Col2a1-CreERT2 transgenic mice. Osteoarthr Cartil 16:129–130PubMedCentralPubMed
47.
go back to reference 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 65:3107–3119PubMedCentralPubMed 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 65:3107–3119PubMedCentralPubMed
48.
go back to reference Valdes AM, Spector TD, Tamm A et al (2010) Genetic variation in the smad3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 62:2347–2352PubMed Valdes AM, Spector TD, Tamm A et al (2010) Genetic variation in the smad3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 62:2347–2352PubMed
49.
go back to reference 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 19:704–712PubMedCentralPubMed 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 19:704–712PubMedCentralPubMed
50.
go back to reference Blaney Davidson EN, van der Kraan PM, van den Berg WB (2007) TGF-beta and osteoarthritis. Osteoarthritis Cartilage 15:597–604PubMed Blaney Davidson EN, van der Kraan PM, van den Berg WB (2007) TGF-beta and osteoarthritis. Osteoarthritis Cartilage 15:597–604PubMed
51.
go back to reference Fortier LA, Barker JU, Strauss EJ et al (2011) The role of growth factors in cartilage repair. Clin Orthop Relat Res 469:2706–2715PubMedCentralPubMed Fortier LA, Barker JU, Strauss EJ et al (2011) The role of growth factors in cartilage repair. Clin Orthop Relat Res 469:2706–2715PubMedCentralPubMed
52.
go back to reference 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 60:2019–2027PubMed 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 60:2019–2027PubMed
53.
go back to reference 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 13:2476–2488PubMed 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 13:2476–2488PubMed
54.
go back to reference 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 113:2532–2542PubMedCentralPubMed 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 113:2532–2542PubMedCentralPubMed
55.
go back to reference 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 282:11110–11121PubMedCentralPubMed 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 282:11110–11121PubMedCentralPubMed
56.
go back to reference 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 420:82–89PubMedCentralPubMed 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 420:82–89PubMedCentralPubMed
57.
go back to reference 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 64:1950–1959PubMedCentralPubMed 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 64:1950–1959PubMedCentralPubMed
58.
go back to reference 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 113:2856–2865PubMedCentralPubMed 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 113:2856–2865PubMedCentralPubMed
59.
go back to reference Andrew SL, Michael BE, Dongyao Y et al (2013) A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 527:440–447 Andrew SL, Michael BE, Dongyao Y et al (2013) A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 527:440–447
60.
go back to reference 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 74:175–177PubMed 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 74:175–177PubMed
61.
go back to reference Usui H, Shibayama M, Ohbayashi N et al (2004) FGF18 is required for embryonic lung alveolar development. Biochem Biophys Res Comm 322:887–892PubMed Usui H, Shibayama M, Ohbayashi N et al (2004) FGF18 is required for embryonic lung alveolar development. Biochem Biophys Res Comm 322:887–892PubMed
62.
go back to reference Davidson D, Blanc A, Filion D (2005) Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J Biol Chem 280:20509–20515PubMed Davidson D, Blanc A, Filion D (2005) Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J Biol Chem 280:20509–20515PubMed
63.
go back to reference 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 302:80–91PubMed 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 302:80–91PubMed
64.
go back to reference 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 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.
go back to reference 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 13:623–631PubMed 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 13:623–631PubMed
66.
go back to reference 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 32:669–676PubMed 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 32:669–676PubMed
67.
go back to reference 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 32:923–927PubMed 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 32:923–927PubMed
68.
go back to reference Geetha-Loganathan P, Nimmagadda S, Scaal M (2008) Wnt signaling in limb organogenesis. Organogenesis 4:109–115 Geetha-Loganathan P, Nimmagadda S, Scaal M (2008) Wnt signaling in limb organogenesis. Organogenesis 4:109–115
69.
