OBJECTIVE:To explore the significance of BMP signaling in osteoarthritis (OA) etiology, and thereafter propose a disease-modifying therapy for OA.METHODS:To examine the role of the BMP signaling in pathogenesis of OA, an Anterior Cruciate Ligament Transection (ACLT) surgery was performed to incite OA in C57BL/6J mouse line at postnatal day 120 (P120). Thereafter, to investigate whether activation of BMP signaling is necessary and sufficient to induce OA, we have used conditional gain- and loss-of-function mouse lines in which BMP signaling can be activated or depleted, respectively, upon intraperitoneal injection of tamoxifen. Finally, we locally inhibited BMP signaling through intra-articular injection of LDN-193189 pre- and post-onset surgically induced OA. The majority of the investigation has been conducted using micro-CT, histological staining, and immuno histochemistry to assess the disease etiology.RESULTS:Upon induction of OA, depletion of SMURF1-an intra-cellular BMP signaling inhibitor in articular cartilage coincided with the activation of BMP signaling, as measured by pSMAD1/5/9 expression. In mouse articular cartilage, the BMP gain-of-function mutation is sufficient to induce OA even without surgery. Further, genetic, or pharmacological BMP signaling suppression also prevented pathogenesis of OA. Interestingly, inflammatory indicators were also significantly reduced upon LDN-193189 intra-articular injection which inhibited BMP signaling and slowed OA progression post onset.CONCLUSION:Our findings showed that BMP signaling is crucial to the etiology of OA and inhibiting BMP signaling locally can be a potent strategy for alleviating OA.

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.

Osteoarthritis is the most prevalent musculoskeletal disorder and one for which there is no disease modifying therapy available at present. Our current understanding of the disease mechanism of osteoarthritis is limited owing to a lacuna of knowledge about the development and maintenance of articular cartilage that is affected during osteoarthritis. All current therapeutic strategies aim at countering inflammation which though mitigates pain but does not arrest the progressive degeneration of articular cartilage. During osteoarthritis, articular cartilage expresses markers for transient cartilage differentiation. Moreover, blocking transient cartilage differentiation is sufficient for halting the progression of experimental osteoarthritis. A developmental biology inspired approach that combines restoration of tissue microenvironment, supplementation with engineered cartilage and built in mechanism to prevent transient cartilage differentiation could be an avenue for developing a disease modifying therapy for osteoarthritis.