WNT Signaling and Cartilage: Of Mice and Men
详细信息 查看全文
- 作者：Bin Ma (1)
Ellie B. M. Landman (1)
Razvan L. Miclea (2)
Jan M. Wit (2)
Els C. Robanus-Maandag (3)
Janine N. Post (1)
Marcel Karperien (1) - 关键词：Cartilage ; Degeneration ; Development ; WNT
- 刊名：Calcified Tissue International
- 出版年：2013
- 出版时间：May 2013
- 年：2013
- 卷：92
- 期：5
- 页码：399-411
- 全文大小：395KB
- 参考文献：1. Goldring MB, Marcu KB (2009) Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther 11:224 CrossRef
2. Miller JR (2002) The Wnts. Genome Biol 3:REVIEWS3001
3. Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781鈥?10 CrossRef
4. van Amerongen R, Mikels A, Nusse R (2008) Alternative wnt signaling is initiated by distinct receptors. Sci Signal 1:re9
5. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469鈥?80 CrossRef
6. Miller JR, Hocking AM, Brown JD, Moon RT (1999) Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 18:7860鈥?872 CrossRef
7. Adler PN, Lee H (2001) Frizzled signaling and cell鈥揷ell interactions in planar polarity. Curr Opin Cell Biol 13:635鈥?40 CrossRef
8. Kuhl M, Sheldahl LC, Park M, Miller JR, Moon RT (2000) The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet 16:279鈥?83 CrossRef
9. Kikuchi A, Yamamoto H, Sato A (2009) Selective activation mechanisms of Wnt signaling pathways. Trends Cell Biol 19:119鈥?29 CrossRef
10. Mikels AJ, Nusse R (2006) Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 4:e115 CrossRef
11. Nalesso G, Sherwood J, Bertrand J, Pap T, Ramachandran M, De Bari C, Pitzalis C, Dell鈥檃ccio F (2011) WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways. J Cell Biol 193:551鈥?64 CrossRef
12. Kawano Y, Kypta R (2003) Secreted antagonists of the Wnt signalling pathway. J Cell Sci 116:2627鈥?634 CrossRef
13. Hoeppner LH, Secreto FJ, Westendorf JJ (2009) Wnt signaling as a therapeutic target for bone diseases. Expert Opin Ther Targets 13:485鈥?96 CrossRef
14. Zhu M, Chen M, Zuscik M, Wu Q, Wang YJ, Rosier RN, O鈥橩eefe RJ, Chen D (2008) Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum 58:2053鈥?064 CrossRef
15. Daniels DL, Weis WI (2002) ICAT inhibits beta-catenin binding to Tcf/Lef-family transcription factors and the general coactivator p300 using independent structural modules. Mol Cell 10:573鈥?84 CrossRef
16. Olsen BR, Reginato AM, Wang W (2000) Bone development. Annu Rev Cell Dev Biol 16:191鈥?20 CrossRef
17. DeLise AM, Fischer L, Tuan RS (2000) Cellular interactions and signaling in cartilage development. Osteoarthritis Cartilage 8:309鈥?34 CrossRef
18. Lefebvre V, Behringer RR, de Crombrugghe B (2001) L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway. Osteoarthritis Cartilage 9(suppl A):S69鈥揝75
19. Ng LJ, Wheatley S, Muscat GE, Conway-Campbell J, Bowles J, Wright E, Bell DM, Tam PP, Cheah KS, Koopman P (1997) SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Dev Biol 183:108鈥?21 CrossRef
20. Zelzer E, Olsen BR (2003) The genetic basis for skeletal diseases. Nature 423:343鈥?48 CrossRef
21. Cohen MM Jr (2006) The new bone biology: pathologic, molecular, and clinical correlates. Am J Med Genet A 140:2646鈥?706
22. Karsenty G (1998) Genetics of skeletogenesis. Dev Genet 22:301鈥?13 CrossRef
23. Karsenty G, Wagner EF (2002) Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2:389鈥?06 CrossRef
24. Hall BK, Miyake T (2000) All for one and one for all: condensations and the initiation of skeletal development. Bioessays 22:138鈥?47 CrossRef
25. Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739鈥?50 CrossRef
26. Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727鈥?38 CrossRef
27. Guo X, Day TF, Jiang X, Garrett-Beal L, Topol L, Yang Y (2004) Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev 18:2404鈥?417 CrossRef
