Connexin43 (Cx43) is the most abundant gap junction protein expressed in bone cells and plays a central role in cell-to-cell communication in the skeleton. Findings of the last decade uncovered functions of Cx43 hemichannels expressed on unopposed plasma cell membranes as mediators of the communication between bone cells and their extracellular milieu. Additionally, through its cytoplasmic C-terminus domain, Cx43 serves as a scaffolding protein that associates with structural and signaling molecules leading to regulation of intracellular signaling, independent of channel activity. This perspective discusses the evidence demonstrating that via these diverse mechanisms Cx43 is a key component of the intracellular machinery responsible for signal transduction in bone in response to pharmacologic, hormonal and mechanical stimuli. This advance in the knowledge of the role of connexins increases our understanding of the pathophysiological mechanisms that regulate bone cell function and provides new opportunities to treat bone diseases.
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