Proteases and Osteoporosis: A Comprehensive Review of Their Role in Bone Health

Abstract: Proteases, once thought to degrade proteins solely, are now recognized as key signaling molecules central to numerous physiological processes, including bone remodeling. Dysregulated protease contributes to various pathological diseases, including cardiovascular diseases, cancer, inflammation, osteoporosis, and neurological disorders. Protease targeting is now quite far along; some small molecules are already on the market, and others are in development. Despite drugs having been successfully developed to inhibit well-defined proteases, including angiotensin-converting enzyme and HIV protease, designing selective inhibitors for the newly identified protease targets is still difficult owing to problems like poor target selectivity. This review covers principles guiding the discovery of protease drugs with a focus on recent approaches, including the use of allosteric sites. In bone remodeling, proteases are involved in the regulation of cell surface properties and extracellular matrix in the degradation process that is fundamental to bone mineral density and quality. In particular, cathepsins, dipeptidyl peptidases, and caspases have become attractive targets for the therapy of osteoporosis. Selective inhibitors are different from other drugs in the way that they selectively inhibit bone resorption processes and do not bear on osteoblast survival factors or bone formation. However, some inhibitors proved to be effective in increasing bone density in osteoporotic patients, but due to side effects, they were withdrawn, highlighting the necessity of selective inhibitors. Newer generations of selective allosteric inhibitors aiming at protease activity would be safer and give an unexplored therapeutic angle to tackle osteoporosis without interfering with other physiological processes.