B. M. Abidin, E. Owusu-kwarteng, and K. M. Heinonen, Frizzled-6 Regulates Hematopoietic Stem/Progenitor Cell Survival and Self-Renewal, J. Immunol, vol.195, pp.2168-2176, 2015.
DOI : 10.4049/jimmunol.1403213

URL : https://hal.archives-ouvertes.fr/pasteur-01351877

S. T. Abraham, H. A. Benscoter, C. M. Schworer, and H. A. Singer, A Role for, 1997.
URL : https://hal.archives-ouvertes.fr/pasteur-01351367

, Ca2+/Calmodulin-Dependent Protein Kinase II in the Mitogen-Activated Protein

, Kinase Signaling Cascade of Cultured Rat Aortic Vascular Smooth Muscle Cells, Circ Res, vol.81, pp.575-584

V. Afonso, R. Champy, D. Mitrovic, P. Collin, and A. Lomri, Reactive oxygen species and superoxide dismutases: Role in joint diseases, Joint Bone Spine, vol.74, pp.324-329, 2007.

N. Alaaeddine, J. A. Dibattista, J. P. Pelletier, J. M. Cloutier, K. Kiansa et al., Osteoarthritic synovial fibroblasts possess an increased level of tumor necrosis factor-receptor 55 (TNF-R55) that mediates biological activation by TNF-alpha, J. Rheumatol, vol.24, pp.1985-1994, 1997.

J. Albers, J. Keller, A. Baranowsky, F. T. Beil, P. Catala-lehnen et al., Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin, J. Cell Biol, vol.200, pp.537-549, 2013.

J. L. Allen, M. E. Cooke, A. , and T. , ECM stiffness primes the TGF? pathway to promote chondrocyte differentiation, Mol Biol Cell, vol.23, pp.3731-3742, 2012.

C. W. Archer, F. , and P. , The chondrocyte, The International Journal of Biochemistry & Cell Biology, vol.35, pp.401-404, 2003.

C. W. Archer, J. Mcdowell, M. T. Bayliss, M. D. Stephens, B. et al., , 1990.

, Phenotypic modulation in sub-populations of human articular chondrocytes in vitro, J, p.155

, Cell. Sci, vol.97, pp.361-371

G. A. Ateshian, W. M. Lai, W. B. Zhu, and V. C. Mow, An asymptotic solution for the contact of two biphasic cartilage layers, J Biomech, vol.27, pp.1347-1360, 1994.

C. Bänziger, D. Soldini, C. Schütt, P. Zipperlen, G. Hausmann et al., , 2006.

, Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells, Cell, vol.125, pp.509-522

A. F. Barakat, C. J. Elson, and C. I. Westacott, Susceptibility to physiological concentrations of IL-1? varies in cartilage at different anatomical locations on human osteoarthritic knee joints, Osteoarthritis and Cartilage, vol.10, pp.264-269, 2002.

P. Barre, F. Redini, K. Boumediene, C. Vielpeau, and J. Pujol, , 2000.

, Semiquantitative reverse transcription-polymerase chain reaction analysis of syndecan1 and-4 messages in cartilage and cultured chondrocytes from osteoarthritic joints, Osteoarthritis and Cartilage, vol.8, pp.34-43

K. Bartscherer, N. Pelte, D. Ingelfinger, and M. Boutros, Secretion of Wnt ligands requires Evi, a conserved transmembrane protein, Cell, vol.125, pp.523-533, 2006.

R. C. Billinghurst, L. Dahlberg, M. Ionescu, A. Reiner, R. Bourne et al.,

P. Mitchell, J. Hambor, O. Diekmann, and H. Tschesche, Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage, J Clin Invest, vol.99, pp.1534-1545, 1997.

A. B. Blom, S. M. Brockbank, P. L. Van-lent, H. M. Van-beuningen, and J. Geurts,

N. Takahashi, P. M. Van-der-kraan, F. A. Van-de-loo, B. W. Schreurs, and K. Clements, Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1, Arthritis Rheum, vol.60, pp.501-512, 2009.

P. Bonaldo, V. Russo, F. Bucciotti, R. Doliana, C. et al., , 1990.

J. Bondeson, S. Lauder, S. Wainwright, N. Amos, A. Evans et al., Adenoviral gene transfer of the endogenous inhibitor IkappaBalpha into human osteoarthritis synovial fibroblasts demonstrates that several matrix metalloproteinases and aggrecanases are nuclear factor-kappaB-dependent, 2007.

. Rheumatol, , vol.34, pp.523-533

J. Bondeson, S. Wainwright, C. Hughes, C. , and B. , The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review, Clin. Exp, 2008.

. Rheumatol, , vol.26, pp.139-145

J. S. Bonifacino, H. , and J. H. , Retromer. Curr. Opin. Cell Biol, vol.20, pp.427-436, 2008.

C. Bonnans, J. Chou, and Z. Werb, Remodelling the extracellular matrix in development and disease, Nat Rev Mol Cell Biol, vol.15, pp.786-801, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01952416

C. Bougault, M. Gosset, X. Houard, C. Salvat, L. Godmann et al., Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models, Arthritis & Rheumatism, vol.64, pp.3972-3981, 2012.

M. Boutros and M. Mlodzik, Dishevelled: at the crossroads of divergent intracellular signaling pathways, Mech. Dev, vol.83, pp.27-37, 1999.

M. Boutros, N. Paricio, D. I. Strutt, and M. Mlodzik, Dishevelled Activates JNK and Discriminates between JNK Pathways in Planar Polarity and wingless Signaling, vol.94, pp.109-118, 1998.

P. S. Burrage, K. S. Mix, and C. E. Brinckerhoff, Matrix metalloproteinases: role in arthritis, Front. Biosci, vol.11, pp.529-543, 2006.

B. Caramés, N. Taniguchi, S. Otsuki, F. J. Blanco, and M. Lotz, Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis, Arthritis Rheum, vol.62, pp.791-801, 2010.

C. Betancourt, M. C. Cailotto, F. Kerkhof, H. J. Cornelis, F. M. Doherty et al.,

D. J. Hart, A. Hofman, F. P. Luyten, R. A. Maciewicz, and M. Mangino, , 2012.

, Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis, Proc Natl Acad Sci U S A, vol.109, pp.8218-8223

B. Caterson, C. R. Flannery, C. E. Hughes, and C. B. Little, Mechanisms involved in cartilage proteoglycan catabolism, Matrix Biol, vol.19, pp.333-344, 2000.

C. Chadjichristos, C. Ghayor, M. Kypriotou, G. Martin, E. Renard et al., Sp1 and Sp3 transcription factors mediate interleukin-1 beta down-regulation of human type II collagen gene expression in articular chondrocytes, J. Biol. Chem, vol.278, pp.39762-39772, 2003.

F. H. Chen, K. T. Rousche, T. , and R. S. , Technology Insight: adult stem cells in cartilage regeneration and tissue engineering, Nat Clin Pract Rheumatol, vol.2, pp.373-382, 2006.

W. Ching, H. C. Hang, N. , and R. , Lipid-independent secretion of a, 2008.

, Drosophila Wnt protein. J. Biol. Chem, vol.283, pp.17092-17098

P. S. Chockalingam, U. Varadarajan, R. Sheldon, E. Fortier, E. R. Lavallie et al., Involvement of protein kinase Czeta in interleukin-1beta induction of ADAMTS-4 and type 2 nitric oxide synthase via NFkappaB signaling in primary human osteoarthritic chondrocytes, Arthritis Rheum, vol.56, pp.4074-4083, 2007.

J. B. Choi, I. Youn, L. Cao, H. A. Leddy, C. L. Gilchrist et al., , 2007.

, Mesenchymal Progenitors Controls Osteoblast and Chondrocyte Differentiation during Vertebrate Skeletogenesis, Developmental Cell, vol.8, pp.739-750

A. De, Wnt/Ca2+ signaling pathway: a brief overview, Acta Biochim. Biophys. Sin. (Shanghai), vol.43, pp.745-756, 2011.

D. Carlo, M. Loeser, and R. F. , Cell death in osteoarthritis, Curr Rheumatol Rep, vol.10, pp.37-42, 2008.

F. Dell'accio, C. De-bari, N. M. Eltawil, P. Vanhummelen, P. et al., , 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 & Rheumatism, vol.58, pp.1410-1421

D. Devenport, The cell biology of planar cell polarity, J Cell Biol, vol.207, pp.171-179, 2014.

D. Bella, C. Fosang, A. Donati, D. M. Wallace, G. G. et al., , p.3, 2015.

, Bioprinting of Cartilage for Orthopedic Surgeons: Reading between the Lines. Front Surg 2

R. Dreier, Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders, Arthritis Res. Ther, vol.12, p.216, 2010.

F. Echtermeyer, J. Bertrand, R. Dreier, I. Meinecke, K. Neugebauer et al., Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis, Nat. Med, vol.15, pp.1072-1076, 2009.

P. S. Eggli, E. B. Hunziker, and R. K. Schenk, Quantitation of structural features characterizing weight-and less-weight-bearing regions in articular cartilage: a stereological analysis of medial femoral condyles in young adult rabbits, Anat. Rec, vol.222, pp.217-227, 1988.

A. Elfenbein and M. Simons, Syndecan-4 signaling at a glance, J. Cell. Sci, vol.126, pp.3799-3804, 2013.
DOI : 10.1242/jcs.124636

URL : http://jcs.biologists.org/content/joces/126/17/3799.full.pdf

Y. Endo, V. Wolf, K. Muraiso, K. Kamijo, L. Soon et al., Wnt-3a-dependent cell motility involves RhoA activation and is specifically regulated by dishevelled-2, J. Biol. Chem, vol.280, pp.777-786, 2005.
DOI : 10.1074/jbc.m406391200

URL : http://www.jbc.org/content/280/1/777.full.pdf

M. Enomoto-iwamoto, J. Kitagaki, E. Koyama, Y. Tamamura, C. Wu et al.,

T. Koike, H. Okada, T. Komori, and T. Yoneda, The Wnt Antagonist Frzb, 2002.

, Regulates Chondrocyte Maturation and Long Bone Development during Limb Skeletogenesis, Developmental Biology, vol.251, pp.142-156

S. L. Etheridge, S. Ray, S. Li, N. S. Hamblet, N. Lijam et al., Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development, 2008.

