Expression of calcitonin gene‐related peptide induces ligament degeneration through endochondral ossification in osteoarthritis

Abstract Aim Osteoarthritis (OA) is a disease in which degeneration occurs in various tissues such as cartilage and subchondral bone. Degeneration of ligaments also plays an important role in OA progression, resulting in an increase in chondrocytes and ossification, but the factor that causes this is still unclear. It is reported that the expression of calcitonin gene‐related peptide (CGRP) increases OA progression, and CGRP might play a role in ligament degeneration because CGRP has a function in endochondral ossification. The purpose of this study is to analyze the mechanism of ligament degeneration and the function of CGRP. Methods To examine the relationship between ligament degeneration and CGRP expression, human posterior cruciate ligaments (PCL) from OA patients, and senescence‐accelerated mouse prone 8 (SAMP8) mice were histologically analyzed. The effect of CGRP on human ligament cells on chondrogenesis, osteogenesis, and adipogenesis was also examined. Results In human PCL and SAMP8 mice, CGRP expression increased as degeneration progressed, and decreased in severe degeneration. CGRP was expressed in the chondrocyte‐like cells with SOX9. CGRP‐positive cells expressing type II collagen increased with OA progression. CGRP upregulated the gene expression of VEGF, SOX9, RUNX2, COL10a1, and MMP13 in the human ligament cells. CGRP also promoted chondrogenesis and osteogenesis from the human ligament cells. Conclusion During OA progression, CGRP plays a role in the transdifferentiation from ligament cells to chondrocytes and promotes endochondral ossification in the ligament. CGRP would be the therapeutic target to prevent ligament degeneration.