28. Hens JR, Wilson KM, Dann P, Chen X, Horowitz MC, Wysolmerski JJ (2005) TOPGAL mice show that the canonical Wnt signaling pathway is active during bone development and growth and is activated by mechanical loading in vitro. J Bone Miner Res 20:1103鈥?113 CrossRef
29. Hill TP, Taketo MM, Birchmeier W, Hartmann C (2006) Multiple roles of mesenchymal beta-catenin during murine limb patterning. Development 133:1219鈥?229 CrossRef
30. Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F (2005) Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132:49鈥?0 CrossRef
31. Parr BA, McMahon AP (1995) Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb. Nature 374:350鈥?53 CrossRef
32. Zhu M, Tang D, Wu Q, Hao S, Chen M, Xie C, Rosier RN, O鈥橩eefe RJ, Zuscik M, Chen D (2009) Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res 24:12鈥?1 CrossRef
33. Yuasa T, Kondo N, Yasuhara R, Shimono K, Mackem S, Pacifici M, Iwamoto M, Enomoto-Iwamoto M (2009) Transient activation of Wnt/尾-catenin signaling induces abnormal growth plate closure and articular cartilage thickening in postnatal mice. Am J Pathol 175:1993鈥?003 CrossRef
34. Rudnicki JA, Brown AM (1997) Inhibition of chondrogenesis by Wnt gene expression in vivo and in vitro. Dev Biol 185:104鈥?18 CrossRef
35. Parr BA, Shea MJ, Vassileva G, McMahon AP (1993) Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds. Development 119:247鈥?61
36. Cho HH, Kim YJ, Kim SJ, Kim JH, Bae YC, Ba B, Jung JS (2006) Endogenous Wnt signaling promotes proliferation and suppresses osteogenic differentiation in human adipose derived stromal cells. Tissue Eng 12:111鈥?21 CrossRef
37. Boland GM, Perkins G, Hall DJ, Tuan RS (2004) Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem 93:1210鈥?230 CrossRef
38. Hwang SG, Yu SS, Lee SW, Chun JS (2005) Wnt-3a regulates chondrocyte differentiation via c-Jun/AP-1 pathway. FEBS Lett 579:4837鈥?842 CrossRef
39. Church V, Nohno T, Linker C, Marcelle C, Francis-West P (2002) Wnt regulation of chondrocyte differentiation. J Cell Sci 115:4809鈥?818 CrossRef
40. Hartmann C (2002) Wnt-signaling and skeletogenesis. J Musculoskelet Neuronal Interact 2:274鈥?76
41. Hartmann C, Tabin CJ (2000) Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development 127:3141鈥?159
42. Kawakami Y, Wada N, Nishimatsu SI, Ishikawa T, Noji S, Nohno T (1999) Involvement of Wnt-5a in chondrogenic pattern formation in the chick limb bud. Dev Growth Differ 41:29鈥?0 CrossRef
43. Akita K, Francis-West P, Vargesson N (1996) The ectodermal control in chick limb development: Wnt-7a, Shh, Bmp-2 and Bmp-4 expression and the effect of FGF-4 on gene expression. Mech Dev 60:127鈥?37 CrossRef
44. Stott NS, Jiang TX, Chuong CM (1999) Successive formative stages of precartilaginous mesenchymal condensations in vitro: modulation of cell adhesion by Wnt-7A and BMP-2. J Cell Physiol 180:314鈥?24 CrossRef
45. Hartmann C, Tabin CJ (2001) Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell 104:341鈥?51 CrossRef
46. Hoang B, Moos M Jr, Vukicevic S, Luyten FP (1996) Primary structure and tissue distribution of FRZB, a novel protein related to Drosophila frizzled, suggest a role in skeletal morphogenesis. J Biol Chem 271:26131鈥?6137 CrossRef
47. Enomoto-Iwamoto M, Kitagaki J, Koyama E, Tamamura Y, Wu C, Kanatani N, Koike T, Okada H, Komori T, Yoneda T, Church V, Francis-West PH, Kurisu K, Nohno T, Pacifici M, Iwamoto M (2002) The Wnt antagonist Frzb-1 regulates chondrocyte maturation and long bone development during limb skeletogenesis. Dev Biol 251:142鈥?56 CrossRef
