The Potential Role of Bone Morphogenetic Protein‐2/‐4 in Excessive Mechanical Overloading‐Initiated Joint Degeneration

Excessive mechanical overloading of articular cartilage caused by excessive exercise or severe trauma is considered a critical trigger in the development of osteoarthritis (OA). However, the available clinical theranostic molecular targets and underlying mechanisms still require more elucidation. Here, we aimed to examine the possibility that bone morphogenetic proteins (BMPs) serve as molecular targets in rat cartilages and human chondrocytes under conditions of excessive mechanical overloading. Two rat models involving high-intensity running training and surgery for destabilization of medial meniscus, along with a cell model subjected to cyclic tensile strain, were established to simulate and investigate excessive mechanical overloading effects on cartilages/chondrocytes. We employed various methods, including immunohistochemistry, real-time polymerase chain reaction, western blot analysis, and enzyme-linked immunosorbent assay, to evaluate the expression, secretion, phosphorylation, and nuclear translocation of mRNA/proteins in cartilages and chondrocytes. Our findings revealed a simultaneous upregulation of BMP-2 and downregulation of BMP-4 in degenerated and inflamed cartilages and chondrocytes under excessive mechanical overloading. Furthermore, toll-like receptor 2 and nuclear factor kappa B-p50/p65 subunits signaling were identified as regulators governing this distinct expression pattern. Treatment with recombinant BMP-2 and/or BMP-4 proteins significantly ameliorated cartilage degeneration and chondrocyte inflammation induced by excessive mechanical overloading. These results strongly suggest that BMP-2 upregulation and BMP-4 downregulation might represent mechanisms for self-rescue and degeneration in damaged cartilage/chondrocytes, respectively. Our findings advance new insights that BMP-2/-4 might be potential molecular targets for excessive mechanical overloading-caused OA development and should be taken into account in future clinical applications.