Connexins, osteocyte survival and regulation of osteoclastogenesis: novel pathways with therapeutic potential

Connexin (Cx) 43 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 cytoplastmic C-terminus domain, Cx43 serves as a scaffolding protein that associates with structural and signaling molecules leading to regulation of intracellular signaling, independently of channel activity. Work from our laboratory has demonstrated that connexins are essential components of the signaling cascade activated by bisphosphonates, drugs widely used for the treatment of osteoporosis and other bone diseases associated with increased fragility. Thus, Cx43 expression is required for the anti-apoptotic effect of bisphosphonates in vitro and in vivo, an effect that is independent of the action of the drugs on osteoclasts. More recently, we showed that Cx43 is also required to maintain osteocyte viability under basal conditions; as evidenced by the increased osteocyte apoptosis in mice lacking Cx43 in osteoblasts and osteocytes, or only in osteocytes. Elevated osteocyte apoptosis is accompanied by increased osteoclast recruitment to areas where apoptotic osteocytes accumulate. Cx37 is also expressed in bone, and is more abundant in osteocytes than in osteoblast. Global deletion of Cx37 results in increased bone mass and reduced osteoclast surface. Consistent with opposite effects on osteoclastogensis, deletion of Cx43 from osteocytic cells increases the production of pro-osteoclastogenic cytokines (high RANKL/OPG ratio), whereas deletion of Cx37 decreases it.. We believe that 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.