48. Gaur T, Rich L, Lengner CJ, Hussain S, Trevant B, Ayers D, Stein JL, Bodine PV, Komm BS, Stein GS, Lian JB (2006) Secreted frizzled related protein 1 regulates Wnt signaling for BMP2 induced chondrocyte differentiation. J Cell Physiol 208:87鈥?6 CrossRef
49. Im GI, Quan Z (2010) The effects of Wnt inhibitors on the chondrogenesis of human mesenchymal stem cells. Tissue Eng Part A 16:2405鈥?413 CrossRef
50. Leijten JC, van Blitterwijk CA, Karperien M, Emons J, van Gool S, Wit JM, Sticht C, Decker E, Rappold G, Uitterlinden A, Rivadeneira F, van Meurs J, Hofman A, Scherjon S (2012) GREM1, FRZB and DKK1 are key regulators of human articular cartilage homeostasis. Arthritis Rheum 64:3302鈥?312 CrossRef
51. Surmann-Schmitt C, Widmann N, Dietz U, Saeger B, Eitzinger N, Nakamura Y, Rattel M, Latham R, Hartmann C, von der Mark H, Schett G, von der Mark K, Stock M (2009) Wif-1 is expressed at cartilage-mesenchyme interfaces and impedes Wnt3a-mediated inhibition of chondrogenesis. J Cell Sci 122:3627鈥?637 CrossRef
52. Goldring MB, Goldring SR (2007) Osteoarthritis. J Cell Physiol 213:626鈥?34 CrossRef
53. Fitzgerald JB, Jin M, Dean D, Wood DJ, Zheng MH, Grodzinsky AJ (2004) Mechanical compression of cartilage explants induces multiple time-dependent gene expression patterns and involves intracellular calcium and cyclic AMP. J Biol Chem 279:19502鈥?9511 CrossRef
54. Kurz B, Lemke AK, Fay J, Pufe T, Grodzinsky AJ, Schunke M (2005) Pathomechanisms of cartilage destruction by mechanical injury. Ann Anat 187:473鈥?85 CrossRef
55. Loeser RF (2006) Molecular mechanisms of cartilage destruction: mechanics, inflammatory mediators, and aging collide. Arthritis Rheum 54:1357鈥?360 CrossRef
56. Sweeney SE, Firestein GS (2004) Rheumatoid arthritis: regulation of synovial inflammation. Int J Biochem Cell Biol 36:372鈥?78 CrossRef
57. Goldring MB, Berenbaum F (2004) The regulation of chondrocyte function by proinflammatory mediators: prostaglandins and nitric oxide. Clin Orthop Relat Res (427 suppl):S37鈥揝46
58. Goldring SR, Goldring MB (2004) The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin Orthop Relat Res (427 suppl):S27鈥揝36
59. Tetlow LC, Adlam DJ, Woolley DE (2001) Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum 44:585鈥?94 CrossRef
60. Hwang SG, Yu SS, Poo H, Chun JS (2005) c-Jun/activator protein-1 mediates interleukin-1beta-induced dedifferentiation but not cyclooxygenase-2 expression in articular chondrocytes. J Biol Chem 280:29780鈥?9787 CrossRef
61. Kim SJ, Ju JW, Oh CD, Yoon YM, Song WK, Kim JH, Yoo YJ, Bang OS, Kang SS, Chun JS (2002) ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. J Biol Chem 277:1332鈥?339 CrossRef
62. Cawston TEW, Wilson AJ (2006) Understanding the role of tissue degrading enzymes and their inhibitors in development and disease. Best Pract Res Clin Rheumatol 20:983鈥?002 CrossRef
63. Plaas A, Osborn B, Yoshihara Y, Bai Y, Bloom T, Nelson F, Mikecz K, Sandy JD (2007) Aggrecanolysis in human osteoarthritis: confocal localization and biochemical characterization of ADAMTS5-hyaluronan complexes in articular cartilages. Osteoarthritis Cartilage 15:719鈥?34 CrossRef
64. Burrage PS, Mix KS, Brinckerhoff CE (2006) Matrix metalloproteinases: role in arthritis. Front Biosci 11:529鈥?43 CrossRef
65. Caterson B, Flannery CR, Hughes CE, Little CB (2000) Mechanisms involved in cartilage proteoglycan catabolism. Matrix Biol 19:333鈥?44 CrossRef
66. Aigner T, Fundel K, Saas J, Gebhard PM, Haag J, Weiss T, Zien A, Obermayr F, Zimmer R, Bartnik E (2006) Large-scale gene expression profiling reveals major pathogenetic pathways of cartilage degeneration in osteoarthritis. Arthritis Rheum 54:3533鈥?544 CrossRef
