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Friend or Foe? Essential Roles of Osteoclast in Maintaining Skeletal Health

Wang H1,2Yang G1Xiao Y3Luo G4,5Li G1,2Li Z6,7.

Biomed Res Int. 2020 Mar 3;2020:4791786. doi: 10.1155/2020/4791786. eCollection 2020.



Heightened activity of osteoclast is considered to be the culprit in breaking the balance during bone remodeling in pathological conditions, such as osteoporosis. As a «foe» of skeletal health, many antiosteoporosis therapies aim to inhibit osteoclastogenesis. However, bone remodeling is a dynamic process that requires the subtle coordination of osteoclasts and osteoblasts. Severe suppression of osteoclast differentiation will impair bone formation because of the coupling effect. Thus, understanding the complex roles of osteoclast in maintaining proper bone remodeling is highly warranted to develop better management of osteoporosis. This review aimed to determine the varied roles of osteoclasts in maintaining skeletal health and to highlight the positive roles of osteoclasts in maintaining normal bone remodeling. Generally, osteoclasts interact with osteocytes to initiate targeted bone remodeling and have crosstalk with mesenchymal stem cells and osteoblasts via secreted factors or cell-cell contact to promote bone formation. We believe that a better outcome of bone remodeling disorders will be achieved when proper strategies are made to coordinate osteoclasts and osteoblasts in managing such disorders.

Summary and Perspectives

.The skeletal system provides mechanical support, protects vital organs, and controls mineral homeostasis in the human body. It is the constant bone remodeling throughout one’s life that removes the old and damaged bone, keeping the skeletal system healthy. During the recent decade, many studies have demonstrated mechanisms for how osteoclastic bone resorption contributes to the subsequent bone formation in bone remodeling (Figure 2) and provided a wellrounded understanding of the roles of OCs in maintaining proper bone remodeling.

Osteoporosis, the most prevalent disorder of bone remodeling by far, is characterized by the heightened activity of OCs [6, 7]. Currently, the available treatments of osteoporosis comprise antiresorptive agents, such as bisphosphonate and denosumab, and anabolic treatments such as PTH [6, 13]. However, most antiresorptive agents that suppress OC differentiation will concomitantly impair bone formation because of the coupling effect, leading to an unsatisfactory long-term effect and potentially increasing the likelihood of long-term adverse events, such as osteonecrosis of the jaw [120]. .us, new agents under development for osteoporosis may try to retain the OC coupling factors while inhibiting OC functions. Odanacatib, a small-molecule inhibitor of CTSK, can decrease bone resorption without affecting OBs and appears to promote bone formation [106, 121, 122], probably because of the suppression on OC activity rather than the inhibition on OC viability, thus allowing continuous crosstalk between OCs and OBs. Unfortunately, because of the unforeseen cerebrovascular events, the clinical development of odanacatib was terminated. .e side effects may result from the off-target effects of CTSK inhibitors on other members of the cathepsin family, such as cathepsins B, L, and S. Nonetheless, the experience learned from the underlying biology of CTSK inhibitors could guide future therapeutic approaches for osteoporosis: dissociating the inhibition of bone resorption from the coupled reduction in bone formation. .is may be a promising strategy in the development of a new drug and we believe that a better outcome will be achieved when proper strategies are made to coordinate OCs and OBs in managing bone remodeling disorders.