BMP signaling is necessary and sufficient for osteoarthritis and a target for disease modifying therapy

Abstract

Osteoarthritis (OA) is a prominent musculoskeletal disorder with no effective therapy. Moreover, molecular aetiology of OA and the development and maintenance of articular cartilage are poorly understood. During OA, articular cartilage undergoes cellular and molecular changes reminiscent of transient cartilage, the embryonic precursor of endochondral bone. Previous studies from our lab suggest that during embryonic development, a precise spatio-temporally regulated WNT-BMP signaling interplay dictates differentiation of a common progenitor pool to either articular or transient cartilage fate in adjacent domains. While Wnt signaling promotes articular cartilage fate, transient cartilage differentiation is critically BMP signaling dependent. Moreover, any ectopic activation of BMP signalling embryonically, leads to ectopic transient cartilage differentiation at the expense of articular cartilage. In this study, we show that BMP signaling is sufficient and necessary for pathogenesis of OA by ectopically activating BMP signaling and depleting BMP ligands in adult mice articular cartilage, respectively. Similarly, human osteoarthritic specimens show upregulation of BMP signaling in the articular cartilage. A recent study based on our work (1), suggests that pharmacological inhibition of BMP signaling allows maintenance of hMSC derived chondrocytes, implanted in mice, for longer time duration (2). Similarly, we observe in vivo local pharmacological inhibition of BMP signaling resulted in delayed onset and reduced severity of OA in a mouse model of OA as well as long term protection from OA like changes. Therefore, pharmacological inhibition of BMP signaling and consequent block of transient cartilage differentiation of joint cartilage cells can be a potential disease modifying therapy for OA. Significance statement This manuscript provides new insights into the mechanistic basis for the maintenance of articular cartilage in adults. Here we demonstrate the role of BMP signaling in the pathogenesis of osteoarthritis in mice and humans. To the best of our understanding, this is the first (3)study investigating the relationship between molecular histological changes observed in the articular cartilage during osteoarthritis and inflammation. Moreover, we demonstrate that local inhibition of BMP signaling can be a potential disease modifying therapy for osteoarthritis which is among the most prominent musculoskeletal disorders.