Transcript-dependent effects of the CALCA gene on the progression of post-traumatic osteoarthritis in mice

Osteoarthritis represents a chronic degenerative joint disease with exceptional clinical relevance. Polymorphisms of the CALCA gene, giving rise to either a procalcitonin/calcitonin ( PCT/CT ) or a calcitonin gene-related peptide alpha ( αCGRP ) transcript by alternative splicing, were reported to be associated with the development of osteoarthritis. The objective of this study was to investigate the role of both PCT/CT and αCGRP transcripts in a mouse model of post-traumatic osteoarthritis (ptOA). WT, αCGRP −/− and CALCA −/− mice were subjected to anterior cruciate ligament transection (ACLT) to induce ptOA of the knee. Mice were sacrificed 4 and 8 weeks post-surgery, followed by micro-CT and histological evaluation. Here we show that the expression of both PCT/CT and αCGRP transcripts is induced in ptOA knees. CALCA −/− mice show increased cartilage degeneration and subchondral bone loss with elevated osteoclast numbers compared to αCGRP −/− and WT mice. Osteophyte formation is reduced to the same extent in CALCA −/− and αCGRP −/− mice compared to WT controls, while a reduced synovitis score is noticed exclusively in mice lacking CALCA . Our data show that expression of the PCT/CT transcript protects from the progression of ptOA, while αCGRP promotes osteophyte formation, suggesting that CALCA -encoded peptides may represent novel targets for the treatment of ptOA.