Figure 1.

Biological procedures of osteoclast differentiation, bone resorption, and mechanisms of current or future therapeutic drugs. Osteoclasts matured from bone marrow hematopoietic stem cells (BMMs) with the stimulation of two critical factors, M-CSF (CSF-1) and receptor activator of nuclear factor kappa-B ligand (RANKL). When binding to its specific receptors [CSF-1R and receptor activator of nuclear factor kappa-B (RANK)] on BMMs membrane, a series of cascades are activated, and BMMs were then differentiated into matured osteoclast. Realizing the importance of M-CSF and RANKL in osteoclast differentiation, inhibitors to CSF-1R and RANKL were considered as available strategy to suppress over-activated osteoclasts. Bisphosphonates, a widely used anti-osteoporosis agent, can be absorbed by osteoclast and induce osteoclast apoptosis. Additionally, it has been indicated that GLP-2 is a negative regulator of osteoclast differentiation, thus, the exact mechanisms are still unclear. Bone resorption is demonstrated as specific function of osteoclast, and bone matrix degradation is induced by the release of cathepsin K, as well as H⁺, and the release of H⁺ is enabled by V-ATPase on the membrane of matured osteoclast. So that, cathepsin K and V-ATPase are considered as another two targets to impair osteoclast function, especially, inhibitors of cathepsin K, such as Odanacatib, Balicatib are undergoing clinical trials. (⊝ represents inhibitory or down-regulated effect, ⊕ represents facilitated or up-regulated effect).