E. Evangelou, K. Chapman, I. Meulenbelt, F. B. Karassa, J. Loughlin et al.,

M. Doherty, S. Doherty, J. J. Gómez-reino, and A. Gonzalez, Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand, Arthritis Rheum, vol.60, pp.1710-1721, 2009.

P. J. Fanning, G. Emkey, R. J. Smith, A. J. Grodzinsky, N. Szasz et al., Mechanical regulation of mitogen-activated protein kinase signaling in articular cartilage, J. Biol. Chem, vol.278, pp.50940-50948, 2003.

T. Furukawa, D. R. Eyre, S. Koide, and M. J. Glimcher, , 1980.

O. Gabay, C. Sanchez, C. Salvat, F. Chevy, M. Breton et al., Stigmasterol: a phytosterol with potential anti161 osteoarthritic properties, Osteoarthritis and Cartilage, vol.18, pp.106-116, 2010.

B. Gao, H. Song, K. Bishop, G. Elliot, L. Garrett et al., Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2, Dev Cell, vol.20, pp.163-176, 2011.

W. E. Garrett, K. P. Speer, and D. T. Kirkendall, Principles and Practice of, 2000.

, Orthopaedic Sports Medicine

K. Gelse, E. Pöschl, A. , and T. , Collagens-structure, function, and biosynthesis, Advanced Drug Delivery Reviews, vol.55, pp.1531-1546, 2003.

C. Gendron, M. Kashiwagi, N. H. Lim, J. J. Enghild, I. B. Thøgersen et al., Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4, J. Biol. Chem, vol.282, pp.18294-18306, 2007.

S. S. Glasson, R. Askew, B. Sheppard, B. A. Carito, T. Blanchet et al., Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice, Arthritis Rheum, vol.50, pp.2547-2558, 2004.

S. S. Glasson, R. Askew, B. Sheppard, B. Carito, T. Blanchet et al., Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis, Nature, vol.434, p.644, 2005.

A. Glinka, W. Wu, H. Delius, A. P. Monaghan, C. Blumenstock et al., Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction, Nature, vol.391, pp.357-362, 1998.

T. Golan, A. Yaniv, A. Bafico, G. Liu, and A. Gazit, The human Frizzled 6, 2004.

, HFz6) acts as a negative regulator of the canonical Wnt. beta-catenin signaling cascade

, J. Biol. Chem, vol.279, pp.14879-14888

M. B. Goldring and M. Otero, Inflammation in osteoarthritis, Curr Opin Rheumatol, vol.23, pp.471-478, 2011.

M. B. Goldring, K. Fukuo, J. R. Birkhead, E. Dudek, and L. J. Sandell, , 1994.

, Transcriptional suppression by interleukin-1 and interferon-gamma of type II collagen gene expression in human chondrocytes, J. Cell. Biochem, vol.54, pp.85-99

M. B. Goldring, M. Otero, D. A. Plumb, C. Dragomir, M. Favero et al., Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis, Eur Cell Mater, vol.21, pp.202-220, 2011.

R. M. Goodman, S. Thombre, Z. Firtina, D. Gray, D. Betts et al., Sprinter: a novel transmembrane protein required for Wg secretion and signaling, Development, vol.133, pp.4901-4911, 2006.

J. N. Gouze, K. Bordji, S. Gulberti, B. Terlain, P. Netter et al., Interleukin-1beta down-regulates the expression of glucuronosyltransferase I, a key enzyme priming glycosaminoglycan biosynthesis: influence of glucosamine on interleukin-1beta-mediated effects in rat chondrocytes, 2001.

, Arthritis Rheum, vol.44, pp.351-360

R. S. Gray, I. Roszko, and L. Solnica-krezel, Planar cell polarity: coordinating morphogenetic cell behaviors with embryonic polarity, Dev. Cell, vol.21, pp.120-133, 2011.

K. E. Gregory, J. T. Oxford, Y. Chen, J. E. Gambee, S. P. Gygi et al., , 2000.

, J. Biol. Chem, vol.275, pp.11498-11506

J. Gross and C. M. Lapiere, Collagenolytic activity in amphibian tissues: a 163 tissue culture assay, Proc. Natl. Acad. Sci. U.S.A, vol.48, pp.1014-1022, 1962.

J. C. Gross and M. Boutros, Secretion and extracellular space travel of Wnt proteins, Curr. Opin. Genet. Dev, vol.23, pp.385-390, 2013.

P. A. Guerne, D. A. Carson, and M. Lotz, IL-6 production by human articular chondrocytes. Modulation of its synthesis by cytokines, growth factors, and hormones in vitro, J. Immunol, vol.144, pp.499-505, 1990.

F. Guilak, L. G. Alexopoulos, M. L. Upton, I. Youn, J. B. Choi et al., The pericellular matrix as a transducer of biomechanical and biochemical signals in articular cartilage, Ann. N. Y. Acad. Sci, vol.1068, pp.498-512, 2006.

N. Guo, C. Hawkins, and J. Nathans, Frizzled6 controls hair patterning in mice, 2004.

, Proc. Natl. Acad. Sci. U.S.A, vol.101, pp.9277-9281

J. Haag, P. M. Gebhard, A. , and T. , SOX gene expression in human osteoarthritic cartilage, Pathobiology, vol.75, pp.195-199, 2008.

C. Halleskog and G. Schulte, Pertussis toxin-sensitive heterotrimeric G(?i/o) proteins mediate WNT/?-catenin and WNT/ERK1/2 signaling in mouse primary microglia stimulated with purified WNT-3A, Cell. Signal, vol.25, pp.822-828, 2013.

N. S. Hamblet, N. Lijam, P. Ruiz-lozano, J. Wang, Y. Yang et al., Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure, Development, vol.129, pp.5827-5838, 2002.

C. Hartmann and C. J. Tabin, Dual roles of Wnt signaling during chondrogenesis in the chicken limb, Development, vol.127, pp.3141-3159, 2000.

D. Heinegård and T. Saxne, The role of the cartilage matrix in osteoarthritis, 2011.

, Nat Rev Rheumatol, vol.7, pp.50-56

B. Henderson, E. R. Pettipher, M. Van-den-heuvel, C. Harryman-samos, J. Klingensmith et al., Arthritogenic actions of recombinant IL-1 and tumour necrosis factor alpha in the rabbit: evidence for synergistic interactions between cytokines in vivo, Clin. Exp. Immunol, vol.75, pp.5293-5302, 1989.

T. P. Hill, D. Später, M. M. Taketo, W. Birchmeier, and C. Hartmann, , 2005.

, Canonical Wnt/?-Catenin Signaling Prevents Osteoblasts from Differentiating into Chondrocytes, Developmental Cell, vol.8, pp.727-738

S. Honsawek, A. Tanavalee, P. Yuktanandana, S. Ngarmukos, N. Saetan et al., Dickkopf-1 (Dkk-1) in plasma and synovial fluid is inversely correlated with radiographic severity of knee osteoarthritis patients, 2010.

, Musculoskelet Disord, vol.11, p.257

J. Hsieh, L. Kodjabachian, M. L. Rebbert, A. Rattner, P. M. Smallwood et al., A new secreted protein that binds to Wnt proteins and inhibits their activites, Nature, vol.398, pp.431-436, 1999.

E. B. Hunziker, M. Michel, and D. Studer, Ultrastructure of adult human articular cartilage matrix after cryotechnical processing, Microsc. Res. Tech, vol.37, pp.271-284, 1997.

S. Hwang, J. Ryu, I. Kim, E. Jho, H. Jung et al.,

J. Chun, Wnt-7a causes loss of differentiated phenotype and inhibits apoptosis of articular chondrocytes via different mechanisms, J. Biol. Chem, vol.279, pp.26597-26604, 2004.

S. Hwang, S. Yu, J. Ryu, H. Jeon, Y. Yoo et al.,

S. , Regulation of ?-Catenin Signaling and Maintenance of Chondrocyte 165, 2005.

, Differentiation by Ubiquitin-independent Proteasomal Degradation of ?-Catenin, J

, Biol. Chem, vol.280, pp.12758-12765

S. Hwang, S. Yu, S. Lee, C. , and J. , Wnt-3a regulates chondrocyte differentiation via c-Jun/AP-1 pathway, FEBS Letters, vol.579, pp.4837-4842, 2005.

M. Illario, A. L. Cavallo, K. U. Bayer, T. Di-matola, G. Fenzi et al., Calcium/calmodulin-dependent protein kinase II binds to Raf-1 and modulates integrin-stimulated ERK activation, J. Biol. Chem, vol.278, pp.45101-45108, 2003.

K. Imai, M. Morikawa, J. D'armiento, H. Matsumoto, K. Komiya et al., Differential expression of WNTs and FRPs in the synovium of rheumatoid arthritis and osteoarthritis, Biochemical and Biophysical Research Communications, vol.345, pp.1615-1620, 2006.

C. Y. Janda, D. Waghray, A. M. Levin, C. Thomas, and K. C. Garcia, Structural basis of Wnt recognition by Frizzled, Science, vol.337, pp.59-64, 2012.

K. S. Joeng, C. Schumacher, C. R. Zylstra-diegel, F. Long, W. et al., , 2011.

, Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo, Dev Biol, vol.359, pp.222-229

T. Kadowaki, E. Wilder, J. Klingensmith, K. Zachary, P. et al., The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing, Genes Dev, vol.10, pp.3116-3128, 1996.

