Background/Purpose: Wnt signaling pathway is a major regulator of bone and cartilage remodeling. Modulation of this pathway has lead to controversial results on joint cartilage in murine osteoarthritis (OA) models. Therefore, this study aims to describe the in vivo activity of Wnt/βcatenin and the expression of Wnt antagonists in joint tissues during the development of OA.

Methods: Joint instability was induced by partial meniscectomy (MNX) at the right knee in TOPGAL mice, which express the lacZ gene under the control of Wnt-RE. Left knee was sham-operated. The mice were sacrificed at baseline, 2, 4, 6 and 9 weeks after surgery (≥ 5 animals per time point). Analysis of the bone microarchitecture of the tibial epiphyses were assessed (Skyscan® 1172) and then the samples were prepared for quantification of OA score, X-gal staining and immunohistochemistry for the expression of Dkk-1, Sclerostin and sFRP-3.

Results: Compared to sham, the number of X-gal positive osteocytes per bone volume decreased at 4 weeks then progressively increased in the subchondral bone (ratios: 0.99 ± 0.01; 0.50 ± 0.08, p<0.05; 1.63 ± 0.43; 2.33 ± 0.81 for each time point, respectively). These changes paralleled those of bone volume/tissue volume. Xgal staining was strongly observed in growing osteophytes. The number of X-gal(+)-chondrocytes was low in articular cartilage at baseline, indicating an inhibition of Wnt pathway, but their number increased in the superficial layers with MNX until 6 weeks. The synovium showed marked staining in MNX knees compared to sham operated knees. Dkk-1 was highly expressed in normal non calcified cartilage and dramatically decreased with OA. Sclerostin and sFRP-3 were only expressed in the calcified layers and moderately increased with OA. The synovium also expressed Dkk-1 and sFRP-3 in OA knees.

Conclusion: During the course of OA, the canonical Wnt signaling pathway is mainly activated in growing osteophytes, subchondral bone and synovium while this activation was moderate in chondrocytes of articular cartilage. Distinct patterns of expression of Wnt antagonists are observed in the joint tissues that indicated multiple mechanisms of regulation of the canonical Wnt signaling pathway.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/activation-of-the-canonical-wnt-signaling-pathway-is-tissue-dependent-in-osteoarthritic-joints-distinct-mechanisms-of-regulation-by-wnt-antagonists/