TY - JOUR

T1 - Transcript-dependent effects of the CALCA gene on the progression of post-traumatic osteoarthritis in mice

AU - Jiang, Shan

AU - Xie, Weixin

AU - Knapstein, Paul Richard

AU - Donat, Antonia

AU - Albertsen, Lilly Charlotte

AU - Sevecke, Jan

AU - Erdmann, Cordula

AU - Appelt, Jessika

AU - Fuchs, Melanie

AU - Hildebrandt, Alexander

AU - Maleitzke, Tazio

AU - Frosch, Karl Heinz

AU - Baranowsky, Anke

AU - Keller, Johannes

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1038/s42003-024-05889-0

DO - 10.1038/s42003-024-05889-0

M3 - Journal article

C2 - 38396204

AN - SCOPUS:85185685316

VL - 7

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

IS - 1

M1 - 223

ER -