M. Kahn, Can we safely target the WNT pathway?, Nat Rev Drug Discov, vol.13, pp.513-532, 2014.

M. Kapoor, J. Martel-pelletier, D. Lajeunesse, J. Pelletier, and H. Fahmi, , 2011.

, Role of proinflammatory cytokines in the pathophysiology of osteoarthritis, Nat Rev Rheumatol, vol.7, pp.33-42

G. A. Karpouzas and R. A. Terkeltaub, New developments in the pathogenesis of articular cartilage calcification, Curr Rheumatol Rep, vol.1, pp.121-127, 1999.

R. Kelwick, I. Desanlis, G. N. Wheeler, and D. R. Edwards, The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family, Genome Biol, vol.16, 2015.

C. Kiani, L. Chen, Y. J. Wu, A. J. Yee, Y. et al., Structure and function of aggrecan, Cell Res, vol.12, pp.19-32, 2002.

E. K. Kim and E. Choi, Pathological roles of MAPK signaling pathways in human diseases, Biochimica et Biophysica Acta, pp.396-405, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00566733

H. A. Kim, M. Cho, H. Y. Choi, C. S. Yoon, J. Y. Jhun et al., The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes, Arthritis Rheum, vol.54, pp.2152-2163, 2006.

S. Kim, D. Im, S. Kim, J. Ryu, S. Hwang et al., ?-Catenin regulates expression of cyclooxygenase-2 in articular chondrocytes, Biochemical and Biophysical Research Communications, vol.296, pp.221-226, 2002.

C. C. King, M. Sastri, P. Chang, J. Pennypacker, T. et al., The Rate of NF-?B Nuclear Translocation Is Regulated by PKA and A Kinase Interacting Protein 1, 2011.

T. Kirsch and K. Mark, Isolation of human type X collagen and immunolocalization in fetal human cartilage, Eur. J. Biochem, vol.6, pp.575-580, 1991.

A. Kleinschmit, T. Koyama, K. Dejima, Y. Hayashi, K. Kamimura et al., Drosophila heparan sulfate 6-O endosulfatase regulates Wingless morphogen gradient formation, biology. Seminars in Cell & Developmental Biology, vol.345, pp.434-443, 2010.

Y. Li, S. A. Rankin, D. Sinner, A. P. Kenny, P. A. Krieg et al., Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling, Genes Dev, vol.22, pp.3050-3063, 2008.

D. Liang, Q. Zeng, Z. Xu, H. Zhang, L. Gui et al., BAFF activates Erk1/2 promoting cell proliferation and survival by Ca2+-CaMKII-dependent inhibition of PP2A in normal and neoplastic B-lymphoid cells, Biochem. Pharmacol, vol.87, pp.332-343, 2014.

S. Lim, R. L. Longley, J. R. Couchman, and A. Woods, Direct Binding of, 2003.

, Syndecan-4 Cytoplasmic Domain to the Catalytic Domain of Protein Kinase C? (PKC?)

, Increases Focal Adhesion Localization of PKC?, J. Biol. Chem, vol.278, pp.13795-13802

K. Lin, S. Wang, M. A. Julius, J. Kitajewski, M. Moos et al., The cysteine-rich frizzled domain of Frzb-1 is required and sufficient for modulation of Wnt signaling, Proc Natl Acad Sci U S A, vol.94, pp.11196-11200, 1997.

L. Ling, C. Dombrowski, K. M. Foong, L. M. Haupt, G. S. Stein et al.,

A. J. Wijnen and S. M. Cool, Synergism between Wnt3a and heparin enhances osteogenesis via a phosphoinositide 3-kinase/Akt/RUNX2 pathway, J. Biol. Chem, vol.285, pp.26233-26244, 2010.

F. C. Linn and L. Sokoloff, MOVEMENT AND COMPOSITION OF INTERSTITIAL FLUID OF CARTILAGE, Arthritis Rheum, vol.8, pp.481-494, 1965.

F. Liu, L. Hung, W. Wu, D. Chang, C. Huang et al.,

J. , Chondroprotective effects and mechanisms of resveratrol in advanced glycation end products-stimulated chondrocytes, Arthritis Res Ther, vol.12, p.167, 2010.

G. M. Liverpool, R. , and S. , Surface Ultrastructure of Mature Adult Human Articular Cartilage, Bone & Joint Journal 51-B, pp.529-539, 1969.

C. Y. Logan, N. , and R. , The Wnt signaling pathway in development and disease, Annu. Rev. Cell Dev. Biol, vol.20, pp.781-810, 2004.

P. G. Loganathan, S. Nimmagadda, R. Huang, M. Scaal, C. et al., , 2005.

, Comparative analysis of the expression patterns of Wnts during chick limb development, Histochem. Cell Biol, vol.123, pp.195-201

P. Lorenzo, M. T. Bayliss, and D. Heinegård, Altered patterns and synthesis of extracellular matrix macromolecules in early osteoarthritis, Matrix Biol, vol.23, pp.381-391, 2004.

R. J. Lories, J. Peeters, A. Bakker, P. Tylzanowski, I. Derese et al.,

J. T. Thomas and F. P. Luyten, Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice, Arthritis & Rheumatism, vol.56, pp.4095-4103, 2007.

M. K. Lotz, C. , and B. , Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA, Nat Rev Rheumatol, vol.7, pp.579-587, 2011.

M. Lotz, R. Terkeltaub, and P. M. Villiger, Regulation of IL-8 expression by human articular chondrocytes, J. Immunol, vol.148, pp.466-473, 1992.

J. Loughlin, Z. Mustafa, A. Smith, C. Irven, A. J. Carr et al., Linkage analysis of chromosome 2q in osteoarthritis, Rheumatology, vol.39, pp.377-381, 2000.

J. Loughlin, B. Dowling, K. Chapman, L. Marcelline, Z. Mustafa et al., , 2004.

, Proc Natl Acad Sci U S A, vol.101, pp.9757-9762

B. Ma, C. A. Van-blitterswijk, and M. Karperien, A Wnt/?-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes, Arthritis Rheum, vol.64, pp.2589-2600, 2012.

B. Ma, J. C. Leijten, L. Wu, M. Kip, C. A. Van-blitterswijk et al., Gene expression profiling of dedifferentiated human articular chondrocytes in monolayer culture, Osteoarthritis and Cartilage, vol.21, pp.599-603, 2013.

M. A. Macconaill, The movements of bones and joints; the mechanical structure of articulating cartilage, J Bone Joint Surg Br, vol.33, pp.251-257, 1951.

T. Mahmoudi, S. F. Boj, P. Hatzis, V. S. Li, N. Taouatas et al., The Leukemia-Associated, 2010.

, Mllt10/Af10-Dot1l Are Tcf4/?-Catenin Coactivators Essential for Intestinal Homeostasis, PLoS Biol, vol.8

E. A. Makris, A. H. Gomoll, K. N. Malizos, J. C. Hu, and K. A. Athanasiou, , 2015.

, Repair and tissue engineering techniques for articular cartilage, Nat Rev Rheumatol, vol.11, pp.21-34

M. Maldonado, N. , and J. , The Role of Changes in Extracellular Matrix of Cartilage in the Presence of Inflammation on the Pathology of Osteoarthritis, Biomed Res Int, 2013.

H. J. Mankin and L. Lippiello, The turnover of adult rabbit articular cartilage, 1969.

, J Bone Joint Surg Am, vol.51, pp.1591-1600

H. J. Mankin, H. Dorfman, L. Lippiello, and A. Zarins, Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data, J Bone Joint Surg Am, vol.53, pp.523-537, 1971.

K. B. Marcu, M. Otero, E. Olivotto, R. M. Borzi, and M. B. Goldring, NF-?B Signaling: Multiple angles to target OA, Curr Drug Targets, vol.11, pp.599-613, 2010.

A. I. Maroudas, Balance between swelling pressure and collagen tension in normal and degenerate cartilage, Nature, vol.260, pp.808-809, 1976.

A. Maroudas, H. Muir, and J. Wingham, The correlation of fixed negative charge with glycosaminoglycan content of human articular cartilage, Biochim. Biophys. Acta, vol.177, pp.492-500, 1969.

A. Maroudas, M. T. Bayliss, N. Uchitel-kaushansky, R. Schneiderman, G. et al., Aggrecan turnover in human articular cartilage: use of aspartic acid racemization as a marker of molecular age, Arch. Biochem. Biophys, vol.350, pp.61-71, 1998.

J. Martel-pelletier, R. Mccollum, J. Dibattista, M. P. Faure, J. A. Chin et al., The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes. Identification as the type I receptor and analysis of binding kinetics and biologic function, Arthritis Rheum, vol.35, pp.530-540, 1992.

J. O. Mason, J. Kitajewski, and H. E. Varmus, Mutational analysis of mouse, 1992.

, Wnt-1 identifies two temperature-sensitive alleles and attributes of Wnt-1 protein essential for transformation of a mammary cell line, Mol. Biol. Cell, vol.3, pp.521-533

M. Mathy-hartert, L. Hogge, C. Sanchez, G. Deby-dupont, J. M. Crielaard et al., Interleukin-1beta and interleukin-6 disturb the antioxidant enzyme system in bovine chondrocytes: a possible explanation for oxidative stress generation, 2008.

, Osteoarthr. Cartil, vol.16, pp.756-763

T. Matsukawa, T. Sakai, T. Yonezawa, H. Hiraiwa, T. Hamada et al., MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes, 2013.

, Arthritis Res. Ther, vol.15, p.28

M. Matsuyama, S. Aizawa, and A. Shimono, Sfrp Controls Apicobasal Polarity and Oriented Cell Division in Developing Gut Epithelium, PLoS Genet, vol.5, 2009.

