Connexins in skeletal biology

The skeleton is a dynamic structure that constantly remodels in response to local and systemic stimuli to meet the needs of structural integrity, mechanical competence, and maintenance of mineral homeostasis. Control of bone remodeling requires coordinated activity among osteoblasts, osteocytes, and osteoclasts. In recent years, knowledge about the biological role of connexins in the skeletal system has significantly advanced, primarily as a result of studies involving mouse and human connexin genetics. Cx43, the most abundant gap junction protein in the skeleton, is required for normal skeletal development (bone modeling) and for its maintenance in postnatal life (bone remodeling). These biological functions are underscored by the skeletal malformations and severe osteopenia present in oculodentodigital dysplasia, a disease linked to CX43 gene (GJA1) mutations, and by Gja1 ablation in mice. Cx43 modulates osteoblast differentiation and function by allowing full responses to extracellular cues via upregulation of specific signaling pathways converging on connexin-sensitive transcriptional units. Other connexins are present in the skeletal tissue, but their function is only partially understood. Gap junctional intercellular communication and gap junction hemichannels are also critical in mechanostransduction, functioning to integrate and amplify mechanical signals throughout bone cell networks.