go back to reference Loughlin J, Mustafa Z, Smith A et al (2000) Linkage analysis of chromosome 2q in osteoarthritis. Rheumatology 39:377–381PubMed Loughlin J, Mustafa Z, Smith A et al (2000) Linkage analysis of chromosome 2q in osteoarthritis. Rheumatology 39:377–381PubMed
70.
go back to reference 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 101:9757–9762PubMedCentralPubMed 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 101:9757–9762PubMedCentralPubMed
71.
go back to reference Valdes AM, Doherty S, Muir KR et al (2012) Genetic contribution to radiographic severity in osteoarthritis of the knee. Ann Rheum Dis 71:1537–1540PubMedCentralPubMed Valdes AM, Doherty S, Muir KR et al (2012) Genetic contribution to radiographic severity in osteoarthritis of the knee. Ann Rheum Dis 71:1537–1540PubMedCentralPubMed
72.
go back to reference Min JL, Meulenbelt I, Riyazi N et al (2005) Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis Rheum 52:1077–1080PubMed Min JL, Meulenbelt I, Riyazi N et al (2005) Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis Rheum 52:1077–1080PubMed
73.
go back to reference Lories RJ, Peeters J, Bakker A et al (2007) Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 56:4095–4103PubMed Lories RJ, Peeters J, Bakker A et al (2007) Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 56:4095–4103PubMed
74.
go back to reference 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:R16PubMedCentralPubMed 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:R16PubMedCentralPubMed
75.
go back to reference 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 24:12–21PubMedCentralPubMed 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 24:12–21PubMedCentralPubMed
76.
go back to reference 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 315:2386–2398PubMedCentralPubMed 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 315:2386–2398PubMedCentralPubMed
77.
go back to reference 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 60:501–512PubMed 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 60:501–512PubMed
78.
go back to reference Zhu M, Chen M, Zuscik M et al (2008) Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum 58:2053–2064PubMedCentralPubMed Zhu M, Chen M, Zuscik M et al (2008) Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum 58:2053–2064PubMedCentralPubMed
79.
go back to reference Alcaraz MJ, Megías J, García-Arnandis I et al (2010) New molecular targets for the treatment of osteoarthritis. Biochem Pharmacol 80:13–21PubMed Alcaraz MJ, Megías J, García-Arnandis I et al (2010) New molecular targets for the treatment of osteoarthritis. Biochem Pharmacol 80:13–21PubMed
80.
go back to reference Huang SM, Mishina YM, Liu S et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461:614–620PubMed Huang SM, Mishina YM, Liu S et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461:614–620PubMed
81.
go back to reference 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 56:3319–3325PubMed 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 56:3319–3325PubMed
82.
go back to reference Diarra D, Stolina M, Polzer K et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163PubMed Diarra D, Stolina M, Polzer K et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163PubMed
83.
go back to reference 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 280:19185–19195PubMed 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 280:19185–19195PubMed
84.
go back to reference Lin AC, Seeto BL, Bartoszko JM et al (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15:1421–1426PubMed Lin AC, Seeto BL, Bartoszko JM et al (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15:1421–1426PubMed
85.
go back to reference Mak KK, Kronenberg HM, Chuang P-T et al (2008) Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 135:1947–1956PubMed Mak KK, Kronenberg HM, Chuang P-T et al (2008) Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 135:1947–1956PubMed
86.
go back to reference Beaupre GS, Stevens SS, Carter DR (2000) Mechanobiology in the development, maintenance, and degeneration of articular cartilage. J Rehabil Res Dev 37:145–151PubMed Beaupre GS, Stevens SS, Carter DR (2000) Mechanobiology in the development, maintenance, and degeneration of articular cartilage. J Rehabil Res Dev 37:145–151PubMed
87.
go back to reference Lin AC, Seeto BL, Bartoszko JM et al (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15:1421–1425PubMed Lin AC, Seeto BL, Bartoszko JM et al (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15:1421–1425PubMed
88.
go back to reference 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:e104547PubMedCentralPubMed 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:e104547PubMedCentralPubMed
89.
go back to reference 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 55:257–261PubMed 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 55:257–261PubMed
90.
