Osteoblasts play key roles in the mechanisms of action of strontium ranelate.
OBJECTIVE
Strontium ranelate reduces fracture risk in postmenopausal women with osteoporosis. Evidence from non-clinical studies and analyses of bone markers in phase III trials indicate that this is due to an increase in osteoblast formation and a decrease of osteoclastic resorption. The aim of this work was to investigate, in human cells, the mechanisms by which strontium ranelate is able to influence the activities of osteoblasts and osteoclasts.


METHODS
Human primary osteoblasts were used to examine effects of strontium ranelate on replication (thymidine incorporation), differentiation (Runx2 and alkaline phosphatase) and cell survival (cell counts and caspase activity). Osteoprotegerin (OPG) was measured by quantitative reverse transcription PCR (qRT-PCR) and elisa and receptor activator of NFkappaB ligand (RANKL) by qRT-PCR and Western blot. As strontium ranelate has been proposed as an agonist of the calcium-sensing receptor (CaSR), the involvement of CaSR in the effects of strontium ranelate on OPG and RANKL expression, and cell replication was examined using siRNA.


RESULTS
Strontium ranelate increased mRNA and protein levels of OPG and suppressed those of RANKL. Strontium ranelate also stimulated osteoblast replication and differentiation and increased cell survival under stress. Knocking down CaSR suppressed strontium ranelate-induced stimulation of OPG mRNA, reduction of RANKL mRNA, and increase in replication, indicating the involvement of CaSR in these responses.


CONCLUSIONS
Our results demonstrate that osteoblasts play a key role in the mechanism of action of the anti-fracture agent, strontium ranelate by mediating both its anabolic and anti-resorptive actions, at least in part, via activation of CaSR.
Brennan
T C
TC
Department of Physiology, University of Sydney, NSW, Australia.
Rybchyn
M S
MS
Green
W
W
Atwa
S
S
Conigrave
A D
AD
Mason
R S
RS
D045930:Anabolic Agents / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects* / Q000502:physiology; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D053244:Osteoprotegerin / Q000096:biosynthesis / Q000235:genetics; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000502:physiology; D013876:Thiophenes / Q000494:pharmacology*
D045930:Anabolic Agents; D050071:Bone Density Conservation Agents; C095550:CASR protein, human; D009942:Organometallic Compounds; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044169:Receptors, Calcium-Sensing; C505688:TNFSF11 protein, human; D013876:Thiophenes; C081587:strontium ranelate