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.MethodsTen-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.ConclusionSclerostin may play an important role in maintaining cartilage integrity in OA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0540-6) contains supplementary material, which is available to authorized users.
Highlights
Sclerostin is a Wingless-related integration site (Wnt) inhibitor produced by osteocytes that regulates bone formation
Expression of sclerostin is increased in calcified cartilage during the development of osteoarthritis in wild-type mice In the destabilization of the medial meniscus (DMM) model, cartilage damage increased timedependently in WT mice (Figure 1A)
Sclerostin was expressed in osteocytes of the subchondral bone, the expression in joint cartilage restricted to chondrocytes in the calcified zone (Figure 1B)
Summary
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. OA involves all joint tissues and results in cartilage breakdown [4]. Increased subchondral bone thickness and stiffness, along with reduced mineral density of the trabecular bone beneath the cartilage, has been reported in the late stage of the disease, which suggests that bone is involved in the onset and progression of OA. At the interface between bone and cartilage, contains chondrocytes that might be regulated by the subchondral bone. Chondrocytes from calcified cartilage are involved in a terminal differentiation process that results in the recapitulation of endochondral ossification. Damaged calcified cartilage is associated with chondrocyte hypertrophy in OA, which releases several factors that contribute to the replacement of cartilage by bone [7,8]
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