Calcium sensing receptor-dependent and -independent activation of osteoblast replication and survival by strontium ranelate.
Résumé
Abstract Age-related osteopenia is characterized by a negative balance between bone resorption and formation. The anti-osteoporotic drug strontium ranelate was found to reduce bone resorption and to promote bone formation. Here, we investigated the implication of the calcium sensing receptor (CaSR) in the response to strontium ranelate using osteoblasts from CaSR knockout [CaSR(-/-)] and wild-type [CaSR(+/+)] mice. We showed that calcium and strontium ranelate increased cell replication in [CaSR(-/-)] and [CaSR(+/+)] osteoblasts. Strontium ranelate rapidly increased ERK1/2 phosphorylation in [CaSR(+/+)] but not [CaSR(-/-)] osteoblasts, indicating that strontium ranelate can act independently of the CaSR/ERK1/2 cascade to promote osteoblast replication. We also showed that strontium ranelate prevented cell apoptosis induced by serum deprivation or the pro-inflammatory cytokines IL1beta and TNFalpha in [CaSR(-/-)] and [CaSR(+/+)] osteoblasts, indicating that CaSR is not the only receptor involved in the protective effect of strontium ranelate on osteoblast apoptosis. Strontium ranelate activated the Akt pro-survival pathway in [CaSR(-/-)] and [CaSR(+/+)] osteoblasts and pharmacological inhibition of Akt abrogated the anti-apoptotic effect of strontium ranelate. Furthermore, both the proliferative and anti-apoptotic effects of strontium ranelate in [CaSR(-/-)] and [CaSR(+/+)] osteoblasts were abrogated by selective inhibition of COX-2. The results provide genetic and biochemical evidence that the effects of strontium ranelate on osteoblast replication and survival involve ERK1/2 and Akt signalling and PGE2 production, independently of CaSR expression. The finding that CaSR-dependent and -independent pathways mediate the beneficial effects of strontium ranelate on osteoblasts provides novel insight into the mechanism of action of this anti-osteoporotic agent on osteoblastogenesis.