Coupling factors involved in preserving bone balance

Abstract

Coupling during bone remodeling refers to the spatial and temporal coordination of bone resorption with bone formation. Studies have assessed the subtle interactions between osteoclasts and osteoblasts to preserve bone balance. Traditionally, coupling research related to osteoclast function has focused on bone resorption activity causing the release of growth factors embedded in the bone matrix. However, considerable evidence from in vitro, animal, and human studies indicates the importance of the osteoclasts themselves in coupling phenomena, and many osteoclast-derived coupling factors have been identified. These include sphingosine-1-phosphate, vesicular-receptor activator of nuclear factor-κB, collagen triple helix repeat containing 1, and cardiotrophin-1. Interestingly, neuronal guidance molecules, such as slit guidance ligand 3, semaphorin (SEMA) 3A, SEMA4D, and netrin-1, originally identified as instructive cues allowing the navigation of growing axons to their targets, have been shown to be involved in the intercellular cross-talk among bone cells. This review discusses osteoclast-osteoblast coupling signals, including recent advances and the potential roles of these signals as therapeutic targets for osteoporosis and as biomarkers predicting human bone health.

Keywords: Axon guidance molecule; Biomarker; Bone remodeling; Coupling factor; Therapeutic target.

Fig. 1

Limitations of current anti-osteoporotic drugs and unmet needs for the effective treatment of osteoporosis. a Current anti-resorptives and bone anabolic agents concomitantly suppress and stimulate bone resorption and formation, respectively. Therefore, there are increasing concerns about long-term adverse events and efficacies. b These limitations may be overcome by identifying novel therapeutic agents that can dissociate bone resorption from bone formation

Fig. 2

SLIT3 is a novel osteoclast-derived coupling factor. SLIT3, a clastokine, induces the recruitment and proliferation of pre-osteoblasts, likely contributing to bone formation during early stages of the reversal phase of bone remodeling. SLIT3 also suppresses osteoclastogenesis in an autocrine manner, suggesting that it may also be involved in completion of the resorption phase of bone remodeling