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

Zhu, L.; Muhammad, H.; Perry, T. A.; Ardasheva, A. A.; Symons, R. A.; McClure, J. J.; Kania, K.; Clark, S. M.; Colella, F.; Koneva, L. A.; Khan, S.; Eldridge, S. E.; Dell'accio, F.; Mastbergen, S.; Jansen, M.; Watt, F. E.; Itoh, Y.; Bennett, J.; Zarebska, J. M.; Attar, M.; Chan, C.; STEpUP OA Consortium,; Roelofs, A. J.; Bari, C. D.; Sansom, S. N.; Riegger, J.; Vincent, T. L.

doi:10.1101/2025.08.21.671507

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bioRxiv · 10.1101/2025.08.21.671507

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

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Abstract

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.

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Zhu, L., Muhammad, H., Perry, T. A., Ardasheva, A. A., Symons, R. A., McClure, J. J., Kania, K., Clark, S. M., Colella, F., Koneva, L. A., Khan, S., Eldridge, S. E., Dell'accio, F., Mastbergen, S., Jansen, M., Watt, F. E., Itoh, Y., Bennett, J., Zarebska, J. M., Attar, M., Chan, C., STEpUP OA Consortium,, Roelofs, A. J., Bari, C. D., Sansom, S. N., Riegger, J., Vincent, T. L.. 2025-08-25. Mechano-activated chondroprogenitors (MACs) drive intrinsic cartilage repair; a process that is arrested in osteoarthritis. https://doi.org/10.1101/2025.08.21.671507

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