Gallium modulates osteoclastic bone resorption in vitro without affecting osteoblasts

Abstract

Background and purpose: Gallium (Ga) has been shown to be effective in the treatment of disorders associated with accelerated bone loss, including cancer-related hypercalcemia and Paget's disease. These clinical applications suggest that Ga could reduce bone resorption. However, few studies have studied the effects of Ga on osteoclastic resorption. Here, we have explored the effects of Ga on bone cells in vitro. Experimental approach:In different osteoclastic models [osteoclasts isolated from long bones of neonatal rabbits (RBC), murine RAW 264.7 cells and human CD14-positive cells], we have performed resorption activity tests, staining for tartrate resistant acid phosphatase (TRAP), real-time polymerase chain reaction analysis, viability and apoptotic assays. We also evaluated the effect of Ga on osteoblasts in terms of proliferation, viability and activity by using an osteoblastic cell line (MC3T3-E1) and primary mouse osteoblasts. Key results: Gallium dose-dependently (0-100 mM) inhibited the in vitro resorption activity of RBC and induced a significant decrease in the expression level of transcripts coding for osteoclastic markers in RAW 264.7 cells. Ga also dramatically reduced the formation of TRAP-positive multinucleated cells. Ga down-regulated in a dose-dependant manner the expression of the transcription factor NFATc1. However, Ga did not affect the viability or activity of primary and MC3T3-E1 osteoblasts. Conclusions and implications:Gallium exhibits a dose-dependent anti-osteoclastic effect by reducing in vitro osteoclastic resorption, differentiation and formation without negatively affecting osteoblasts. We provide evidence that this inhibitory mechanism involves down-regulation of NFATc1 expression, a master regulator of RANK-induced osteoclastic differentiation.

Modification of honeycomb bioceramic scaffolds for bone regeneration under the condition of excessive bone resorption

“…The cytotoxicity of high concentration of Ga has been confirmed . Verron et al revealed that 0–100 μ M Ga 3+ (0–7 ppm) were not cytotoxic, but not distinctly beneficial for cell proliferation either . Maeno et al demonstrated the enhancing effect of Ca 2+ on cell proliferation .…”

“…Blair et al demonstrated that the Ga 3+ with concentrations of 100 µ M (7 ppm) in vitro or 7–12 µ M (0.49–0.84 ppm) in vivo were enough to inhibit osteoclastogenesis . Verron et al reported that 10 μ M Ga 3+ (0.7 ppm) dramatically decreased the expression level of osteoclastic genes in RAW264.7 cells, and markedly decreased the generation of multinucleated cells . The Ga 3+ inhibits bone resorption in a concentration‐dependent manner .…”

Storage media enhance osteoclastogenic potential of human periodontal ligament cells via RANKL‐independent signaling

“…GAPDH GAGCCAAACGGGTCATCA CATATTTCTCGTGGTTCACACC (23) differentiation, using the leukocyte acid phosphatase kit (386-A; Sigma). Images were obtained with a light microscope (Nikon TE2000-S, Japan) using a SPOT RT camera (USA).…”

The impact of gallium content on degradation, bioactivity, and antibacterial potency of zinc borate bioactive glass

“…However, Ga 3+ is not reduced under physiological conditions like Fe 3+ allowing it to perturb the metabolism of both eukaryotic and prokaryotic cells . With regard to tissue engineering, studies have shown that Ga 3+ can increase the calcium content of the bone while blocking bone resorption by osteoclasts . Ga 3+ has also been shown to have the most significant in vivo anti‐tumor activity among the group IIIa metal ions .…”