go back to reference Semenza GL (2011) Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb Symp Quant Biol 76:347–353PubMed Semenza GL (2011) Regulation of metabolism by hypoxia-inducible factor 1. Cold Spring Harb Symp Quant Biol 76:347–353PubMed
91.
go back to reference Lando D, Peet DJ, Whelan DA et al (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295:858–861PubMed Lando D, Peet DJ, Whelan DA et al (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295:858–861PubMed
92.
go back to reference Bracken CP, Whitelaw ML, Peet DJ (2003) The hypoxia-inducible factors: key transcriptional regulators of hypoxic responses. Cell Mol Life Sci 60:1376–1393PubMed Bracken CP, Whitelaw ML, Peet DJ (2003) The hypoxia-inducible factors: key transcriptional regulators of hypoxic responses. Cell Mol Life Sci 60:1376–1393PubMed
93.
go back to reference Kiss J, Kirchberg J, Schneider M (2012) Molecular oxygen sensing: implications for visceral surgery. Langenbecks Arch Surg 397(4):603–610PubMed Kiss J, Kirchberg J, Schneider M (2012) Molecular oxygen sensing: implications for visceral surgery. Langenbecks Arch Surg 397(4):603–610PubMed
94.
go back to reference 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 60:3038–3048PubMed 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 60:3038–3048PubMed
95.
go back to reference Pfander D, Cramer T, Schipani E et al (2003) HIF-1alpha controls extracellular matrix synthesis by epiphyseal chondrocytes. J Cell Sci 116:1819–1826PubMed Pfander D, Cramer T, Schipani E et al (2003) HIF-1alpha controls extracellular matrix synthesis by epiphyseal chondrocytes. J Cell Sci 116:1819–1826PubMed
96.
go back to reference 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 16:678–686PubMed 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 16:678–686PubMed
97.
go back to reference Yang S, Kim J, Ryu JH et al (2010) Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 16:687–693PubMed Yang S, Kim J, Ryu JH et al (2010) Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 16:687–693PubMed
98.
go back to reference 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 17:1137–1143PubMed 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 17:1137–1143PubMed
99.
go back to reference Lafont JE, Talma S, Murphy CL (2007) Hypoxia-inducible factor 2alpha is essential for hypoxic induction of the human articular chondrocyte phenotype. Arthritis Rheum 56:3297–3306PubMed Lafont JE, Talma S, Murphy CL (2007) Hypoxia-inducible factor 2alpha is essential for hypoxic induction of the human articular chondrocyte phenotype. Arthritis Rheum 56:3297–3306PubMed
100.
go back to reference 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 283:4778–4786PubMed 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 283:4778–4786PubMed
101.
go back to reference Domm C, Schunke M, Christesen K et al (2002) Redifferentiation of dedifferentiated bovine articular chondrocytes in alginate culture under low oxygen tension. Osteoarthr Cartil 10:13–22PubMed Domm C, Schunke M, Christesen K et al (2002) Redifferentiation of dedifferentiated bovine articular chondrocytes in alginate culture under low oxygen tension. Osteoarthr Cartil 10:13–22PubMed
102.
go back to reference 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:R55PubMedCentralPubMed 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:R55PubMedCentralPubMed
103.
go back to reference van den Berg WB (2011) Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthr Cartil 19:338–341PubMed van den Berg WB (2011) Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthr Cartil 19:338–341PubMed
104.
go back to reference Wang M, Shen J, Jin H et al (2011) Recent progress in understanding molecular mechanisms of cartilage degeneration during osteoarthritis. Ann NY Acad Sci 1240:61–69PubMedCentralPubMed Wang M, Shen J, Jin H et al (2011) Recent progress in understanding molecular mechanisms of cartilage degeneration during osteoarthritis. Ann NY Acad Sci 1240:61–69PubMedCentralPubMed
105.
go back to reference 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 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.