67. Fukui N, Zhu Y, Maloney WJ, Clohisy J, Sandell LJ (2003) Stimulation of BMP-2 expression by pro-inflammatory cytokines IL-1 and TNF-alpha in normal and osteoarthritic chondrocytes. J Bone Joint Surg Am 85-A(suppl 3):59鈥?6
68. Hermansson M, Sawaji Y, Bolton M, Alexander S, Wallace A, Begum S, Wait R, Saklatvala J (2004) Proteomic analysis of articular cartilage shows increased type II collagen synthesis in osteoarthritis and expression of inhibin betaA (activin A), a regulatory molecule for chondrocytes. J Biol Chem 279:43514鈥?3521 CrossRef
69. Ryu JH, Kim SJ, Kim SH, Oh CD, Hwang SG, Chun CH, Oh SH, Seong JK, Huh TL, Chun JS (2002) Regulation of the chondrocyte phenotype by beta-catenin. Development 129:5541鈥?550 CrossRef
70. Miclea RL, Karperien M, Bosch CA, van der Horst G, van der Valk MA, Kobayashi T, Kronenberg HM, Rawadi G, Akcakaya P, Lowik CW, Fodde R, Wit JM, Robanus-Maandag EC (2009) Adenomatous polyposis coli鈥搈ediated control of beta-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors. BMC Dev Biol 9:26 CrossRef
71. Hwang SG, Ryu JH, Kim IC, Jho EH, Jung HC, Kim K, Kim SJ, Chun JS (2004) Wnt-7a causes loss of differentiated phenotype and inhibits apoptosis of articular chondrocytes via different mechanisms. J Biol Chem 279:26597鈥?6604 CrossRef
72. Ma B, van Blitterswijk CA, Karperien M (2012) A Wnt/beta-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes. Arthritis Rheum 64:2589鈥?600 CrossRef
73. Ryu JH, Chun JS (2006) Opposing roles of WNT-5A and WNT-11 in interleukin-1beta regulation of type II collagen expression in articular chondrocytes. J Biol Chem 281:22039鈥?2047 CrossRef
74. Valdes AM, Loughlin J, Oene MV, Chapman K, Surdulescu GL, Doherty M, Spector TD (2007) Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee. Arthritis Rheum 56:137鈥?46 CrossRef
75. Loughlin J, Dowling B, Chapman K, Marcelline L, Mustafa Z, Southam L, Ferreira A, Ciesielski C, Carson DA, Corr M (2004) Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci U S A 101:9757鈥?762 CrossRef
76. Lane NE, Lian K, Nevitt MC, Zmuda JM, Lui L, Li J, Wang J, Fontecha M, Umblas N, Rosenbach M, de Leon P, Corr M (2006) Frizzled-related protein variants are risk factors for hip osteoarthritis. Arthritis Rheum 54:1246鈥?254 CrossRef
77. Min JL, Meulenbelt I, Riyazi N, Kloppenburg M, Houwing-Duistermaat JJ, Seymour AB, Pols HA, van Duijn CM, Slagboom PE (2005) Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis Rheum 52:1077鈥?080 CrossRef
78. Lane NE, Nevitt MC, Lui LY, de Leon P, Corr M (2007) Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women. Arthritis Rheum 56:3319鈥?325 CrossRef
79. Sen M, Lauterbach K, El-Gabalawy H, Firestein GS, Corr M, Carson DA (2000) Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc Natl Acad Sci U S A 97:2791鈥?796 CrossRef
80. Nakamura Y, Nawata M, Wakitani S (2005) Expression profiles and functional analyses of Wnt-related genes in human joint disorders. Am J Pathol 167:97鈥?05 CrossRef
81. Blom AB, Brockbank SM, van Lent PL, van Beuningen HM, Geurts J, Takahashi N, van der Kraan PM, van de Loo FA, Schreurs BW, Clements K, Newham P, van den Berg WB (2009) Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum 60:501鈥?12 CrossRef
82. Dell鈥檃ccio F, De Bari C, Eltawil NM, Vanhummelen P, Pitzalis C (2008) Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt-16 expression and signaling after injury and in osteoarthritis. Arthritis Rheum 58:1410鈥?421 CrossRef
83. Bodine PV, Zhao W, Kharode YP, Bex FJ, Lambert AJ, Goad MB, Gaur T, Stein GS, Lian JB, Komm BS (2004) The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol 18:1222鈥?237 CrossRef
84. Lories RJ, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten J, Thomas JT, Luyten FP (2007) Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 56:4095鈥?103 CrossRef
