Strontium ranelate inhibits wear particle-induced aseptic loosening in mice

Abstract

The imbalance between bone formation and osteolysis plays a key role in the pathogenesis of aseptic loosening. Strontium ranelate (SR) can promote bone formation and inhibit osteolysis. The aim of this study was to explore the role and mechanism of SR in aseptic loosening induced by wear particles. Twenty wild-type (WT) female C57BL/6j mice and 20 sclerostin-/- female C57BL/6j mice were used in this study. Mice were randomly divided into four groups: WT control group, WT SR group, knockout (KO) control group, and KO SR group. We found that SR enhanced the secretion of osteocalcin (0.72±0.007 in WT control group, 0.98±0.010 in WT SR group, P=0.000), Runx2 (0.34±0.005 in WT control group, 0.47±0.010 in WT SR group, P=0.000), β-catenin (1.04±0.05 in WT control group, 1.22±0.02 in WT SR group, P=0.000), and osteoprotegerin (OPG) (0.59±0.03 in WT control group, 0.90±0.02 in WT SR group, P=0.000). SR significantly decreased the level of receptor activator for nuclear factor-κB ligand (RANKL) (1.78±0.08 in WT control group, 1.37±0.06 in WT SR group, P=0.000) and improved the protein ratio of OPG/RANKL, but these effects were not observed in sclerostin-/- mice. Our findings demonstrated that SR enhanced bone formation and inhibited bone resorption in a wear particle-mediated osteolysis model in wild-type mice, and this effect relied mainly on the down-regulation of sclerostin levels to ameliorate the inhibition of the canonical Wnt pathway.

The Effects of Biomaterial Implant Wear Debris on Osteoblasts

“…Strontium ranelate, which is currently approved for the treatment of post-menopausal osteoporosis, is considered a potential treatment for particle-induced osteolysis (Geng et al, 2018c). Previous studies showed that it can promote osteoblast proliferation, suppress inflammatory osteoclastogenesis both in vitro and in wear particle-induced mouse models (Zhu et al, 2016;Karakan et al, 2017;Geng et al, 2018a,b).…”

“…Previous studies showed that it can promote osteoblast proliferation, suppress inflammatory osteoclastogenesis both in vitro and in wear particle-induced mouse models (Zhu et al, 2016;Karakan et al, 2017;Geng et al, 2018a,b). These effects were dependent on down-regulation of SOST levels to ameliorate subsequent WNT/β-catenin pathway inhibition in osteoblasts, as no protective effect on Ti particle-induced osteolysis was observed in sclerostin −/− mice (Geng et al, 2018c). In addition, a potential role of the BMP signaling pathway should not be neglected Quade et al, 2020).…”

“…In addition, a potential role of the BMP signaling pathway should not be neglected Quade et al, 2020). Wang et al, 2016;Yu and He, 2016;Gu et al, 2017;Ping et al, 2017;Geng et al, 2018c;Lian et al, 2018;Qu et al, 2019 Statins (e.g., simvastatin) RhoA/ROCK Inhibitor Inflammatory reaction↓, new bone formation↑, osteoclastic bone resorption↓ von Knoch et al, 2005b;Vallés et al, 2013;Zhang et al, 2015 SB203580, triptolide Statins, a class of cholesterol-lowering drugs used clinically to reduce the risk of cardiovascular diseases, have been documented to have a beneficial effect on bone metabolism (Zhang et al, 2014). The use of statins is associated with a substantially lower risk of developing femoral osteolysis, and lower revision risk following primary total hip arthroplasty (Thillemann et al, 2010;Lübbeke et al, 2013).…”

Strontium promotes osteogenic differentiation by activating autophagy via the the AMPK/mTOR signaling pathway in MC3T3‑E1 cells

“…Evidence from in vitro and in vivo studies have shown that Sr may promote osteogenic differentiation and mineralization in the dental pulp via PI3K/Akt signaling (26,27). In addition, Wnt/β-catenin signaling has been shown to mediate the protective effects of Sr in mice (28-30). Although the beneficial effects of Sr have been demonstrated in numerous studies (1,9,10), no drug comprising Sr has yet been approved by the Food and Drug Administration for osteoporosis treatment in the USA (4,20,31).…”