J. A. Mengshol, M. P. Vincenti, C. I. Coon, A. Barchowsky, and C. E. Brinckerhoff, 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, vol.43, pp.801-811, 2000.

A. J. Mikels, N. , and R. , Purified Wnt5a Protein Activates or Inhibits ?Catenin-TCF Signaling Depending on Receptor Context, PLOS Biol, vol.4, p.115, 2006.

S. J. Millward-sadler, M. O. Wright, L. W. Davies, G. Nuki, and D. M. Salter, , 2000.

, Mechanotransduction via integrins and interleukin-4 results in altered aggrecan and matrix metalloproteinase 3 gene expression in normal, but not osteoarthritic, human articular chondrocytes, Arthritis Rheum, vol.43, pp.2091-2099

J. L. Min, I. Meulenbelt, N. Riyazi, M. Kloppenburg, J. J. Houwing-duistermaat et al., Association of the frizzled-related protein gene with symptomatic osteoarthritis at multiple sites, 2005.

, Arthritis & Rheumatism, vol.52, pp.1077-1080

S. Monaco, M. Illario, M. R. Rusciano, G. Gragnaniello, G. D. Spigna et al.,

L. Pastore, G. Fenzi, G. Rossi, and M. Vitale, Insulin stimulates fibroblast proliferation through calcium-calmodulin-dependent kinase II, Cell Cycle, vol.8, pp.2024-2030, 2009.

R. Muñoz, M. Moreno, C. Oliva, C. Orbenes, and J. Larraín, Syndecan-4 regulates non-canonical Wnt signalling and is essential for convergent and extension movements in Xenopus embryos, Nat Cell Biol, vol.8, pp.492-500, 2006.

H. Nagase and M. Kashiwagi, Aggrecanases and cartilage matrix degradation, 2003.

, Arthritis Res. Ther, vol.5, pp.94-103

H. Nagase, R. Visse, M. , and G. , Structure and function of matrix metalloproteinases and TIMPs, Cardiovasc. Res, vol.69, pp.562-573, 2006.

Y. Nakamura, M. Nawata, and S. Wakitani, Expression Profiles and Functional Analyses of Wnt-Related Genes in Human Joint Disorders, The American Journal of Pathology, vol.167, pp.97-105, 2005.

G. Nalesso, J. Sherwood, J. Bertrand, T. Pap, M. Ramachandran et al., WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways, J. Cell Biol, vol.193, pp.551-564, 2011.

J. Nam, B. D. Aguda, B. Rath, and S. Agarwal, Biomechanical thresholds regulate inflammation through the NF-kappaB pathway: experiments and modeling, 2009.

, PLoS ONE, vol.4, p.5262

J. Nam, P. Perera, J. Liu, B. Rath, J. Deschner et al.,

S. Agarwal, Sequential alterations in catabolic and anabolic gene expression parallel pathological changes during progression of monoiodoacetate-induced arthritis, 2011.

, PLoS ONE, vol.6, 24320.

C. Niehrs, The complex world of WNT receptor signalling, Nat Rev Mol Cell Biol, vol.13, pp.767-779, 2012.

K. Nishitani, H. Ito, T. Hiramitsu, R. Tsutsumi, S. Tanida et al., PGE2 inhibits MMP expression by suppressing MKK4-JNK MAP kinase-c-JUN pathway via EP4 in human articular chondrocytes, J. Cell. Biochem, vol.109, pp.425-433, 2010.

R. Nusse, A. Van-ooyen, D. Cox, Y. K. Fung, and H. Varmus, Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15, Nature, vol.307, pp.131-136, 1984.

O. , A. Crowley, C. , P. , M. et al., Cartilage Tissue Engineering: the Application of Nanomaterials and Stem Cell Technology. In Tissue Engineering for Tissue and Organ Regeneration, 2011.

A. Oeckinghaus, M. S. Hayden, G. , and S. , Crosstalk in NF-?B signaling 175 pathways, Nat Immunol, vol.12, pp.695-708, 2011.

H. Oh, C. Chun, C. , and J. , Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice, Arthritis & Rheumatism, vol.64, pp.2568-2578, 2012.

J. P. Overington, B. Al-lazikani, and A. L. Hopkins, How many drug targets are there?, Nat Rev Drug Discov, vol.5, pp.993-996, 2006.
DOI : 10.1038/nrd2199

G. Palmer, P. Guerne, F. Mezin, M. Maret, J. Guicheux et al., Production of interleukin-1 receptor antagonist by human articular chondrocytes, Arthritis Res, vol.4, pp.226-231, 2002.
URL : https://hal.archives-ouvertes.fr/inserm-00124790

T. Pap and A. Korb-pap, Cartilage damage in osteoarthritis and rheumatoid arthritis-two unequal siblings, Nat Rev Rheumatol, vol.11, pp.606-615, 2015.

E. L. Radin, R. , and R. M. , Role of subchondral bone in the initiation and progression of cartilage damage, Clin. Orthop. Relat. Res, pp.34-40, 1986.

P. Reboul, J. P. Pelletier, G. Tardif, J. M. Cloutier, and J. Martel-pelletier, The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis, J. Clin. Invest, vol.97, pp.2011-2019, 1996.
URL : https://hal.archives-ouvertes.fr/hal-01705146

I. Redler, V. C. Mow, M. L. Zimny, and J. Mansell, The ultrastructure and biomechanical significance of the tidemark of articular cartilage, Clin. Orthop. Relat, 1975.

. Res, , pp.357-362

E. Reichenberger, T. Aigner, K. Mark, H. Stöß, and W. Bertling, In situ hybridization studies on the expression of type X collagen in fetal human cartilage, Developmental Biology, vol.148, pp.562-572, 1991.

S. Rigoglou and A. G. Papavassiliou, The NF-?B signalling pathway in osteoarthritis, The International Journal of Biochemistry & Cell Biology, vol.45, pp.2580-2584, 2013.

M. Rottmar, R. Mhanna, S. Guimond-lischer, V. Vogel, M. Zenobi-wong et al., Interference with the contractile machinery of the fibroblastic chondrocyte cytoskeleton induces re-expression of the cartilage phenotype through involvement of PI3K, PKC and MAPKs. Experimental Cell Research, vol.320, pp.175-187, 2014.

J. A. Rudnicki and A. M. Brown, Inhibition of Chondrogenesis byWntGene, 1997.

. Expressionin-vivoandin and . Vitro, Developmental Biology, vol.185, pp.104-118

J. Ryu, C. , and J. , Opposing roles of WNT-5A and WNT-11 in interleukin-1beta regulation of type II collagen expression in articular chondrocytes, J. Biol. Chem, vol.281, pp.22039-22047, 2006.

M. B. Sadouk, J. P. Pelletier, G. Tardif, K. Kiansa, J. M. Cloutier et al., Human synovial fibroblasts coexpress IL-1 receptor type I and type II mRNA, 1995.

, The increased level of the IL-1 receptor in osteoarthritic cells is related to an increased level of the type I receptor, Lab. Invest, vol.73, pp.347-355

J. Saklatvala, Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage, Nature, vol.322, pp.547-549, 1986.

J. Saklatvala, Inflammatory signaling in cartilage: MAPK and NF-kappaB pathways in chondrocytes and the use of inhibitors for research into pathogenesis and therapy of osteoarthritis, Curr Drug Targets, vol.8, pp.305-313, 2007.

M. Salzano, M. R. Rusciano, E. Russo, M. Bifulco, L. Postiglione et al., Calcium/calmodulin-dependent protein kinase II, 2012.

, Raf-1 at serine 338 and mediates Ras-stimulated Raf-1 activation, Cell Cycle, vol.11, pp.2100-2106

J. D. Sandy, P. J. Neame, R. E. Boynton, and C. R. Flannery, , 1991.

, J. Biol. Chem, vol.266, pp.8683-8685

A. Santoro, J. Conde, M. Scotece, V. Abella, A. Lois et al., SERPINE2 Inhibits IL-1?-Induced MMP13 Expression in Human Chondrocytes: Involvement of ERK/NF-?B/AP-1 Pathways, vol.10, p.135979, 2015.

T. Saxne and D. Heinegård, Synovial fluid analysis of two groups of proteoglycan epitopes distinguishes early and late cartilage lesions, Arthritis & Rheumatism, vol.35, pp.385-390, 1992.

G. Schett, J. Zwerina, D. , and J. , The role of Wnt proteins in arthritis, 2008.

, Nat Clin Pract Rheum, vol.4, pp.473-480

J. L. Scott, C. Gabrielides, R. K. Davidson, T. E. Swingler, I. M. Clark et al., , 2010.

, Superoxide dismutase downregulation in osteoarthritis progression and end-stage disease, Ann Rheum Dis, vol.69, pp.1502-1510

C. A. Séguin and S. M. Bernier, TNFalpha suppresses link protein and type II collagen expression in chondrocytes: Role of MEK1/2 and NF-kappaB signaling pathways, J. Cell. Physiol, vol.197, pp.356-369, 2003.

C. A. Séguin, M. Bojarski, R. M. Pilliar, P. J. Roughley, and R. A. Kandel, , 2006.

, Differential regulation of matrix degrading enzymes in a TNFalpha-induced model of nucleus pulposus tissue degeneration, Matrix Biol, vol.25, pp.409-418

M. V. Semënov, K. Tamai, B. K. Brott, M. Kühl, S. Sokol et al., Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6, Current Biology, vol.11, pp.951-961, 2001.

M. Shakibaei, G. Schulze-tanzil, T. John, and A. Mobasheri, Curcumin protects human chondrocytes from IL-l1beta-induced inhibition of collagen type II and beta1-integrin expression and activation of caspase-3: an immunomorphological study, p.178, 2005.

