Bone is a dynamic structure, constantly built up by osteoblasts and torn down by osteoclasts. In youth there is a balance between these two cell types, but the processes of aging cause osteoclast activity to dominate, and thus bones inexorably lose density and strength. Osteoporosis lies at the end of this road. The research community has over the years investigated numerous possible approaches to force balance in the activity of osteoblasts and osteoclasts, and the work here is just one example of many. It is typical of most, in that it doesn't attempt to identify and address root causes, but instead seeks to intervene in signaling and regulatory processes that are disarrayed as a consequence of the underlying damage of aging. This is probably not the best strategy.
With advancing age, osteoclast-induced bone resorption outpaces osteoblast-induced bone deposition, leading to a gradual loss of bone mass. The use of therapeutic agents that inhibit osteoclast activity and differentiation has been proposed as a strategy to prevent osteoporosis and other bone-related diseases. Osteoclast differentiation is induced by macrophage-colony stimulating factor (M-CSF), receptor activator of nuclear factor (NF)-κB ligand (RANKL), and osteoprotegerin. These cytokines are involved in signaling pathways that balance the activities of osteoblasts and osteoclasts to maintain bone mass homeostasis. The monoclonal antibody denosumab is the only RANKL inhibitor currently approved by the FDA, and has been reported to reduce bone turnover and increase bone mineral density (BMD).
Given that plasma proteins include aging-related factors, we hypothesized that aging would dynamically alter the plasma levels of proteins involved in age-related bone loss. We used a proteomic approach to identify plasma proteins that were differentially expressed between young and old mice, and investigated their effects on osteoclasts and osteoblasts. We focused on Cadherin-13 (CDH-13), examining its impact on osteoclast differentiation and bone resorption. Finally, we tested whether intraperitoneal administration of CDH-13 could prevent age-related bone loss in mice.
Our results demonstrated that CDH-13 inhibits osteoclast differentiation by blocking RANKL signaling. Although the underlying molecular mechanisms remain to be elucidated, we speculate that plasma CDH-13 may function as a decoy receptor of RANKL or as a RANK receptor antagonist. We also found that CDH-13 was enriched in the blood of young mice and helped to preserve bone mass by inhibiting RANKL-induced osteoclast differentiation. Multiple circulating factors regulate bone mass. Our results suggested that CDH-13 is an age-related bone factor, and that lower levels of CDH-13 disrupt the balance of bone remodeling and promote age-related bone loss. Since the inhibition of RANKL has long been recognized as a therapeutic strategy for osteoporosis, our findings suggest that CDH-13 could be used as a novel therapeutic molecule to inhibit bone loss.