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Introduction
Advanced age is associated with skeletal fragility as a result of decreases in bone quantity and quality due to changes in the structural and material properties of bone. Bone remodeling, a coordinated process critical for the maintenance of bone quality, occurs throughout life; however, the rate of bone turnover significantly decreases with advancing skeletal age. Alterations in bone turnover where resorption outweighs formation eventually result in bone loss in old age. Initial age‐induced bone loss is observed in trabecular bone due to decreased osteoblast activity, whereas cortical bone losses occur later. In addition to the alterations in bone structure, bone material is also affected in aging, as changes in bone mineral matrix and collagen composition as well as accumulation of microdamage further contribute to the increased skeletal fragility with aging.
Numerous studies suggest that the extensive osteocyte network within the mineralized bone matrix plays an essential role in orchestrating bone remodeling through cell‐cell communication among neighboring osteocytes and with cells on the bone surface. Consistent with this notion, old age and conditions of increased skeletal fragility are associated with reductions in osteocyte viability and increased prevalence of empty lacunae, and disruptions in the osteocyte network alter osteocytic regulation of bone remodeling. Osteocytes control intercellular signaling with distant cells both through the extracellular release of molecules and cytokines via hemichannels formed via connexins (Cx) and directly with adjacent cells through gap junction channels, formed by connexons present on the surface of neighboring cells. Cx transmembrane proteins are expressed in osteoblasts, osteocytes, and osteoclasts, with Cx43 being the most highly expressed connexin in bone.(12)
The critical role of Cx43 in early and mature osteoblasts as well as in osteocytes has been demonstrated in numerous studies. We previously showed that removal of Cx43 from osteocytes results in a skeletal phenotype that resembles that of aged mice with increased osteocyte apoptosis, enhanced osteoclast recruitment to bone surfaces, and defective bone material properties. Further, Cx43 is significantly decreased in old mice and humans. Overall, these findings demonstrate the essential role that Cx43 plays in maintaining osteocyte viability and bone homeostasis, thus underscoring the potential contribution of reduced levels of Cx43 in osteocytes to the bone weakness in aging. However, the specific role that osteocytic Cx43 plays in controlling...