, Ann. Anat, vol.187, pp.487-497

R. P. Sharma and V. L. Chopra, Effect of the Wingless (wg1) mutation on wing and haltere development in Drosophila melanogaster, Dev. Biol, vol.48, pp.461-465, 1976.

J. Shi, C. Zhang, Z. Yi, L. , and C. , Explore the variation of MMP3, JNK, p38 MAPKs, and autophagy at the early stage of osteoarthritis, IUBMB Life, vol.68, p.293, 2016.

F. H. Silver, G. Bradica, and A. Tria, Elastic energy storage in human articular cartilage: estimation of the elastic modulus for type II collagen and changes associated with osteoarthritis, Matrix Biology, vol.21, pp.129-137, 2002.

K. Simons, T. , and D. , Lipid rafts and signal transduction, Nat. Rev. Mol, 2000.
DOI : 10.1038/35036052

, Cell Biol, vol.1, pp.31-39

M. Simons and M. Mlodzik, Planar cell polarity signaling: from fly development to human disease, Annu. Rev. Genet, vol.42, pp.517-540, 2008.

M. Simons, W. J. Gault, D. Gotthardt, R. Rohatgi, T. J. Klein et al., Electrochemical cues regulate assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization, Nat. Cell Biol, vol.11, pp.286-294, 2009.

D. C. Slusarski, J. Yang-snyder, W. B. Busa, and R. T. Moon, Modulation of embryonic intracellular Ca2+ signaling by Wnt-5A, Dev. Biol, vol.182, pp.114-120, 1997.

D. C. Slusarski, V. G. Corces, and R. T. Moon, Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling, Nature, vol.390, pp.410-413, 1997.

B. D. Smolich, J. A. Mcmahon, A. P. Mcmahon, P. , and J. , Wnt family proteins are secreted and associated with the cell surface, Mol. Biol. Cell, vol.4, pp.1267-1275, 1993.

R. Song, M. D. Tortorella, A. Malfait, J. T. Alston, Z. Yang et al.,

D. W. Griggs, Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5, Arthritis Rheum, vol.56, pp.575-585, 2007.

S. Fox, A. J. Bedi, A. Rodeo, and S. A. , The Basic Science of Articular Cartilage, Sports Health, vol.1, pp.461-468, 2009.

D. Später, T. P. Hill, R. J. O'sullivan, M. Gruber, D. A. Conner et al., Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis, Development, vol.133, pp.3039-3049, 2006.

R. A. Stockwell, The interrelationship of cell density and cartilage thickness in mammalian articular cartilage, J Anat, vol.109, pp.411-421, 1971.

D. G. Stokes, G. Liu, R. Dharmavaram, D. Hawkins, and S. Piera-velazquez,

S. A. Jimenez, Regulation of type-II collagen gene expression during human chondrocyte de-differentiation and recovery of chondrocyte-specific phenotype in culture involves Sry-type high-mobility-group box (SOX) transcription factors, 2001.

, Biochem J, vol.360, pp.461-470

J. Stöve, K. Huch, K. P. Günther, and H. P. Scharf, Interleukin-1beta induces different gene expression of stromelysin, aggrecan and tumor-necrosis-factorstimulated gene 6 in human osteoarthritic chondrocytes in vitro, Pathobiology, vol.68, pp.144-149, 2000.

S. Ströbel, M. Loparic, D. Wendt, A. D. Schenk, C. Candrian et al., Anabolic and catabolic responses of human articular chondrocytes to varying oxygen percentages, Arthritis Res. Ther, vol.12, p.34, 2010.

S. Su, C. Tsai, C. Lee, D. M. Salter, and H. Lee, Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee, Arthritis & Rheumatism, vol.56, pp.137-146, 2005.

P. Verma and K. Dalal, ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis, J. Cell. Biochem, vol.112, pp.3507-3514, 2011.

T. Videman, I. Eronen, C. , and T. , [3H]proline incorporation and hydroxyproline concentration in articular cartilage during the development of osteoarthritis caused by immobilization. A study in vivo with rabbits, Biochem. J, vol.200, pp.435-440, 1981.

P. M. Villiger, R. Terkeltaub, and M. Lotz, Monocyte chemoattractant protein1 (MCP-1) expression in human articular cartilage. Induction by peptide regulatory factors and differential effects of dexamethasone and retinoic acid, J. Clin. Invest, vol.90, pp.488-496, 1992.

G. D. Walker, M. Fischer, J. Gannon, R. C. Thompson, and T. R. Oegema, , 1995.

, Expression of type-X collagen in osteoarthritis, J. Orthop. Res, vol.13, pp.4-12

J. B. Wallingford and R. Habas, The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity, Development, vol.132, pp.4421-4436, 2005.

F. Wan and M. J. Lenardo, The nuclear signaling of NF-?B: current knowledge, new insights, and future perspectives, Cell Res, vol.20, pp.24-33, 2009.

H. Wang, M. Xu, J. Ma, Y. Zhang, and C. Xie, Frizzled-8 as a putative therapeutic target in human lung cancer, Biochem. Biophys. Res. Commun, vol.417, p.62, 2012.

J. Wang, D. Markova, D. G. Anderson, Z. Zheng, I. M. Shapiro et al., TNF-? and IL-1? Promote a Disintegrin-like and Metalloprotease with, 2011.

, Thrombospondin Type I Motif-5-mediated Aggrecan Degradation through Syndecan-4 183

, Intervertebral Disc, vol.286, pp.39738-39749

S. Wang, M. Krinks, K. Lin, F. P. Luyten, M. et al., Frzb, a Secreted Protein Expressed in the Spemann Organizer, Binds and Inhibits Wnt-8, Cell, vol.88, pp.757-766, 1997.

C. Wellbrock, M. Karasarides, and R. Marais, The RAF proteins take centre stage, Nat Rev Mol Cell Biol, vol.5, pp.875-885, 2004.

K. Willert, J. D. Brown, E. Danenberg, A. W. Duncan, I. L. Weissman et al., Wnt proteins are lipid-modified and can act as stem cell growth factors, Nature, vol.423, pp.448-452, 2003.

R. E. Wilusz, J. Sanchez-adams, G. , and F. , The Structure and Function of the Pericellular Matrix of Articular Cartilage, Matrix Biol, vol.0, pp.25-32, 2014.

A. Wise, K. Gearing, R. , and S. , Target validation of G-protein coupled receptors, Drug Discov. Today, vol.7, pp.235-246, 2002.

F. Witte, J. Dokas, F. Neuendorf, S. Mundlos, and S. Stricker, Comprehensive expression analysis of all Wnt genes and their major secreted antagonists during mouse limb development and cartilage differentiation, Gene Expression Patterns, vol.9, pp.215-223, 2009.

D. E. Woolley, R. W. Glanville, M. J. Crossley, and J. M. Evanson, Purification of rheumatoid synovial collagenase and its action on soluble and insoluble collagen, 1975.

, Eur. J. Biochem, vol.54, pp.611-622

J. J. Wu, P. E. Woods, and D. R. Eyre, Identification of cross-linking sites in bovine cartilage type IX collagen reveals an antiparallel type II-type IX molecular relationship and type IX to type IX bonding, J. Biol. Chem, vol.267, pp.23007-23014, 1992.

Q. Wu, M. Zhu, R. N. Rosier, M. J. Zuscik, R. J. O'keefe et al., Betacatenin, cartilage, and osteoarthritis, Ann. N. Y. Acad. Sci, vol.1192, pp.344-350, 2010.

A. Wynshaw-boris, Chapter Nine-Dishevelled: In Vivo Roles of a Multifunctional Gene Family During Development, Current Topics in Developmental Biology, pp.213-235, 2012.

C. Yang, S. Li, H. J. Helminen, J. S. Khillan, Y. Bao et al., , 1997.

, Apoptosis of Chondrocytes in Transgenic Mice Lacking Collagen II. Experimental Cell Research, vol.235, pp.370-373

K. G. Yang, D. B. Saris, R. E. Geuze, M. H. Van-rijen, Y. J. Van-der-helm et al., Altered in vitro chondrogenic properties of chondrocytes harvested from unaffected cartilage in osteoarthritic joints, 2006.

, Osteoarthr. Cartil, vol.14, pp.561-570

Y. Yang, N. Lijam, D. J. Sussman, and M. Tsang, Genomic organization of mouse Dishevelled genes, Gene, vol.180, pp.121-123, 1996.

Y. Yang, L. Topol, H. Lee, and J. Wu, Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation, Development, vol.130, pp.1003-1015, 2003.

R. Yasuhara, T. Yuasa, J. A. Williams, S. W. Byers, S. Shah et al., Wnt/beta-catenin and retinoic acid receptor signaling pathways interact to regulate chondrocyte function and matrix turnover, 2010.
DOI : 10.1074/jbc.m109.053926

URL : http://www.jbc.org/content/285/1/317.full.pdf

, Biol. Chem, vol.285, pp.317-327

R. Yasuhara, Y. Ohta, T. Yuasa, N. Kondo, T. Hoang et al., Roles of ?-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells, Lab. Invest, vol.91, pp.1739-1752, 2011.

N. Yokoyama, D. Yin, and C. C. Malbon, Abundance, complexation, and trafficking of Wnt/beta-catenin signaling elements in response to Wnt3a, J Mol Signal, vol.2, p.11, 2007.

J. You, T. Belenkaya, L. , and X. , Sulfated is a negative feedback regulator of wingless in Drosophila, Dev. Dyn, vol.240, pp.640-648, 2011.

T. Yuasa, T. Otani, T. Koike, M. Iwamoto, and M. Enomoto-iwamoto, Wnt/?catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration, Lab Invest, vol.88, pp.264-274, 2008.

