Semaphorin 7A Regulates the Balance Between Cartilaginous and Fibrous Tissues in the Repair Process of Articular Cartilage Damage

Objective Damage to the joint-surface repair itself as fibrocartilage, a mixture of cartilaginous and fibrous tissues, which leads to debilitating conditions with persistent joint pain. The regulatory mechanisms that control the formation of these tissues are poorly understood. Methods We analyzed single-cell RNA-sequencing data from the repaired tissue formed in a chondral defect model of the monkey knee joint to identify genes specifically expressed in the repaired tissue. We used primary chondrocytes from semaphorin 7A (Sema7A) knockout mice to analyze the function of Sema7A in the dedifferentiation of chondrocytes in vitro . We introduced articular cartilage defect model in the knee joints in Sema7A knockout mice. Results Single-cell RNA-sequencing analysis revealed that Sema7A is specifically expressed in the cartilaginous tissue in the repaired tissue formed in the articular cartilage defect. In vitro analysis showed that Sema7A autonomously induced the dedifferentiation of chondrocytes at passage 2, which is assumed to correspond to cartilaginous tissue cells, toward a fibroblastic state. In addition, Sema7A heteronomously suppressed the re-differentiation of passage 8 fibroblastic cells, which were assumed to correspond to fibrous tissue cells. Addition of anti-integrin β1 neutralizing antibody abolished Sema7A-induced suppression of Col2a1 and Col9a1 expression, suggesting that integrin β1 mediates Sema7A function. Sema7A knockout mice showed significantly improved healing in an articular surface defect model of the knee joints. Sema7A deletion increased cartilaginous tissue formation and decreased fibrous tissue formation in joint-surface defects. Conclusions Sema7A regulates the balance between cartilaginous and fibrous tissues during articular cartilage damage repair.