title: Loss of sclerostin promotes osteoarthritis in mice via β-catenin-dependent and -independent Wnt pathways.
abstract: BACKGROUND
  Sclerostin is a Wnt inhibitor produced by osteocytes that regulates bone formation. Because bone tissue contributes to the development of osteoarthritis (OA), we investigated the role of sclerostin in bone and cartilage in a joint instability model in mice.
  
  
  METHODS
  Ten-week-old SOST-knockout (SOST-KO) and wild-type (WT) mice underwent destabilization of the medial meniscus (DMM). We measured bone volume at the medial femoral condyle and osteophyte volume and determined the OA score and expression of matrix proteins. Primary murine chondrocytes were cultured with Wnt3a and sclerostin to assess the expression of matrix proteins, proteoglycan release and glycosaminoglycan accumulation.
  
  
  RESULTS
  Sclerostin was expressed in calcified cartilage of WT mice with OA. In SOST-KO mice, cartilage was preserved despite high bone volume. However, SOST-KO mice with DMM had a high OA score, with increased expression of aggrecanases and type X collagen. Moreover, SOST-KO mice with OA showed disrupted anabolic-catabolic balance and cartilage damage. In primary chondrocytes, sclerostin addition abolished Wnt3a-increased expression of a disintegrin and metalloproteinase with thrombospondin motifs, matrix metalloproteinases and type X collagen by inhibiting the canonical Wnt pathway. Moreover, sclerostin inhibited Wnt-phosphorylated c-Jun N-terminal kinase (JNK) and rescued the expression of anabolic genes. Furthermore, sclerostin treatment inhibited both Wnt canonical and non-canonical JNK pathways in chondrocytes, thus preserving metabolism.
  
  
  CONCLUSIONS
  Sclerostin may play an important role in maintaining cartilage integrity in OA.
authors: Inserm U1132 and university Paris 7, hopital Lariboisiere, 2 rue Ambroise Pare, 75010, Paris, France. w-bouaziz@hotmail.com.
authors: Wafa
authors: W
authors: Bouaziz
authors: Inserm U1132 and university Paris 7, hopital Lariboisiere, 2 rue Ambroise Pare, 75010, Paris, France. tfb@free.fr.
authors: Thomas
authors: T
authors: Funck-Brentano
authors: Inserm U1132 and university Paris 7, hopital Lariboisiere, 2 rue Ambroise Pare, 75010, Paris, France. hilene.lin@hotmail.fr.
authors: Hilène
authors: H
authors: Lin
authors: Inserm U1132 and university Paris 7, hopital Lariboisiere, 2 rue Ambroise Pare, 75010, Paris, France. caroline.marty@inserm.fr.
authors: Caroline
authors: C
authors: Marty
authors: Inserm U1132 and university Paris 7, hopital Lariboisiere, 2 rue Ambroise Pare, 75010, Paris, France. korngea@yahoo.fr.
authors: Hang-Korng
authors: HK
authors: Ea
authors: Inserm U1132 and university Paris 7, hopital Lariboisiere, 2 rue Ambroise Pare, 75010, Paris, France. eric.hay@inserm.fr.
authors: Eric
authors: E
authors: Hay
authors: Inserm U1132 and university Paris 7, hopital Lariboisiere, 2 rue Ambroise Pare, 75010, Paris, France. martine.cohen-solal@inserm.fr.
authors: Martine
authors: M
authors: Cohen-Solal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D024121:Collagen Type X / Q000378:metabolism; D019483:Disintegrins / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D007593:Joint Instability / Q000378:metabolism; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000494:pharmacology; D051176:beta Catenin / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D024121:Collagen Type X; D019483:Disintegrins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D060509:Wnt3A Protein; D051176:beta Catenin; D045726:Metalloproteases
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