• Open Access

Calcium sensing receptor-dependent and receptor-independent activation of osteoblast replication and survival by strontium ranelate

Authors


Correspondence to: Dr. P. J. MARIE,
INSERM U606, Hopital Lariboisiere,
2 rue Ambroise Pare,
75475 Paris cedex 10, France.
Tel.: +33 1 49956389
Fax: +33 1 49958452
E-mail: pierre.marie@inserm.fr

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 ranelates increased cell replication in [CaSR−/−] and [CaSR+/+] osteoblasts. Strontium ranelate rapidly increased ERK1/2 phosphorylation in [CaSR+/+] but not in [CaSR−/−] osteoblasts, indicating that strontium ranelate can act independent 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 IL-1β and TNF-α 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, independent of CaSR expression. The finding that CaSR-dependent and CaSR-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.

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