Low-dose strontium stimulates osteogenesis but high-dose doses cause apoptosis in human adipose-derived stem cells via regulation of the ERK1/2 signaling pathway

Abstract

BackgroundStrontium is a widely used anti-osteoporotic agent due to its dual effects on inhibiting bone resorption and stimulating bone formation. Thus, we studied the dose response of strontium on osteo-inductive efficiency in human adipose-derived stem cells (hASCs).MethodQualitative alkaline phosphatase (ALP) staining, quantitative ALP activity, Alizarin Red staining, real-time polymerase chain reaction and Western blot were used to investigate the in vitro effects of a range of strontium concentrations on hASC osteogenesis and associated signaling pathways.ResultsIn vitro work revealed that strontium (25–500 μM) promoted osteogenic differentiation of hASCs according to ALP activity, extracellular calcium deposition, and expression of osteogenic genes such as runt-related transcription factor 2, ALP, collagen-1, and osteocalcin. However, osteogenic differentiation of hASCs was significantly inhibited with higher doses of strontium (1000–3000 μM). These latter doses of strontium promoted apoptosis, and phosphorylation of ERK1/2 signaling was increased and accompanied by the downregulation of Bcl-2 and increased phosphorylation of BAX. The inhibition of ERK1/2 decreased apoptosis in hASCs.ConclusionLower concentrations of strontium facilitate osteogenic differentiation of hASCs up to a point; higher doses cause apoptosis of hASCs, with activation of the ERK1/2 signaling pathway contributing to this process.

Synergistic effect of strontium, bioactive glass and nano‐hydroxyapatite promotes bone regeneration of critical‐sized radial bone defects

“…The number of viable cells was decreased by incorporation of Sr (65 μM) into the G/nHAp scaffold, but there was no significant difference among all groups which is in agreement with data in literature. Lower concentrations of Sr facilitated osteogenic differentiation of MSCs (up to 500 μM), while higher doses caused cell death …”

Chitosan/hydroxyapatite composite bone tissue engineering scaffolds with dual and decoupled therapeutic ion delivery: copper and strontium

“…Strontium release at this concentration sits within the therapeutic window (2-45 ppm) and it is expected to help osteogenesis throughout the first months of regeneration in vivo. 59 The different nature of the TMI loading in the two materials highlights the convenience of the present strategy to obtain very different release profiles depending on the desired ion, tailoring the uniformity of release according to need independently of the intrinsic scaffold degradation kinetics (Fig. 15).…”

Strontium enhances proliferation and osteogenic behavior of bone marrow stromal cells of mesenchymal and ectomesenchymal origins in vitro

“…The pathway determining the anabolic effect of Sr on bone remains poorly understood. In vitro studies suggest that Sr can promote osteoblast proliferation and osteoblastic differentiation in populations rich in precursor cells, such as BMSCs (Bianco et al, 2001;Choudhary, Halbout, Alander, Raisz, & Pilbeam, 2007;Friedenstein, Latzinik, Grosheva, & Gorskaya, 1982;Peng et al, 2009), human adipose-derived stem cells (Aimaiti et al, 2017), and human periodontal ligament cells (PDLCs; Bizelli-Silveira et al, 2018).…”