title: Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis.
abstract: OBJECTIVE
  To investigate the regulation of sclerostin (SOST) in osteoarthritis (OA) and its potential effects on articular cartilage degradation.
  
  
  METHODS
  SOST and other Wnt-β-catenin components were immuno-localised in osteochondral sections of surgically-induced OA in knees of sheep and mice, and human OA samples obtained at arthroplasty. Regulation of SOST mRNA and protein expression by ovine chondrocytes in response to interleukin-1α (IL-1α) or tumour necrosis factor-α (TNFα) was examined in explant cultures. The effect of 25 or 250 ng/ml recombinant SOST alone or in combination with IL-1α, on ovine articular cartilage explant aggrecan degradation, and chondrocyte gene expression of Wnt-β-catenin pathway proteins, metalloproteinases and their inhibitors, and cartilage matrix proteins was quantified.
  
  
  RESULTS
  Contrary to being an osteocyte-specific protein, SOST was expressed by articular chondrocytes, and mRNA levels were upregulated in vitro by IL-1α but not TNFα. Chondrocyte SOST staining was significantly increased only in the focal area of cartilage damage in surgically-induced OA in sheep and mice, as well as end-stage human OA. In contrast, osteocyte SOST was focally decreased in the subchondral bone in sheep OA in association with bone sclerosis. SOST was biologically active in chondrocytes, inhibiting Wnt-β-catenin signalling and catabolic metalloproteinase [matrix metalloproteinases (MMP) and distintegrin and metalloproteinase with thrombospndin repeats (ADAMTS)] expression, but also decreasing mRNA levels of aggrecan, collagen II and tissue inhibitors of metalloproteinaes (TIMPs). Despite this mixed effect, SOST dose-dependently inhibited IL-1α-stimulated cartilage aggrecanolysis in vitro.
  
  
  CONCLUSIONS
  These results implicate SOST in regulating the OA disease processes, but suggest opposing effects by promoting disease-associated subchondral bone sclerosis while inhibiting degradation of cartilage.
authors.affiliation: Raymond Purves Bone and Joint Research Labs, Kolling Institute of Medical Research, Institute of Bone and Joint Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: B Y
authors.initials: BY
authors.lastname: Chan
authors.forename: E S
authors.initials: ES
authors.lastname: Fuller
authors.forename: A K
authors.initials: AK
authors.lastname: Russell
authors.forename: S M
authors.initials: SM
authors.lastname: Smith
authors.forename: M M
authors.initials: MM
authors.lastname: Smith
authors.forename: M T
authors.initials: MT
authors.lastname: Jackson
authors.forename: M A
authors.initials: MA
authors.lastname: Cake
authors.forename: R A
authors.initials: RA
authors.lastname: Read
authors.forename: J F
authors.initials: JF
authors.lastname: Bateman
authors.forename: P N
authors.initials: PN
authors.lastname: Sambrook
authors.forename: C B
authors.initials: CB
authors.lastname: Little
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053582:Interleukin-1alpha / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012756:Sheep; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D019485:Bone Morphogenetic Proteins; D053582:Interleukin-1alpha; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha