Background Osteoarthritis (OA) is characterized by cartilage and subchondral bone dammage. The Wnt family is involved in joint homeostasis. We have shown that the Wnt/β-catenin pathway is activated in bone during OA, but the effect of Wnt inhibition in the subchondral bone on cartilage remodeling is unknown.
Objectives We here investigated how the bone-specific inhibition of Wnt impacts the development of OA.
Methods Joint destabilization by partial meniscectomy (MNX) was performed in mice overexpressing Dkk1 in bone (2.3 Col1-Dkk1Tg). Bone and cartilage lesions were assessed by microCT and histology. The effects of Dkk-1 in chondrocyte and osteoblast metabolism were further assessed using supernatant transfer and MMP expression.
Results At baseline, Dkk1-Tg mice had lower bone volume which was further reduced in MNX knees. This was accompanied by a reduction of the subchondral bone and osteophyte volume. At 6 weeks after MNX, Dkk1-Tg experienced a lower OA score than WT mice (5.1±0.63 vs 8.4±0.6, p=0.002). The number of Dkk1(+) chondrocytes was high at baseline (84.2±3.1%), decreased markedly during the course of OA from week 4 (14.4±3.8%) to week 6 (5.7±1.6%), whatever the genotype. However, direct effect of Dkk1 on chondrocytes or cartilage explants induced the expression of agreccanases and metallproteinases and proteoglycans loss. When supernatants of osteoblasts previously cultured with Dkk1 were transferred on chondrocytes, this procatabolic effect was reversed, indicating and indirect underlying mechanism via osteoblasts. Because Dkk1-Tg osteoblasts produced low VEGF, we tested whether VEGF could mediate the anti-catabolic effect observed in vivo. Blocking VEGF in the supernatant of osteoblast cultures reversed the expression of MMPs by chondrocytes, and VEGF expression was decreased in vivo in the MNX knees of Dkk1-Tg mice.
Conclusions Inhibition of the Wnt pathway in bone cells decreased OA severity by reducing VEGF production in the subchondral bone. Targeting bone could be a useful approach for the treatment of OA.
Disclosure of Interest None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.