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Chris Or, Jing Cui, Joanne Matsubara, Farzin Forooghian; Effects of bisphosphonates on cytotoxicity and cytokine expression in hRPE cells in vitro. Invest. Ophthalmol. Vis. Sci. 2013;54(15):146.
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Bisphosphonates are the most commonly prescribed drugs used to treat osteoporosis. In addition to a recent report supporting an association between bisphosphonate use and ocular inflammation (Etminan et al., 2012), preliminary data also support an association between bisphosphonate use and age-related macular degeneration (AMD). Therefore, we studied the effects of bisphosphonates on primary culture of human retinal pigment epithelium (hRPE), a cell type known to secrete pro-inflammatory cytokines in the outer retina. Alendronate, an amino-bisphosphonate, and etidronate, a non-amino-bisphosphonate, were selected for this experiment as they are members of the two structurally different classes of bisphosphonates.
Primary cultures of hRPE were serum-starved for 24 hours and then treated for 24 hours with alendronate (0.0001, 0.1, 100 µM) and etidronate (0.01, 1 µM). Cell viability was measured using the MTT assay. Investigation of cytokines induced by bisphosphonates was performed using a human cytokine 29-Plex Panel (Bio-Plex) array and the results were analyzed with an ANOVA.
Etidronate, at the lower concentration, significantly increased the expression of IL-6 (p=0.03) and IL-8 (p=0.04). At the higher concentration, etidronate significantly decreased the expression of GM-CSF (p=0.02) and bFGF (p=0.02). Alendronate, at the highest concentration, significantly increased the expression of IL-8 (p=0.02) and decreased the expression of eotaxin (p=0.02). Alendronate also significantly decreased the expression of bFGF at all concentrations (p<0.05). Alendronate and etidronate did not significantly alter the expression of the other cytokines measured. Cell viability was not significantly affected by either alendronate or etidronate treatment for 24h.
Alendronate and etidronate display dose dependent effects in hRPE cells. Etidronate at lower concentration and alendronate at higher concentration appear to induce pro-inflammatory effects. In addition, anti-angiogenic effects of both drugs were demonstrated by the reduction in bFGF and eotaxin expression observed with the highest concentration of alendronate. The anti-angiogenic effects observed are consistent with a previous study (Nagai et al., 2007). Further studies are required to elucidate the association between bisphosphonate use and AMD.
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