Original Full Length ArticleStrontium Ranelate affects signaling from mechanically-stimulated osteocytes towards osteoclasts and osteoblasts

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 24 h with SrRan (0.1-3 mM) and either or not mechanically stimulated by pulsating fluid flow (PFF; 0.7 ± 0.3 Pa, 5 Hz) for 60 min. 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 7 days to assess osteoclastogenesis, or MC3T3-E1 osteoblasts for 4-16 days to measure osteogenic gene expression.SrRan (3 mM) 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 3 mM SrRan. CM from PFF-treated osteocytes inhibited osteoclastogenesis by 1.9-fold. The combination of PFF and 3 mM 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.

► Strontium Ranelate affected paracrine signaling from mechanically stimulated osteocytes towards osteoclast-precursors and osteoblasts in vitro. ► Mechanical stimulation and Strontium Ranelate had an additive effect on nitric oxide and prostaglandin E2 production by osteocytes. ► The combination of 3 mM Strontium Ranelate and mechanical stimulation strongly reduced osteocyte-stimulated osteoclastogenesis. ► Strontium Ranelate affects paracrine signaling by osteocytes, which may partly explain how Strontium Ranelate reduces risk of bone fractures.