M. Yun, S. Kim, S. H. Jeon, J. Lee, and K. Choi, Both ERK and, 2005.

, Wnt/?-catenin pathways are involved in Wnt3a-induced proliferation, Journal of Cell Science, vol.118, pp.313-322

G. Zhai, J. Doré, and P. Rahman, TGF-? signal transduction pathways and osteoarthritis, Rheumatol Int, vol.35, pp.1283-1292, 2015.
DOI : 10.1007/s00296-015-3251-z

L. Zhai, D. Chaturvedi, C. , and S. , Drosophila wnt-1 undergoes a hydrophobic modification and is targeted to lipid rafts, 2004.
DOI : 10.1074/jbc.m403407200

URL : http://www.jbc.org/content/279/32/33220.full.pdf

, J. Biol. Chem, vol.279, pp.33220-33227

Y. Zhou, F. Bi, G. Yang, C. , and J. , Association between single nucleotide polymorphisms of DOT1L gene and risk of knee osteoarthritis in a Chinese Han population, Cell Biochem. Biophys, vol.70, pp.1677-1682, 2014.

M. Zhu, M. Chen, M. Zuscik, Q. Wu, Y. Wang et al., Inhibition of ?-Catenin Signaling in Articular Chondrocytes Results in Articular Cartilage Destruction, Arthritis Rheum, vol.58, pp.2053-2064, 2008.

M. Zhu, D. Tang, Q. Wu, S. Hao, M. Chen et al., Activation of ?-Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis-Like Phenotype in Adult ?-Catenin Conditional Activation Mice, Inderbir Singh's Textbook of Human Histology: With Colour Atlas and Practical Guide, vol.24, pp.12-21, 2009.

, RESUME EN FRANÇAIS, vol.189

R. Amerongen, . Van, A. Mikels, N. , and R. , Alternative Wnt Signaling Is Initiated by Distinct Receptors, Sci. Signal, vol.1, pp.9-9, 2008.

P. Barre, F. Redini, K. Boumediene, C. Vielpeau, and J. Pujol, , 2000.

, Semiquantitative reverse transcription-polymerase chain reaction analysis of syndecan1 and-4 messages in cartilage and cultured chondrocytes from osteoarthritic joints, Osteoarthritis and Cartilage, vol.8, pp.34-43

A. B. Blom, S. M. Brockbank, P. L. Van-lent, H. M. Van-beuningen, J. Geurts et al., Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1, Arthritis Rheum, vol.60, pp.501-512, 2009.

J. Chun, H. Oh, S. Yang, P. , and M. , Wnt signaling in cartilage development and degeneration, BMB Rep, vol.41, pp.485-494, 2008.

F. Echtermeyer, J. Bertrand, R. Dreier, I. Meinecke, K. Neugebauer et al., Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis, Nat. Med, vol.15, pp.1072-1076, 2009.

A. Elfenbein and M. Simons, Syndecan-4 signaling at a glance, J. Cell. Sci, vol.126, pp.3799-3804, 2013.

S. Hwang, J. Ryu, I. Kim, E. Jho, H. Jung et al., Wnt-7a causes loss of differentiated phenotype and inhibits apoptosis of articular chondrocytes via different mechanisms, J. Biol. Chem, vol.279, p.200, 2004.

S. Hwang, S. Yu, S. Lee, C. , and J. , Wnt-3a regulates chondrocyte differentiation via c-Jun/AP-1 pathway, FEBS Letters, vol.579, pp.4837-4842, 2005.

M. Kühl, L. C. Sheldahl, M. Park, J. R. Miller, and R. T. Moon, The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape, Trends in Genetics, vol.16, pp.279-283, 2000.

M. Kühl, L. C. Sheldahl, C. C. Malbon, and R. T. Moon, Ca(2+)/calmodulindependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus, J. Biol. Chem, vol.275, pp.12701-12711, 2000.

B. Ma, C. A. Van-blitterswijk, and M. Karperien, A Wnt/?-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes, Arthritis Rheum, vol.64, pp.2589-2600, 2012.

B. T. Macdonald, M. V. Semenov, and X. He, SnapShot: Wnt/beta-catenin signaling, Cell, vol.131, p.1204, 2007.

J. R. Miller, A. M. Hocking, J. D. Brown, and R. T. Moon, Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways, Oncogene, vol.18, pp.7860-7872, 1999.

R. Muñoz, M. Moreno, C. Oliva, C. Orbenes, and J. Larraín, Syndecan-4 regulates non-canonical Wnt signalling and is essential for convergent and extension movements in Xenopus embryos, Nat Cell Biol, vol.8, pp.492-500, 2006.

G. Nalesso, J. Sherwood, J. Bertrand, T. Pap, M. Ramachandran et al., WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways, J. Cell Biol, vol.193, pp.551-564, 2011.

I. Papathanasiou, K. N. Malizos, and A. Tsezou, Bone morphogenetic protein2-induced Wnt/?-catenin signaling pathway activation through enhanced low-densitylipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes, Arthritis Res Ther, vol.14, p.82, 2012.

T. Yuasa, T. Otani, T. Koike, M. Iwamoto, and M. Enomoto-iwamoto, Wnt/?catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration, Lab Invest, vol.88, pp.264-274, 2008.

B. T. Macdonald, M. V. Semenov, and X. He, SnapShot: Wnt/beta-catenin signaling, Cell, vol.131, p.1204, 2007.

M. V. Semenov, R. Habas, B. T. Macdonald, and X. He, SnapShot: Noncanonical Wnt Signaling Pathways. Cell, vol.131, p.1378, 2007.

B. T. Macdonald, K. Tamai, and X. He, Wnt/beta-catenin signaling: components, mechanisms, and diseases, Dev. Cell, vol.17, pp.9-26, 2009.

H. Clevers, Wnt/beta-catenin signaling in development and disease, Cell, vol.127, pp.469-480, 2006.

J. R. Miller, A. M. Hocking, J. D. Brown, and R. T. Moon, Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways, Oncogene, vol.18, pp.7860-7872, 1999.

B. Gao, Wnt regulation of planar cell polarity (PCP), Curr. Top. Dev. Biol, vol.101, pp.263-295, 2012.

M. Kühl, L. C. Sheldahl, M. Park, J. R. Miller, and R. T. Moon, The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape, Trends in Genetics, vol.16, pp.279-283, 2000.

T. Grigoryan, P. Wend, A. Klaus, and W. Birchmeier, Deciphering the function of canonical Wnt signals in development and disease: conditional loss-and gain-offunction mutations of beta-catenin in mice, Genes Dev, vol.22, pp.2308-2341, 2008.

R. Nusse, Wnt signaling in disease and in development, Cell Res, vol.15, pp.28-32, 2005.

J. Chun, H. Oh, S. Yang, and M. Park, Wnt signaling in cartilage development and degeneration, BMB Rep, vol.41, pp.485-494, 2008.

G. Nalesso, WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways, J. Cell Biol, vol.193, pp.551-564, 2011.

R. Yasuhara, Roles of ?-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells, Lab. Invest, vol.91, pp.1739-1752, 2011.

D. G. Monroe, M. E. Mcgee-lawrence, M. J. Oursler, and J. J. Westendorf, Update on Wnt signaling in bone cell biology and bone disease, Gene, vol.492, pp.1-18, 2012.

F. Dell'accio, C. De-bari, N. M. Eltawil, P. Vanhummelen, and C. Pitzalis, Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt-16 expression and signaling after injury and in osteoarthritis, Arthritis & Rheumatism, vol.58, pp.1410-1421, 2008.

A. Merlos-suárez, The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse, Cell Stem Cell, vol.8, pp.511-524, 2011.

L. Vermeulen, Wnt activity defines colon cancer stem cells and is regulated by the microenvironment, Nat. Cell Biol, vol.12, pp.468-476, 2010.

E. I. Leonova and O. V. Galzitskaya, Structure and functions of syndecans in vertebrates, Biochemistry Mosc, vol.78, pp.1071-1085, 2013.

A. Elfenbein and M. Simons, Syndecan-4 signaling at a glance, J. Cell. Sci, vol.126, pp.3799-3804, 2013.

M. Simons and A. Horowitz, Syndecan-4-mediated signalling, Cellular Signalling, vol.13, pp.855-862, 2001.

A. Elfenbein, Suppression of RhoG activity is mediated by a syndecan 4synectin-RhoGDI1 complex and is reversed by PKCalpha in a Rac1 activation pathway, J. Cell Biol, vol.186, pp.75-83, 2009.

K. Burridge, K. Wennerberg, R. , and R. Stage, Cell, vol.116, pp.167-179, 2004.

R. Muñoz, M. Moreno, C. Oliva, C. Orbenes, and J. Larraín, Syndecan-4 regulates noncanonical Wnt signalling and is essential for convergent and extension movements in Xenopus embryos, Nat Cell Biol, vol.8, pp.492-500, 2006.

B. Ohkawara, A. Glinka, and C. Niehrs, Rspo3 binds syndecan 4 and induces Wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis, Dev. Cell, vol.20, pp.303-314, 2011.

M. F. Smith, J. K. Gautam, S. G. Black, and P. B. Ernst, Microbial-induced regulation of syndecan expression: important host defense mechanism or an opportunity for pathogens?, ScientificWorldJournal, vol.6, pp.442-445, 2006.

P. Barre, F. Redini, K. Boumediene, C. Vielpeau, and J. Pujol, Semiquantitative reverse transcription-polymerase chain reaction analysis of syndecan-1 and-4 messages in cartilage and cultured chondrocytes from osteoarthritic joints, Osteoarthritis and Cartilage, vol.8, pp.34-43, 2000.

F. Echtermeyer, Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis, Nat. Med, vol.15, pp.1072-1076, 2009.

Y. Tamamura, Developmental Regulation of Wnt/?-Catenin Signals Is Required for Growth Plate Assembly, Cartilage Integrity, and Endochondral Ossification

, Biol. Chem, vol.280, pp.19185-19195, 2005.