go back to reference Francis-West PH, Abdelfattah A, Chen P et al (1999) Mechanisms of GDF-5 action during skeletal development. Development 126:1305–1315PubMed Francis-West PH, Abdelfattah A, Chen P et al (1999) Mechanisms of GDF-5 action during skeletal development. Development 126:1305–1315PubMed
107.
go back to reference 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 271:21345–21352PubMed 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 271:21345–21352PubMed
108.
go back to reference Mikic B, Battaglia TC, Taylor EA (2002) The effect of growth/differentiation factor-5 deficiency on femoral composition and mechanical behavior in mice. Bone 30:733–737PubMed Mikic B, Battaglia TC, Taylor EA (2002) The effect of growth/differentiation factor-5 deficiency on femoral composition and mechanical behavior in mice. Bone 30:733–737PubMed
109.
go back to reference 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 16:2366–2375PubMed 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 16:2366–2375PubMed
110.
go back to reference Chhabra A, Tsou D, Clark RT et al (2003) GDF-5 deficiency in mice delays Achilles tendon healing. J Orthop Res 21:826–835PubMed Chhabra A, Tsou D, Clark RT et al (2003) GDF-5 deficiency in mice delays Achilles tendon healing. J Orthop Res 21:826–835PubMed
111.
go back to reference 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 15:468–474PubMed 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 15:468–474PubMed
112.
go back to reference Nickel J, Kotzsch A, Sebald W (2005) A single residue of GDF-5 defines binding specificity to BMP receptor IB. J Mol Biol 349:933–947PubMed Nickel J, Kotzsch A, Sebald W (2005) A single residue of GDF-5 defines binding specificity to BMP receptor IB. J Mol Biol 349:933–947PubMed
113.
go back to reference Byrnes AM, Racacho L, Nikkel SM et al (2010) Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat 31:1155–1162PubMed Byrnes AM, Racacho L, Nikkel SM et al (2010) Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat 31:1155–1162PubMed
114.
go back to reference 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 39:529–533PubMed 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 39:529–533PubMed
115.
go back to reference Byrnes AM, Racacho L, Nikkel SM et al (2010) Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat 31:1155–1162PubMed Byrnes AM, Racacho L, Nikkel SM et al (2010) Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat 31:1155–1162PubMed
116.
go back to reference Egli R, Southam L, Wilkins JM et al (2009) Functional analysis of the osteoarthritis susceptibility-associated GDF5 regulatory polymorphism. Arthritis Rheum 60:2055–2064PubMed Egli R, Southam L, Wilkins JM et al (2009) Functional analysis of the osteoarthritis susceptibility-associated GDF5 regulatory polymorphism. Arthritis Rheum 60:2055–2064PubMed
117.
go back to reference 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 26:136–140PubMed 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 26:136–140PubMed
118.
go back to reference 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 368:639–643PubMed 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 368:639–643PubMed
119.
go back to reference Takahara M, Harada M, Guan D et al (2004) Developmental failure of phalanges in the absence of growth/differentiation factor 5. Bone 35:1069–1076PubMed Takahara M, Harada M, Guan D et al (2004) Developmental failure of phalanges in the absence of growth/differentiation factor 5. Bone 35:1069–1076PubMed
120.
go back to reference 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 70:208–213PubMed 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 70:208–213PubMed
121.
go back to reference Mikic B, Clark RT, Battaglia TC (2004) Altered hypertrophic chondrocyte kinetics in GDF-5 deficient murine tibial growth plates. J Orthop Res 22:552–556PubMed Mikic B, Clark RT, Battaglia TC (2004) Altered hypertrophic chondrocyte kinetics in GDF-5 deficient murine tibial growth plates. J Orthop Res 22:552–556PubMed
122.
go back to reference 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 10:394–401PubMed 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 10:394–401PubMed
123.
