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 acalcitonin gene-related peptide alpha (αCGRP) transcript by alternative splicing, were reported to beassociated with the development of osteoarthritis. The objective of this study was to investigate therole 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) toinduce ptOA of the knee. Mice were sacrificed 4 and 8 weeks post-surgery, followed by micro-CT andhistological evaluation. Here we show that the expression of both PCT/CT and αCGRP transcripts isinduced in ptOA knees. CALCA−/− mice show increased cartilage degeneration and subchondral boneloss with elevated osteoclast numbers compared to αCGRP−/− and WT mice. Osteophyte formation isreduced to the same extent in CALCA−/− and αCGRP−/− mice compared to WT controls, while areduced synovitis score is noticed exclusively in mice lacking CALCA. Our data show that expressionof the PCT/CT transcript protects from the progression of ptOA, while αCGRP promotes osteophyteformation, suggesting that CALCA-encoded peptides may represent novel targets for the treatmentof ptOA.