Crim1 involves in mechanical overloading-caused extracellular matrix degradation and type H vessels formation through the FAK-MAPK signaling pathway in osteoarthritis

Abstract

Abstract Background Osteoarthritis (OA) is the most common bone disease with the high disability rate. Mechanical overloading is vital for the pathogenesis of OA, and the precise mechanisms by which mechanical overloading regulates chondrocytes remain largely unclear. Methods The expression of Crysteine-Rich Transmembrane BMP Regulator-1 (Crim1) was assessed in vitro, in mice with experimental OA, and in cartilage of humans with OA. Destabilized medial meniscus surgery was performed to induce OA and mice with Crim1 knockout in chondrocytes were made. The effects of Crim1 gene silencing in chondrocytes on extracellular matrix metabolism and angiogenesis were observed in vivo and in vitro. Results Elevated the Crysteine-Rich Transmembrane BMP Regulator-1 (Crim1) levels are found in OA patients and OA mouse model. The silencing of Crim1 in human chondrocytes significantly alleviates the imbalance of extracellular matrix metabolism induced by mechanical overloading. Furthermore, chondrocytes with silenced Crim1 inhibits tube formation of human umbilical vein endothelial cells (HUVECs) and endothelial cells migration through VEGF production. Col2a1cre; Crim1flox/flox mice protects against the development of OA by alleviating the degradation of articular cartilage and inhibiting the formation of type H vessels in the subchondral bone. Mechanistically, Crim1 is involved in the activation of the FAK/MAPK signaling pathway by mechanical overloading in chondrocytes. Conclusions The findings indicate that Crim1 is a promising candidate for targeting in the regulatory network of OA.