go back to reference Chubinskaya S, Segalite D, Pikovsky D et al (2008) Effects induced by BMPs in cultures of human articular chondrocytes: comparative studies. Growth Factors 26:275–283PubMed Chubinskaya S, Segalite D, Pikovsky D et al (2008) Effects induced by BMPs in cultures of human articular chondrocytes: comparative studies. Growth Factors 26:275–283PubMed
124.
go back to reference 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:e86590PubMedCentralPubMed 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:e86590PubMedCentralPubMed
125.
go back to reference Borden P, Heller RA (1997) Transcriptional control of matrix metalloproteinases and the tissue inhibitors of matrix metalloproteinases. Crit Rev Eukaryot Gene Expr 7:159–178PubMed Borden P, Heller RA (1997) Transcriptional control of matrix metalloproteinases and the tissue inhibitors of matrix metalloproteinases. Crit Rev Eukaryot Gene Expr 7:159–178PubMed
126.
go back to reference 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 43:801–811PubMed 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 43:801–811PubMed
127.
go back to reference 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 331:341–346PubMedCentralPubMed 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 331:341–346PubMedCentralPubMed
128.
go back to reference 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 151:121–148PubMed 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 151:121–148PubMed
129.
go back to reference 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 60:477–496PubMedCentralPubMed 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 60:477–496PubMedCentralPubMed
130.
go back to reference Knäuper V, Lopez Otin C, Smith B, Knight G (1996) Biochemical characterization of human collagenase-3. J Biol Chem 271:1544–1550PubMed Knäuper V, Lopez Otin C, Smith B, Knight G (1996) Biochemical characterization of human collagenase-3. J Biol Chem 271:1544–1550PubMed
131.
go back to reference 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 11:854–863PubMed 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 11:854–863PubMed
132.
go back to reference 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 52:3110–3124PubMed 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 52:3110–3124PubMed
133.
go back to reference 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 101:17192–17197PubMedCentralPubMed 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 101:17192–17197PubMedCentralPubMed
134.
go back to reference Stickens D, Behonick DJ, Ortega N et al (2004) Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131:5883–5895PubMedCentralPubMed Stickens D, Behonick DJ, Ortega N et al (2004) Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131:5883–5895PubMedCentralPubMed
135.
go back to reference 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 107:35–44PubMedCentralPubMed 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 107:35–44PubMedCentralPubMed
136.
go back to reference 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 60:3723–3733PubMedCentralPubMed 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 60:3723–3733PubMedCentralPubMed
137.
go back to reference Glasson SS, Askew R, Sheppard B et al (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644–648PubMed Glasson SS, Askew R, Sheppard B et al (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644–648PubMed
138.
go back to reference 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 56:3670–3674PubMed 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 56:3670–3674PubMed
139.
go back to reference Stanton H, Rogerson FM, East CJ et al (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434:648–652PubMed Stanton H, Rogerson FM, East CJ et al (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434:648–652PubMed
140.
go back to reference Stetler Stevenson WG, Seo DW (2005) TIMP-2: an endogenous inhibitor of angiogenesis. Trends in molecular medicine 11:97–103PubMed Stetler Stevenson WG, Seo DW (2005) TIMP-2: an endogenous inhibitor of angiogenesis. Trends in molecular medicine 11:97–103PubMed
141.
go back to reference Wang M, Sampson ER, Jin H et al (2013) MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther 15:R5PubMedCentralPubMed Wang M, Sampson ER, Jin H et al (2013) MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther 15:R5PubMedCentralPubMed
142.
go back to reference Enomoto H, Enomoto Iwamoto M, Iwamoto M et al (2000) Cbfa1 is a positive regulatory factor in chondrocyte maturation. J Biol Chem 275:8695–8702PubMed Enomoto H, Enomoto Iwamoto M, Iwamoto M et al (2000) Cbfa1 is a positive regulatory factor in chondrocyte maturation. J Biol Chem 275:8695–8702PubMed
143.
go back to reference Inada M, Yasui T, Nomura S et al (1999) Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn 214:279–290PubMed Inada M, Yasui T, Nomura S et al (1999) Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev Dyn 214:279–290PubMed
144.
