Connexin 43 and Bone: Not Just a Gap Junction Protein

Abstract

Connexins are essential for the communication of cells among themselves and with their environment. Connexin hexamers assemble at the plasma membrane to form hemichannels that allow the exchange of cellular contents with the extracellular milieu. In addition, hemichannels expressed in neighboring cells align to form gap junction channels that mediate the exchange of contents among cells. Connexin 43 (Cx43) is the most abundant connexin expressed in bone cells and its deletion in all tissues leads to osteoblast dysfunction, as evidenced by reduced expression of osteoblast markers and delayed ossification. Moreover, Cx43 is essential for the survival of osteocytes; and mice lacking Cx43 in these cells exhibit increased prevalence of osteocyte apoptosis and empty lacunae in cortical bone. Work of several groups for the past few years has unveiled the role of Cx43 on the response of bone cells to a variety of stimuli. Thus, the preservation of the viability of osteoblasts and osteocytes by the anti-osteoporotic drugs bisphosphonates depends on Cx43 expression in vitro and in vivo. This survival effect does not require cell-to-cell communication and is mediated by unopposed hemichannels. Cx43 hemichannels are also required for the release of prostaglandins and ATP by osteocytes induced by mechanical stimulation in vitro. More recent evidence showed that the cAMP-mediated survival effect of parathyroid hormone (PTH) also requires Cx43 expression. Moreover, the hormone does not increase bone mineral content in mice haploinsufficient for Cx43 or lacking Cx43 in osteoblastic cells. Since inhibition of osteoblast apoptosis contributes, at least in part, to bone anabolism by PTH, the lack of response to the hormone might be due to the requirement of Cx43 for the effect of PTH on osteoblast survival. In summary, mounting evidence indicate that Cx43 is a key component of the intracellular machinery responsible for the transduction of signals in the skeleton in response to pharmacologic, hormonal and mechanical stimuli.