Sclerostin is expressed in articular cartilage but loss or inhibition does not affect cartilage remodeling during aging or following mechanical injury

Dept Comparative Biology &Safety Sciences, 1201 Amgen Court West, Seattle WA 98119.
Arthritis & Rheumatology (Impact Factor: 7.87). 03/2013; 65(3). DOI: 10.1002/art.37802
Source: PubMed

ABSTRACT OBJECTIVE.: Sclerostin plays a major role in regulating skeletal bone mass but its effects in articular cartilage are not known. The purpose of this study was to determine if genetic loss or pharmacological inhibition of sclerostin impacted knee joint articular cartilage. METHODS.: Sclerostin expression was determined in articular cartilage and bone tissue taken from mouse, rat and human specimens, including patients with osteoarthritis (OA). Sclerostin knockout (KO) mice and pharmacological inhibition of sclerostin with sclerostin monoclonal antibody (Scl-Ab) in aged male and ovariectomized (OVX) female rats were used to study effects on joint pathology. The rat medial meniscus tear (MMT) model of OA was used to investigate the pharmacological efficacy of systemic Scl-Ab or intra-articular delivery of sclerostin antibody Fab fragment (Scl-Fab). RESULTS.: Sclerostin expression was detected in rodent and human articular chondrocytes. No difference was observed in the magnitude or distribution of sclerostin expression in normal and OA cartilage or bone. Sclerostin KO mice showed no difference in knee joint pathology compared to age-matched wild-type (WT) mice. Pharmacological treatment of intact aged male rats or OVX female rats with Scl-Ab had no effect on morphology of articular cartilage. In the rat MMT model, pharmacological treatment of animals with either systemic Scl-Ab or intra-articular injection of Scl-Fab had no effect on lesion development or severity. CONCLUSION.: Genetic absence of sclerostin does not alter normal development of age-dependent OA in mice and pharmacological inhibition of sclerostin with Scl-Ab does not impact articular cartilage in rats with post-traumatic OA. © 2012 American College of Rheumatology.


Available from: Qing-Tian Niu, Feb 16, 2015
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    ABSTRACT: IntroductionSclerostin 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.ResultsSclerostin 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.Conclusion Sclerostin may play an important role in maintaining cartilage integrity in OA.
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