Q. Wu, Beta-catenin, cartilage, and osteoarthritis, Ann. N. Y. Acad. Sci, vol.1192, pp.344-350, 2010.

Y. Nakamura, M. Nawata, and S. Wakitani, Expression Profiles and Functional Analyses of Wnt-Related Genes in Human Joint Disorders, The American Journal of Pathology, vol.167, pp.97-105, 2005.

M. Yun, S. Kim, S. H. Jeon, J. Lee, and K. Choi, Both ERK and Wnt/?-catenin pathways are involved in Wnt3a-induced proliferation, Journal of Cell Science, vol.118, pp.313-322, 2005.

C. Halleskog and G. Schulte, Pertussis toxin-sensitive heterotrimeric G(?i/o) proteins mediate WNT/?-catenin and WNT/ERK1/2 signaling in mouse primary microglia stimulated with purified WNT-3A, Cell. Signal, vol.25, pp.822-828, 2013.

C. Y. Logan and R. Nusse, The Wnt signaling pathway in development and disease, Annu. Rev. Cell Dev. Biol, vol.20, pp.781-810, 2004.

N. S. Hamblet, Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure, Development, vol.129, pp.5827-5838, 2002.

Y. Lee, Y. Gao, and H. Wang, Differential mediation of the Wnt canonical pathway by mammalian Dishevelleds-1,-2, and-3, Cell. Signal, vol.20, pp.443-452, 2008.

S. L. Etheridge, Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development, PLoS Genet, vol.4, p.1000259, 2008.

M. Boutros, N. Paricio, D. I. Strutt, and M. Mlodzik, Dishevelled Activates JNK and Discriminates between JNK Pathways in Planar Polarity and wingless Signaling, vol.94, pp.109-118, 1998.

J. B. Wallingford and R. Habas, The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity, Development, vol.132, pp.4421-4436, 2005.

M. Simons, Electrochemical cues regulate assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization, Nat. Cell Biol, vol.11, pp.286-294, 2009.

S. T. Abraham, H. A. Benscoter, C. M. Schworer, and H. A. Singer, A Role for
URL : https://hal.archives-ouvertes.fr/pasteur-01351367

, Ca2+/Calmodulin-Dependent Protein Kinase II in the Mitogen-Activated Protein

, Kinase Signaling Cascade of Cultured Rat Aortic Vascular Smooth Muscle Cells, Circ Res, vol.81, pp.575-584, 1997.

R. S. Gray, I. Roszko, and L. Solnica-krezel, Planar cell polarity: coordinating morphogenetic cell behaviors with embryonic polarity, Dev. Cell, vol.21, pp.120-133, 2011.

N. Guo, C. Hawkins, and J. Nathans, Frizzled6 controls hair patterning in mice, Proc

, Natl. Acad. Sci. U.S.A, vol.101, pp.9277-9281, 2004.

T. Golan, A. Yaniv, A. Bafico, G. Liu, and A. Gazit, The human Frizzled 6 (HFz6) acts as a negative regulator of the canonical Wnt. beta-catenin signaling cascade, J. Biol

, Chem, vol.279, pp.14879-14888, 2004.

J. Haag, P. M. Gebhard, and T. Aigner, SOX gene expression in human osteoarthritic cartilage, Pathobiology, vol.75, pp.195-199, 2008.

R. Dreier, Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders, Arthritis Res. Ther, vol.12, p.216, 2010.

T. Pap and A. Korb-pap, Cartilage damage in osteoarthritis and rheumatoid arthritis-two unequal siblings, Nat Rev Rheumatol, vol.11, pp.606-615, 2015.

J. Ryu and J. Chun, Opposing roles of WNT-5A and WNT-11 in interleukin-1beta regulation of type II collagen expression in articular chondrocytes, J. Biol. Chem, vol.281, pp.22039-22047, 2006.

V. Lefebvre, P. Li, and B. De-crombrugghe, Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene, A new long form of Sox5 (L-Sox5), vol.17, pp.5718-5733, 1998.

M. J. Taschner, M. Rafigh, F. Lampert, S. Schnaiter, and C. Hartmann, Ca2+/Calmodulindependent kinase II signaling causes skeletal overgrowth and premature chondrocyte maturation, Dev. Biol, vol.317, pp.132-146, 2008.

M. Salzano, Calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates Raf-1 at serine 338 and mediates Ras-stimulated Raf-1 activation, Cell Cycle, vol.11, pp.2100-2106, 2012.

D. Liang, BAFF activates Erk1/2 promoting cell proliferation and survival by Ca2+-CaMKII-dependent inhibition of PP2A in normal and neoplastic B-lymphoid cells, Biochem. Pharmacol, vol.87, pp.332-343, 2014.

E. Cipolletta, Calmodulin-dependent kinase II mediates vascular smooth muscle cell proliferation and is potentiated by extracellular signal regulated kinase, Endocrinology, vol.151, pp.2747-2759, 2010.

M. Illario, Calcium/calmodulin-dependent protein kinase II binds to Raf-1 and modulates integrin-stimulated ERK activation, J. Biol. Chem, vol.278, pp.45101-45108, 2003.

S. Monaco, Insulin stimulates fibroblast proliferation through calciumcalmodulin-dependent kinase II, Cell Cycle, vol.8, pp.2024-2030, 2009.

B. M. Abidin, E. Owusu-kwarteng, and K. M. Heinonen, Frizzled-6 Regulates Hematopoietic Stem/Progenitor Cell Survival and Self-Renewal, J. Immunol, vol.195, pp.2168-2176, 2015.
URL : https://hal.archives-ouvertes.fr/pasteur-01351877

M. Kühl, L. C. Sheldahl, C. C. Malbon, and R. T. Moon, Ca(2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus, J. Biol. Chem, vol.275, pp.12701-12711, 2000.

H. J. Mankin, H. Dorfman, L. Lippiello, and A. Zarins, Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data, J Bone Joint Surg Am, vol.53, pp.523-537, 1971.

, DVL-2 is essential for Wnt-3a-induced down-regulation of COL2A1. Knockdown of DVL-2 reversed the inhibition by Wnt-3a of COL2A1 as evaluated by PCR (n=3). (D) Knock down of DVL-2 but not of DVL-1 or DVL-3 inhibited Wnt-3a

, Primary chondrocytes were transfected with siRNA specific to DVL-1, DVL-2, DVL-3 or siRNA unpaired Student's t-test (*, p.0

*. , After being washed three times with PBS, cartilage explants were treated with Wnt-3a, IL-1? or both in the DMEM-F12 medium supplemented with 10% FBS, 1% glutamine and 1% penicillin/ streptomycin for 48 h. 35 S-labeled proteoglycans in the medium were digested with papain (1 mg/ml), precipitated by cetylpyridinium chloride then dissolved in scintillation fluid, The radioactivity associated with GAGs was measured by liquid scintillation counting

, After the treatment, cells were washed with PBS and fixed with 4% (w/v) para-formaldehyde solution and permeabilized with 0.1% Triton-X100 then blocked in PBS containing 0.2% fish skin gelatin. Next, cells were incubated with anti-NF?B/p65 antibodies (1/400, Cell signaling), then washed with PBS and incubated with fluorophore-conjugated secondary antibodies. The nuclei were stained with DAPI. Digital images were captured with an inverted microscope, Leica DMI3000 B (Leica Microsystems, Germany), Immunofluorescence Chondrocytes were seeded onto the coverslips in 24-well plates and allowed to grow for 24 h, then treated or not with Wnt-3a and/or IL-1? for 20 min

, Given that loss of ?-catenin abolished the effect of Wnt-3a on ADAMTS-4 (Figure 3G), these data support the notion that inhibition of NF-?B pathway by Wnt-3a is ?-catenin-dependent, NF-?B/p65 into the nucleus

, Wnt-3a but even promoted its expression (Figure 3G). Altogether, these results demonstrated that Wnt-3a down regulates the expression of ADAMTS-4 by attenuating NF-?B signaling through ?-catenin-dependent pathway

, Wnt-3a counteracts IL-1?-induced up-regulation of ADAMTS-4 by reducing nuclear translocation of NF?B/p65

, therefore suggesting that induction of ADAMTS-4 is involved in the pathogenesis of OA. In line with these studies, treatment of human primary chondrocytes with IL-1? strongly increased the expression of ADAMTS-4 and did not significantly affect that of ADAMTS-5 (Figure. 4A). In addition, the knockdown of NF-?B/p65/RELA reduced by 80% the expression of ADAMTS-4 induced by IL-1? in primary chondrocytes (Figure 4B). Given that Wnt-3a reduced the activation of NF?B signaling pathway, the ability of Wnt-3a to counteract IL-1?-induced up-regulation of ADAMTS-4 was tested. As expected, co-treatment with Wnt-3a attenuated by about 60% the induction of ADAMTS-4 by IL-1? (Figure 4C), indicating that Wnt-3a is able to antagonize the effect of IL-1? on ADAMTS-4 expression. Similarly, analysis of ADAMTS-4 activity indicated co-treatment with Wnt-3a reduced by 30% the IL-1?-induced activity of ADAMTS-4 (Figure 4D). Altogether, these results clearly demonstrate that Wnt, human chondrocytes, the aggrecanase ADAMTS-4 but not ADAMTS-5 is induced by IL-1?, the main cytokine incriminated in OA pathogenesis, through activation of NF?B signaling pathway

, To gain insight into the Discussion WNT signaling was considered to be associated with arthritic cartilage destruction, since the level of ?-catenin was found to be, SAPK/JNK and NF?B signaling pathways have been suggested to be involved in the regulation of the expression of ADAMTSs by IL-1?

