Bisphosphonates, connexins and apoptosis of osteocytes and osteoblasts: a novel mechanism of action with therapeutic potential

Abstract

Bisphosphonates are widely used for the treatment of conditions with increased bone fragility. These agents stop bone loss by inhibiting the activity of osteoclasts, the bone resorbing cells. However, the modest effect of bisphosphonates on bone mass cannot completely explain the reduction in fractures observed in patient treated with these agents. Based on the lack of correlation between increased bone mass and decreased fracture incidence, we have explored the possibility that part of the beneficial effect of bisphosphonates on the skeleton is due to prevention of osteocyte apoptosis. Osteocytes, mature osteoblasts that become surrounded by bone matrix, constitute the majority of the cells in bone. Osteocytes and their projections form a network that spreads out throughout the bone. Due to their position within the bone matrix, osteocytes are ideally located to perceive changes in mechanical and hormonal stimuli and to trigger signals that lead to bone repair, preventing the deterioration of the bone quality and the possibility of bone fractures. Osteocytes communicate among themselves and with cells on the bone surface through connexin (Cx) channels, in particular, those formed by Cx43. Work of our group has demonstrated that bisphosphonates, even those that do not have anti-catabolic actions, are able to prevent osteocyte apoptosis in vitro and in vivo. This survival effect requires the opening of Cx43 hemichannels, but it is independent of gap junctions. Hemichannel opening is followed by activation of the kinases Src and ERKs. This leads to the phosphorylation of cytoplasmic factors and to inhibition of apoptosis. Using genetically modified mice in which Cx43 expression was specifically deleted from osteoblastic cells, we have demonstrated that Cx43 is also required for the effect of bisphosphonates on these cells in vivo. In addition, we found that a bisphosphonate analog that does not inhibit osteoclast activity is still able to prevent apoptosis of osteoblasts and osteocytes, and the loss of bone mass and strength induced by glucocorticoids. Our studies revealed a novel mechanism of action triggered by opening of Cx43 hemichannels, which results in the maintenance of the osteocytic network. This action of bisphosphonates and its dissociation from their effect on osteoclasts using analogs that lack anti-catabolic actions open new therapeutic possibilities for conditions in which a decreased in bone resorption is not desired.