- Paper Report
- Open Access
Bisphosphonates prevent osteocyte apoptosis
- Mike Rogers1
© Current Science Ltd 1999
- Published: 30 November 1999
Bone quality is maintained by the concerted action of osteoclasts (bone-resorbing cells), osteoblasts (bone-forming cells), and osteocytes, which appear to have a mechanosensory function and respond to microdamage. Glucocorticoid treatment causes an increase in apoptosis of osteoblasts and osteocytes, which may contribute to increased bone fragility and the higher incidence of fractures in glucocorticoid-treated patients. Bisphosphonates are currently the most important class of antiresorptive drugs used in the treatment of such metabolic bone disorders. As well as inhibiting bone resorption by osteoclasts and decreasing the risk of fractures, long-term treatment with bisphosphonates can modestly increase bone mass, suggesting that these drugs may have effects in addition to their antiresorptive action. To determine whether bisphosphonates and calcitonin could help to reduce fracture risk and increase bone mass in vivoby preventing apoptosis of osteocytes and osteoblasts, thereby preserving the osteocytic network in bone and causing a net increase in bone density.
Concentrations of 1 nM-1 ?M bisphosphonates suppressed apoptosis (nuclear degeneration, caspase activation and loss of cell viability) of MLO-Y4 cells and osteoblasts. This protective effect was evident regardless of the apoptosis-inducing agent (etoposide, TNF-a or dexamethasone). Similar effects were observed with 5 ng/ml calcitonin, which was shown to bind specifically to MLO-Y4 cells. Inhibition of apoptosis by bisphosphonates and calcitonin was associated with a rapid but transient increase in phosphorylation of ERKs 1 and 2. ERK activation appeared to be necessary for the antiapoptotic effect, since the ERK inhibitors PD98059 and U0126 prevented the suppression of apoptosis. Finally, alendronate treatment in vivo prevented bone loss and decreased the prevalence of osteocyte and osteoblast apoptosis in prednisolone-treated mice.
The osteocytic cell line MLO-Y4 or calvarial osteoblasts were treated in vitrowith calcitonin or bisphosphonates (etidronate, pamidronate, alendronate, olpadronate or an amino-derivative of olpadronate) for 1 h. Apoptosis was then induced by the addition of tumour necrosis factor alpha(TNF-a), etoposide or dexamethasone. Apoptosis was quantitated by examination of nuclear morphology, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay, the presence of caspase activity and increased trypan blue uptake. The effects of bisphosphonates and calcitonin on phosphorylation of extracellular signal-regulated kinases (ERKs) was assessed by western blotting. Apoptosis of osteocytes and osteoblasts was also quantitated, using TUNEL assay, on undecalcified sections of vertebral bone from prednisolone-treated mice.