Strontium Ranelate affects signaling from mechanically-stimulated osteocytes towards osteoclasts and osteoblasts

Abstract: Strontium Ranelate (SrRan) is used to decrease the risk of bone fractures. Any factor that alters the release of paracrine signals by osteocytes in response to mechanical stimuli potentially affects bone mass and structure, and thus fracture resistance. We hypothesized that SrRan affects paracrine signaling from mechanically-stimulated osteocytes towards osteoclast-precursors and osteoblasts. MLO-Y4 osteocytes were cultured for 24h with SrRan (0.1–3mM) and either or not mechanically stimulated by pulsating fluid flow (PFF; 0.7±0.3Pa, 5Hz) for 60min. Nitric oxide (NO) and prostaglandin E2 (PGE2) release, and expression of mechanoresponsive genes were quantified. Conditioned medium (CM) from osteocytes was added to mouse bone marrow cells for 7days to assess osteoclastogenesis, or MC3T3-E1 osteoblasts for 4–16days to measure osteogenic gene expression. SrRan (3mM) enhanced NO and PGE2 release to the same extent in static osteocytes (NO: 1.6-fold; PGE2: 2.8-fold) and PFF-stimulated osteocytes (NO: 1.3-fold; PGE2: 2.6-fold). CM from PFF-treated osteocytes without SrRan enhanced Ki67 expression but reduced Runx2 and Ocn expression in osteoblasts. This effect on gene expression was not observed with CM obtained from osteocytes treated with the combination of PFF and 3mM SrRan. CM from PFF-treated osteocytes inhibited osteoclastogenesis by 1.9-fold. The combination of PFF and 3mM SrRan reduced osteocyte-stimulated osteoclastogenesis even more strongly (4.3-fold). In conclusion, SrRan affects paracrine signaling between mechanically-stimulated MLO-Y4 osteocytes and both osteoblasts and osteoclast precursors. The positive effects of SrRan on bone fracture resistance may thus be partly explained by altered paracrine signaling by osteocytes. [Copyright &y& Elsevier]