001] (IC50 50 μM) Cr6+ ions had the greatest inhibitory effect o

001] (IC50 50 μM). Cr6+ ions had the greatest inhibitory effect on the formation of functional osteoclasts. Increasing Cr6+

resulted in a reduction in the number of osteoclasts (IC50 = 0.37 μM) and total resorption (IC50 = 0.30 μM), ( Figs. 3A–B and 4G–I, p < 0.0001 for 1 μM to 100 μM). To determine the effects of metal ions AZD2281 on mature, fully functional and active human osteoclasts, human monocytes were isolated, settled onto dentine disks and cultured as above but in the absence of metal ions to allow the fusion cells and formation of osteoclasts. The onset of resorption (an indicator of fully functional and active osteoclasts) was monitored daily from day 10 and once resorption had been detected (typically after 14 days), the osteoclast culture medium was then replaced to include 0.01 μM to 200 μM Co2+ and Cr3+ and 0.01 μM to 100 μM Cr6+

ions for the last 7 days of culture. The pattern of response for Co2+ and Cr3+ was different to that seen for newly forming osteoclasts in that no transient increase in cell number or activity was found, and that the inhibitory buy Quizartinib effects of all ions were seen at a lower ion concentration. Seven days treatment with Co2+ ions ≥ 10 μM reduced mature osteoclast number (IC50 = 5.4 μM (p < 0.001, Fig. 3C). Total amount of resorption per disk was only reduced at the high (200 μM) concentration (p < 0.0001 and p < 0.001, Figs. 3D and 4J–L). Treatment with Cr3+ ions reduced mature osteoclast number and resorption per disk, but only at the 200 μM dose (p < 0.05, Figs. 3C–D

and 4M–O, IC50 for osteoclast number = 221 μM and IC50 for resorption per disk = 77 μM). Casein kinase 1 No trend towards increased osteoclast number or resorption was seen for mature osteoclasts at the lower Cr3+ concentration range. Cr6+ ions had the greatest effect on osteoclast number and resorption. Cr6+ at concentration ≥ 10 μM caused a reduction in osteoclast number and resorption per disk (p < 0.01 all analyses, Figs. 3C–D and 4P–R, IC50 for osteoclast number = 1.8 μM and IC50 for resorption per disk = 3.9 μM). In this study we examined the effect of chronic exposure of human osteoblast and primary human osteoclast cells to Co and Cr ions at concentrations including the clinically equivalent range defined by previous reports of measured metal levels in the serum and hip synovial fluid taken from patients after MOMHR. We found that ions of both metals affected osteoblast and osteoclast cell proliferation and function. These effects were greatest for Cr6+, then Co2+, with Cr3+ showing the least effect. The observed responses also varied with metal ion concentration, cell type and cell maturity. Our findings are consistent with in-vitro studies using animal cells that supra-physiological concentrations of cobalt and chromium ions induce apoptosis in human osteoblast-like cells in-vitro in a dose-dependent manner [12], and suppress osteoblast synthetic function [11], [21] and [22].

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