Session Title: Biology and Pathology of Bone and Joint
Session Type: Abstract Submissions (ACR)
Background/Purpose: Cartilage homeostasis is regulated by several mechanisms that influence the anabolic and catabolic tissue balance. Among them, the local activation of Wnt signaling pathway plays a major role in chondrocyte metabolism. Sclerostin, a Wnt inhibitor mainly produced by osteocytes, might regulate chondrocyte differentiation. Therefore, we aim to assess the role of Sclerostin in chondrocyte maintenance.
Methods: Primary murine chondrocytes, isolated from long bone epiphysis of 6 day-old mice, were cultured with or without Wnt3a and in the presence or absence of mouse recombinant Sclerostin (20ng/ml). Proteoglycan release induced by Wnt was quantified in the supernatant of chondrocytes by a colorimetric assay. Activation of the Wnt pathway was analyzed by the translocation of β-catenin (IF, TOP-GAL activity). Chondrocyte proliferation and apoptosis were investigated by BrdU and Tunel assays. The mRNA gene expression of anabolic and catabolic genes was quantified by RT-qPCR. We assessed the expression of Sclerostin in normal and osteoarthritic cartilage in mice with joint instability induced by partial meniscectomy (immunohistochemistry).
Results: The proteoglycan amount released in the chondrocyte culture supernatants was reduced by Wnt while it was rescued in the presence of Sclerostin. Wnt inhibited the gene expression of collagen type II (X18-fold), Sox9 (X140 fold) and Aggrecan (X90-fold) and increased the gene expression of metalloproteinases such as Adamts-4 (X5-fold), Adamts-5 (X5.5-fold), MMP3 (X7-fold) and MMP13 (X6.6-fold). In contrast, Sclerostin significantly prevented the increase of the catabolic genes induced by Wnt (X1.7-fold Adamts-4, X1.6-fold Adamts-5, X3.4-fold MMP3 and X4-fold MMP13) and rescued partially the expression of the anabolic genes (X5- fold collagen type II, X6-fold Sox-9 and X11-fold Aggrecan). Furthermore, Wnt enhanced the gene expression of collagen type X (X3-fold) which was abolished by Sclerostin (X1.6-fold). However, Sclerostin failed to exert any effect on the proliferation or the apoptosis of chondrocytes regardless of the presence of Wnt. Finally, we found that Sclerostin is expressed only in the calcified zone of the normal articular cartilage and this is increased after meniscectomy, suggesting that Sclerostin might participate to cartilage damage.
Conclusion: Herein, we showed that the inhibition of Wnt/β-catenin pathway by Sclerostin preserves chondrocyte maintenance by inhibiting chondrocyte catabolism and hypertrophy. These results further indicate the importance of Wnt antagonists in targeting cartilage degradation in OA.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-wnt-signaling-pathway-by-sclerostin-maintains-cartilage-homeostasis/