Calcium sensing receptor-dependent and receptor-independent activation of osteoblast replication and survival by strontium ranelate.
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-1beta and TNF-alpha 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.
Laboratory of osteoblast biology and pathology, INSERM U606 and University Paris 7, Paris, France.
Olivia
O
Fromigué
Eric
E
Haÿ
Alain
A
Barbara
Christophe
C
Petrel
Elisabeth
E
Traiffort
Martial
M
Ruat
Pierre J
PJ
Marie
D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D005260:Female; D008297:Male; D051379:Mice; D009942:Organometallic Compounds / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology*
D009942:Organometallic Compounds; D044169:Receptors, Calcium-Sensing; D013876:Thiophenes; C081587:strontium ranelate