go back to reference 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 89:755–764PubMed 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 89:755–764PubMed
145.
go back to reference 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 278:319–326PubMed 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 278:319–326PubMed
146.
go back to reference 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 177:413–421PubMed 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 177:413–421PubMed
147.
go back to reference Tou L, Quibria N, Alexander JM (2001) Regulation of human cbfa1 gene transcription in osteoblasts by selective estrogen receptor modulators (SERMs). Mol Cell Endocrinol 183:71–79PubMed Tou L, Quibria N, Alexander JM (2001) Regulation of human cbfa1 gene transcription in osteoblasts by selective estrogen receptor modulators (SERMs). Mol Cell Endocrinol 183:71–79PubMed
148.
go back to reference 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 9:2001–2008PubMed 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 9:2001–2008PubMed
149.
go back to reference 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 278:27939–27944PubMed 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 278:27939–27944PubMed
150.
go back to reference Zhao M, Qiao M, Harris SE et al (2004) Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. J Biol Chem 279:12854–12859PubMedCentralPubMed Zhao M, Qiao M, Harris SE et al (2004) Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo. J Biol Chem 279:12854–12859PubMedCentralPubMed
151.
go back to reference 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 281:3569–3576PubMedCentralPubMed 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 281:3569–3576PubMedCentralPubMed
152.
go back to reference Shen R, Wang X, Drissi H et al (2006) Cyclin D1-cdk4 induce runx2 ubiquitination and degradation. J Biol Chem 281:16347–16353PubMedCentralPubMed Shen R, Wang X, Drissi H et al (2006) Cyclin D1-cdk4 induce runx2 ubiquitination and degradation. J Biol Chem 281:16347–16353PubMedCentralPubMed
153.
go back to reference Jeon EJ, Lee KY, Choi NS et al (2006) Bone morphogenetic protein-2 stimulates Runx2 acetylation. J Biol Chem 281:16502–16511PubMed Jeon EJ, Lee KY, Choi NS et al (2006) Bone morphogenetic protein-2 stimulates Runx2 acetylation. J Biol Chem 281:16502–16511PubMed
154.
go back to reference Jonason JH, Xiao G, Zhang M et al (2009) Post-transcriptional regulation of runx2 in bone and cartilage. J Dent Res 88:693–703PubMedCentralPubMed Jonason JH, Xiao G, Zhang M et al (2009) Post-transcriptional regulation of runx2 in bone and cartilage. J Dent Res 88:693–703PubMedCentralPubMed
155.
go back to reference Akhtar N, Rasheed Z, Ramamurthy S et al (2010) MicroRNA-27b regulates the expression of MMP-13 in human osteoarthritis chondrocytes. Arthritis Rheum 62:1361–1371PubMedCentralPubMed Akhtar N, Rasheed Z, Ramamurthy S et al (2010) MicroRNA-27b regulates the expression of MMP-13 in human osteoarthritis chondrocytes. Arthritis Rheum 62:1361–1371PubMedCentralPubMed
156.
go back to reference 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 60:2723–2730PubMedCentralPubMed 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 60:2723–2730PubMedCentralPubMed
157.
go back to reference Yamasaki K, Nakasa T, Miyaki S et al (2009) Expression of microRNA-146a in osteoarthritis cartilage. Arthritis Rheum 60:1035–1041PubMedCentralPubMed Yamasaki K, Nakasa T, Miyaki S et al (2009) Expression of microRNA-146a in osteoarthritis cartilage. Arthritis Rheum 60:1035–1041PubMedCentralPubMed
Metadata
Title
Osteoarthritis Pathogenesis: A Review of Molecular Mechanisms
Authors
Bingjiang Xia
Di Chen
Jushi Zhang
Songfeng Hu
Hongting Jin
Peijian Tong
Publication date
01-12-2014
Publisher
Springer US
Published in
Calcified Tissue International / Issue 6/2014
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-014-9917-9

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