Statins regulate interleukin-1β-induced RANKL and osteoprotegerin production by human gingival fibroblasts

Abstract

Three-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase competitive inhibitors, or 'statins', are widely used for lowering cholesterol and thereby reducing the risk of a heart attack. Recent data suggest that statins influence metabolic bone activity by their actions on three molecules: RANKL; RANK; and osteoprotegerin (OPG), the soluble decoy receptor for RANKL. The purpose of this study was to evaluate OPG and RANKL production in resting and interleukin-1β (IL-1β)-activated human gingival fibroblasts (HGFs), and to determine the effect of statins on their production. Fibroblasts were pre-incubated with atorvastatin or simvastatin for 24h in serum-free medium, and then incubated with IL-1β for 6d. The concentration of OPG or RANKL in culture supernatants was measured by specific ELISA. Data were analyzed using analysis of variance and Scheffe's F procedure for post hoc comparison. IL-1β (1×10(-8) m) stimulated a significant increase in the production of OPG on days 1, 3 and 6. There was a trend towards an increase in RANKL production as a result of stimulation with IL-1β. Both statins, at multiple concentrations, significantly increased the constitutive RANKL/OPG ratio. Only atorvastatin at the highest concentration (5×10(-6) m) significantly increased the IL-1β-stimulated RANKL/OPG ratio. IL-1β significantly increased OPG production by HGFs. The statins differed minimally in their effects on OPG and RANKL production by resting and IL-1β-activated HGFs. Both statins increased constitutive RANKL/OPG ratios, but generally not IL-1β-stimulated ratios. Thus, statins may influence the production of RANKL and OPG by HGFs to favor bone catabolism, under noninflammatory conditions.