. Here, we provide evidence that Wnt/?-catenin signaling is a potent inhibitor of ADAMTS-4 in human primary chondrocytes and cartilage explants, remarkable contrast to what has been observed in animal models

, The presence of four putative NF-?B motifs in human ADAMTS4 gene promoter [24] suggests that it may be regulated by NF-?B and that Wnt-3a may inhibit ADAMTS-4 by suppressing the activation of NF-?B signaling. In agreement with this hypothesis, the knockdown of NF-?B/p65/RelA strongly reduced basal and IL-1?-induced expression of ADAMTS-4. Investigation of the mechanism involved in Wnt-3a down regulation of ADAMTS4 showed that Wnt3a impaired the activation of NF-?B signaling by reducing nuclear translocation of NF-?B/p65. In line with this, Wnt-3a inhibited the expression of IL6 and IL-1?, two established target genes of NF-?B pathway in human chondrocytes. It is well known that activation of NF-?B signaling by proinflammatory cytokines such as IL-1? potently induced cartilage matrix degradation. Investigation of the effect of Wnt/?-catenin signaling on the stimulatory effect of IL-1? on ADAMTS-4 expression and activity revealed that Wnt/?-catenin signaling counteracts these effects by reducing the nuclear translocation of NF-?B/p65 induced by the cytokine. This suggests that Wnt/?-catenin signaling counteracts NF-?B signaling in cartilage and may safeguard cartilage from degradation, These observations strongly argue for differential regulation of ADAMTS-4 by Wnt/?-catenin signaling in human and animal chondrocytes

G. Musumeci, M. A. Szychlinska, and A. Mobasheri, Age-related degeneration of articular cartilage in the pathogenesis of osteoarthritis: molecular markers of senescent chondrocytes, Histol Histopathol, vol.30, pp.1-12, 2015.

P. Wojdasiewicz, ?. A. Poniatowski, and D. Szukiewicz, The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis, Mediators Inflamm, p.561459, 2014.

S. Hwang, S. Yu, and J. Ryu, Regulation of ?-Catenin Signaling and Maintenance of Chondrocyte Differentiation by Ubiquitin-independent Proteasomal Degradation of ?-Catenin, J Biol Chem, vol.280, pp.12758-65, 2005.

Y. Nakamura, M. Nawata, and S. Wakitani, Expression Profiles and Functional Analyses of Wnt-Related Genes in Human Joint Disorders, The American Journal of Pathology, vol.167, pp.97-105, 2005.

S. Hwang, S. Yu, and S. Lee, Wnt-3a regulates chondrocyte differentiation via c-Jun/AP-1 pathway, FEBS Letters, vol.579, pp.4837-4879, 2005.

G. Nalesso, J. Sherwood, and J. Bertrand, WNT-3A modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways, J Cell Biol, vol.193, pp.551-64, 2011.

J. Ryu and J. Chun, Opposing roles of WNT-5A and WNT-11 in interleukin-1beta regulation of type II collagen expression in articular chondrocytes, J Biol Chem, vol.281, pp.22039-22086, 2006.

R. Yasuhara, T. Yuasa, and J. A. Williams, Wnt/beta-catenin and retinoic acid receptor signaling pathways interact to regulate chondrocyte function and matrix turnover, J Biol Chem, vol.285, pp.317-344, 2010.

T. Yuasa, T. Otani, and T. Koike, Wnt/?-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration, Lab Invest, vol.88, pp.264-74, 2008.

B. Ma, C. A. Van-blitterswijk, and M. Karperien, A Wnt/?-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes, Arthritis Rheum, vol.64, pp.2589-600, 2012.

R. S. Thomas, A. R. Clarke, and V. C. Duance, Effects of Wnt3A and mechanical load on cartilage chondrocyte homeostasis, Arthritis Res Ther, vol.13, 2011.

M. Khair, M. Bourhim, and L. Barré, Regulation of xylosyltransferase I gene expression by interleukin 1? in human primary chondrocyte cells: mechanism and impact on proteoglycan synthesis, J Biol Chem, vol.288, pp.1774-84, 2013.
URL : https://hal.archives-ouvertes.fr/hal-01464669

M. Zhu, D. Tang, and Q. Wu, Activation of ?-Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis-Like Phenotype in Adult ?-Catenin Conditional Activation Mice, J Bone Miner Res, vol.24, pp.12-21, 2009.

C. A. Séguin, M. Bojarski, and R. M. Pilliar, Differential regulation of matrix degrading enzymes in a TNFalpha-induced model of nucleus pulposus tissue degeneration, Matrix Biol, vol.25, pp.409-427, 2006.

J. Bondeson, S. Lauder, and S. Wainwright, Adenoviral gene transfer of the endogenous inhibitor IkappaBalpha into human osteoarthritis synovial fibroblasts demonstrates that several matrix metalloproteinases and aggrecanases are nuclear factor-kappaB-dependent, J Rheumatol, vol.34, pp.523-556, 2007.

B. Caterson, C. R. Flannery, and C. E. Hughes, Mechanisms involved in cartilage proteoglycan catabolism, Matrix Biol, vol.19, pp.333-377, 2000.
DOI : 10.1016/s0945-053x(00)00078-0

H. Nagase and M. Kashiwagi, Aggrecanases and cartilage matrix degradation, Arthritis Res Ther, vol.5, pp.94-103, 2003.

T. Matsukawa, T. Sakai, and T. Yonezawa, MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes, Arthritis Res Ther, vol.15, p.28, 2013.

P. S. Chockalingam, U. Varadarajan, and R. Sheldon, Involvement of protein kinase Czeta in interleukin-1beta induction of ADAMTS-4 and type 2 nitric oxide synthase via NF-kappaB signaling in primary human osteoarthritic chondrocytes, Arthritis Rheum, vol.56, pp.4074-83, 2007.

R. Song, M. D. Tortorella, and A. Malfait, Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5, Arthritis Rheum, vol.56, pp.575-85, 2007.
DOI : 10.1002/art.22334

URL : https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.22334

J. Bondeson, S. Wainwright, and C. Hughes, The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review, Clin Exp Rheumatol, vol.26, pp.139-184, 2008.

S. Hwang, J. Ryu, and I. Kim, Wnt-7a causes loss of differentiated phenotype and inhibits apoptosis of articular chondrocytes via different mechanisms, J Biol Chem, vol.279, pp.26597-604, 2004.

H. Oh, C. Chun, and J. Chun, Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice, Arthritis & Rheumatism, vol.64, pp.2568-78, 2012.
DOI : 10.1002/art.34481

URL : http://onlinelibrary.wiley.com/doi/10.1002/art.34481/pdf

Y. Tian, W. Yuan, and N. Fujita, Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-?B, Am J Pathol, vol.182, pp.2310-2331, 2013.
DOI : 10.1016/j.ajpath.2013.02.037

URL : https://doi.org/10.1016/j.ajpath.2013.02.037

A. Wise, K. Gearing, and S. Rees, Target validation of G-protein coupled receptors, Drug Discov Today, vol.7, pp.235-281, 2002.

J. P. Overington, B. Al-lazikani, and A. L. Hopkins, How many drug targets are there?, Nat Rev Drug Discov, vol.5, pp.993-999, 2006.
DOI : 10.1038/nrd2199

M. Kühl, L. C. Sheldahl, and C. C. Malbon, 2+)/calmodulin-dependent protein kinase II is stimulated by Wnt and Frizzled homologs and promotes ventral cell fates in Xenopus, J Biol Chem, vol.275, pp.12701-12712, 2000.

H. Wang, M. Xu, and J. Ma, Frizzled-8 as a putative therapeutic target in human lung cancer, Biochem Biophys Res Commun, vol.417, pp.62-68, 2012.
DOI : 10.1016/j.bbrc.2011.11.055

J. Albers, J. Keller, and A. Baranowsky, Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin, J Cell Biol, vol.200, pp.537-586, 2013.
DOI : 10.1084/jem2104oia1

URL : http://europepmc.org/articles/pmc3575535?pdf=render

Y. Lee, Y. Gao, and H. Wang, Differential mediation of the Wnt canonical pathway by mammalian Dishevelleds-1,-2, and-3, Cell Signal, vol.20, pp.443-52, 2008.
DOI : 10.1016/j.cellsig.2007.11.005

URL : http://europepmc.org/articles/pmc2233603?pdf=render

, Supporting Information

, Wnt/?-catenin signaling counteracts interleukine-1-induced ADAMTS4 si-RNA

, Human chondrocytes were pretreated with vehicle or DKK1 for 30 minutes then exposed to 100ng/ml Wnt-3a for 12 hours, the Western blot showed the Wnt-induced accumulation of ?-catenin was abolished by DKK1 (n=3), the ?-actin was used as loading control. (E) si-CTNNB1 was transfected into chondrocytes for 48 hours, Western blot revealed the ?-catenin level was lower comparing to the si-control group (n=3). (F) Silencing of ?-catenin by si-CTNNB1 suppressed the Wnt-3a-induced-C) Primary chondrocytes were transfected with siRNA specific to (A) DVL-1 (SiDVL-1), (B) DVL-2

, for 48 h and the level of DVL-1, DVL-2 and DVL-3 was determined by RT-PCR (n?3)

, Data are expressed as mean ± S.D. Statistical analysis was performed with an unpaired Student's t-test (*, p < 0

, Specific DNA segment for each of the ten Fz receptors (standards) was amplified by RT-PCR, purified on agarose gel, quantified and used as template for Q-PCR. Absolute quantification was determined compared to standards that are run in parallel

, Human chondrocytes were transfected with si-control, si-Fz-6 or si-Fz-8 for 48 h, knockdown efficiency of si-Fz-6 (B, n=6) and si-Fz-8 (C, n=5) was determined by RTPCR. Data are expressed as mean ± S.D. of 3 separate experiments. Statistical analysis was performed with an unpaired Student