Cell autonomous requirement of connexin 43 for osteocyte survival: Consequences for endocortical resorption and periosteal bone formation

Abstract

Connexin43 (Cx43) mediates osteocyte communication with other cells and with the extracellular milieu and regulates osteoblastic cell signaling and gene expression. We now report that mice lacking Cx43 in osteoblasts/osteocytes or only in osteocytes (Cx43Ot mice)exhibit increased osteocyte apoptosis, endocortical resorptionand periosteal bone formation, resulting in higher marrow cavityand total tissueareas measured at the femoral mid-diaphysis.Blockade of resorption reversed the increasedmarrow cavity but not total tissue area, demonstrating that endocortical resorption andperiosteal apposition are independently regulated.Anatomical mappingof apoptotic osteocytes,osteocytic protein expression, and resorption and formation,suggeststhat Cx43 controls osteoclast and osteoblast activity by regulating osteoprotegerin and sclerostinlevels, respectively, in osteocytes located in specific areas of the cortex.Whereas empty lacunae and living osteocytes lacking osteoprotegerinwere distributed throughout cortical bone in Cx43Ot mice, apoptotic osteocyteswere preferentially located in areas containing osteoclasts, suggesting that osteoclast recruitment requires active signaling from dying osteocytes.Furthermore, Cx43 deletion in cultured osteocytic cells resulted in increased apoptosis and decreased osteoprotegerin expression. Thus, Cx43 is essential in a cell-autonomous fashionin vivo and in vitrofor osteocyte survivaland for controlling the expression of osteocytic genesthat affectosteoclast and osteoblast function.