85. Dell鈥橝ccio F, De Bari C, El Tawil NM, Barone F, Mitsiadis TA, O鈥橠owd J, Pitzalis C (2006) Activation of WNT and BMP signaling in adult human articular cartilage following mechanical injury. Arthritis Res Ther 8:R139 CrossRef
86. Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe B (2004) Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev 18:1072鈥?087 CrossRef
87. Yuasa T, Otani T, Koike T, Iwamoto M, Enomoto-Iwamoto M (2008) Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration. Lab Invest 88:264鈥?74 CrossRef
88. Yasuhara R, Yuasa T, Williams JA, Byers SW, Shah S, Pacifici M, Iwamoto M, Enomoto-Iwamoto M (2010) Wnt/beta-catenin and retinoic acid receptor signaling pathways interact to regulate chondrocyte function and matrix turnover. J Biol Chem 285:317鈥?27 CrossRef
89. Yun K, Im SH (2007) Transcriptional regulation of MMP13 by Lef1 in chondrocytes. Biochem Biophys Res Commun 364:1009鈥?014 CrossRef
90. Sen M, Reifert J, Lauterbach K, Wolf V, Rubin JS, Corr M, Carson DA (2002) Regulation of fibronectin and metalloproteinase expression by Wnt signaling in rheumatoid arthritis synoviocytes. Arthritis Rheum 46:2867鈥?877 CrossRef
91. Ge X, Ma X, Meng J, Zhang C, Ma K, Zhou C (2009) Role of Wnt-5A in interleukin-1beta-induced matrix metalloproteinase expression in rabbit temporomandibular joint condylar chondrocytes. Arthritis Rheum 60:2714鈥?722 CrossRef
92. Pritchard S, Guilak F (2006) Effects of interleukin-1 on calcium signaling and the increase of filamentous actin in isolated and in situ articular chondrocytes. Arthritis Rheum 54:2164鈥?174 CrossRef
93. Shimazaki A, Wright MO, Elliot K, Salter DM, Millward-Sadler SJ (2006) Calcium/calmodulin-dependent protein kinase II in human articular chondrocytes. Biorheology 43:223鈥?33 - 作者单位：Bin Ma (1)
Ellie B. M. Landman (1)
Razvan L. Miclea (2)
Jan M. Wit (2)
Els C. Robanus-Maandag (3)
Janine N. Post (1)
Marcel Karperien (1)
1. Department of Developmental BioEngineering, University of Twente, Drienerlolaan 5, 7522NB, Enschede, The Netherlands
2. Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
3. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands - ISSN：1432-0827
文摘
In adult articular cartilage, the extracellular matrix is maintained by a balance between the degradation and the synthesis of matrix components. Chondrocytes that sparsely reside in the matrix and rarely proliferate are the key cellular mediators for cartilage homeostasis. There are indications for the involvement of the WNT signaling pathway in maintaining articular cartilage. Various WNTs are involved in the subsequent stages of chondrocyte differentiation during development, and deregulation of WNT signaling was observed in cartilage degeneration. Even though gene expression and protein synthesis can be activated upon injury, articular cartilage has a limited ability of self-repair and efforts to regenerate articular cartilage have so far not been successful. Because WNT signaling was found to be involved in the development and maintenance of cartilage as well as in the degeneration of cartilage, interfering with this pathway might contribute to improving cartilage regeneration. However, most of the studies on elucidating the role of WNT signaling in these processes were conducted using in vitro or in vivo animal models. Discrepancies have been found in the role of WNT signaling between chondrocytes of mouse and human origin, and extrapolation of results from mouse models to the human situation remains a challenge. Elucidation of detailed WNT signaling functions will provide knowledge to improve cartilage regeneration.