Roelofs, A. J. | Search bioRxiv

bioRxiv2025

Mechano-activated chondroprogenitors (MACs) drive intrinsic cartilage repair; a process that is arrested in osteoarthritis

Articular cartilage, an avascular, matrix-rich tissue, is thought to have limited repair, thereby contributing to osteoarthritis (OA), the common degenerative disease of joints. Cartilage regeneration does occur, however, in OA joints that are mechanically off-loaded. Here we show that mechanical stress, through release of matrix-bound growth factors, reprogrammes chondrocytes, the primary cells of cartilage, into mechano-activated chondroprogenitors (MACs). Studying OA joint fluid before and after mechanical off-loading, reveals evidence of chronic MAC activity, which switches back to a chondrogenic one when mechanical stress is removed. Taken together, we conclude that OA is a disease of arrested repair in which mechanical stress signals need to be switched off before full repair can occur. This novel paradigm uncovers exciting new treatment opportunities.

cell biology↗

bioRxiv2021

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

ObjectiveTo investigate the role of BMP signaling in osteoarthritis' pathogenesis and propose a disease-modifying therapy for OA. MethodsC57BL6/J mouse line was used to perform ACLT surgery at P120 to study the expression pattern of the BMP signaling readout pSMAD1/5/9. To investigate whether activation of BMP signaling is sufficient and necessary to induce osteoarthritis, we have used conditional GOF and LOF mouse lines in which BMP signaling can be activated or depleted, respectively, upon intra-peritoneal injection of tamoxifen. Finally, we locally inhibited BMP signaling through intra-articular injection of LDN-193189 pre- and post-onset surgically induced OA. Most of the analysis has been done through immunohistochemistry, histopathological staining, and micro-CT to evaluate the status of the pathogenesis of the disease. ResultsWe observed concomitant activation of BMP signaling, as judged by pSMAD1/5/9 immunoreactivity in the articular cartilage, upon induction of osteoarthritis with simultaneous depletion of SMURF1, an intra-cellular BMP signaling inhibitor in articular cartilage. Even without surgical induction of osteoarthritis, only BMP gain-of-function mutation induces OA in mouse articular cartilage. Also, genetic, or pharmacological inhibition of BMP signaling offered significant protection against OA pathogenesis. Interestingly, post-onset of the disease, inhibition of BMP signaling by intra-articular injection of LDN-193189 retarded OA progression with a significant reduction in inflammatory markers. ConclusionOur study demonstrated that BMP signaling plays an essential role in the pathogenesis of OA and that local BMP inhibition can be an effective therapeutic strategy to mitigate osteoarthritis.

developmental biology↗