The role of neprilysin in musculoskeletal diseases

Neprilysin (NEP) is a membrane-bound endopeptidase that degrades various substrates, including natriuretic peptide, bradykinin, and substance P. It is distributed in various organs such as the heart, kidneys, and brain, regulating multiple physiological processes. This paper elucidates the role of NEP in osteogenic, chondrogenic, and myogenic differentiation processes, along with its time-specific expression during differentiation. We focus on how NEP regulates key pathways in skeletal muscle disorders, explores potential mechanisms, and demonstrates clinical symptom improvement. NEP degrades pro-inflammatory neuropeptides, thereby reducing local inflammation. Furthermore, NEP has been demonstrated to be responsible for the degradation of endogenous opioids, thus contributing to the regulation of pain. In the repair of skeletal muscle injury, NEP promotes the osteogenic, chondrogenic and myogenic differentiation of mesenchymal stem cells in animals, and achieves tissue regeneration. By discussing the therapeutic effect of NEP inhibitors and activators approved in clinic on skeletal muscle diseases, it was found that Shakubitril, a NEP inhibitor, promotes the thickening of cartilage growth plates and bone growth in animal models of chondrodysplasia. NEP activators promote muscle growth in castrated rats, rather than NEP inhibitor. This review emphasized the role of NEP in skeletal muscle growth and development, the changes in its levels in different skeletal muscle diseases, and its impact on disease progression. Finally, the efficacy of NEP related drugs in skeletal muscle diseases was discussed, hoping to provide a new way for the treatment of skeletal muscle diseases.