Dose-dependent Effects of Strontium Ranelate on Ovariectomy Rat Bone Marrow Mesenchymal Stem Cells and Human Umbilical Vein Endothelial Cells

Abstract

In clinic, strontium ranelate (SrR) is a useful drug to treat osteoporosis by orally taken method, but some side effect appeared in recent years. The aim of this study is to evaluate the effectiveness and safety of SrR on cells by direct application, to study the possibility of local application of this drug. Qualitative ALP staining, quantitative ALP activity assay, alizarin red staining, realtime PCR and westernblot assay were used to evaluate the osteogenesis ability of SrR under normal or osteogenic induction environment of ovariectomy bone marrow mesenchymal stem cells (OVX-BMSCs). The angiogenesis ability of SrR was studied by immunofluorescence staining of CD31 and vWF of OVX-BMSCs under angiogenesis induction environment, transwell, tubeformation and realtime PCR assay of HUVECs. Signaling pathway of PI3K/AKT/mTOR was also studied. The result demonstrated that SrR could enhance proliferation and osteogenic differentiation of OVX-BMSCs. The osteogenesis effect of SrR has been proved by the better performed of ALP activity, alizarin red staining and the remarkable up-regulation of ALP, Col-I, Runx2, OCN, BMP-2, BSP, OPG of the OVX-BMSCs, and reduction of RANKL. In addition, SrR promotes angiogenesis differentiation of both OVX-BMSCs and HUVECs. Higher intensity of immunostaining of CD31 and vWF, better result of transwell and tubeformation assay could be observed in SrR treated group, and increasing mRNA levels of VEGF and Ang-1 in the OVX-BMSCs, VEGF in HUVECs were learnt. Signaling pathway assay showed that PI3K/AKT/mTOR signaling pathway was involved in this SrR triggered angiogenesis procedure. The thrombosis marker ET-1, PAI-1 and t-PA were up-regulated, but no significant differences for low concentration (<0.5mM). The concentration between 0.25-0.5mM may be more appropriate for local application, and locally application of SrR could be considered as a promising way for bone regeneration.

Strontium ranelate-induced anti-adipocytic effects are involved in negative regulation of autophagy in rat bone marrow mesenchymal stem cells

“…However, in previous studies, SrRN or strontium chloride exhibited different proliferative effects on BMMSCs at different concentrations [11,17]. Although, our finding was not consistent with past reports, the results still verified the safety of SrRN below 2 mM.…”

“…Guo et al presented similar results in their recent study about the internal mechanism of SrRN. The PI3K/Akt/mTOR signaling pathway was activated by SrRN to trigger angiogenesis in human umbilical vein endothelial cells [17].…”

Effects of Programmed Local Delivery from a Micro/Nano‐Hierarchical Surface on Titanium Implant on Infection Clearance and Osteogenic Induction in an Infected Bone Defect

“…The release measurement (Figure A) suggested early high doses of Sr 2+ could promote the alternative M2 polarization of macrophages in the early stage of immune response and then decrease inflammation. Interestingly, the concentration of Sr 2+ in our assay which orchestrated M2 polarization did not match the therapeutic window of Sr 2+ described by Guo et al which promote osteogenic differentiation of osteoblast precursors. We conjectured the therapeutic window of different kinds of cells were not the same and the immunocytes maybe more sensitive to divalent cation stimulation.…”

HnRNPL inhibits the osteogenic differentiation of PDLCs stimulated by SrCl2 through repressing Setd2

“…Furthermore, AKT pathway was involved in Sr induced osteogenesis and angiogenesis. 27 Therefore, we investigated the…”