Strontium Ranelate Prevents Advanced Glycation End Product Induced Deleterious Effects on Osteoblastic Cells: Role of Pro−Inflammatory Cytokines

SEDLINSKY C; FERNÁNDEZ JM; MOLINUEVO MS; SCHURMAN L; CORTIZO AM; MCCARTHY A

Boston

Congreso; The Endocrine Society, Endo 2011; 2011

The formation and accumulation of advanced end glycation products (AGE) has been implicated in the pathogenesis of several metabolic disorders, including diabetes. In patients suffering from diabetes type 2 it has been found alterations on bone tissue, possibly associated to an accumulation of AGE on bone tissue. Bone loss is usually treated with antiresorptive drugs such as biphosphonates or more recently strontium ranelate. We have previously demonstrated that AGE causes a deleterious effect on bone related cells. The mechanisms underlying these effects include induction of osteoblastic apoptosis, increase in reactive oxygen species as well as a decrease in osteoblastic differentiation. It has also been demonstrated that the interaction of AGE with its specific receptor RAGE induces NFk-b activation that in turn increase pro-inflammatory cytoquines secretion such as interleukin 1-b (IL-1b) and TNF-a. In the present work we evaluated the action of strontium ranelate on the deleterious action of AGE on osteoblasts. MC3T3E1 osteoblastic line was cultured in the presence of glycated bovine serum albumin (AGE) or unmodified-albumin (BSA) as control. After 24h incubation, 0.1 mM of Strontium Ranelate (SR) increased cell proliferation (122 ± 5 % of BSA) while AGE inhibited cell proliferation in a dose dependent manner, being the maximum effect at 200 ug/ml AGE (63 ± 4 % of BSA, p<0.01). AGE also inhibited alkaline phosphatase activity (100 µg/ml AGE: 60 ± 8 % vs BSA, p<0.01) and collagen production (100 µg/ml AGE: 79 ± 4 % vs BSA, p<0.01) after 15 days of culture. Evaluation of cytokines production shown that SR tends to decrease secretion of both IL-1b and TNF-a while AGE increased IL 1-b and TNF-a secretion (two-folds over control BSA, p<0.01). AGE-induced cytokines secretion was prevented by 0.1 mM of SR co-incubation. In order to elucidate the role of calcium channels on the action of SR, we MC3T3E1 osteoblasts were incubated for 24h with nifedipine, a type L calcium channel blocker. Nifedipine was able to inhibit the anabolic action of SR on osteoblastic cells as well as the effect of SR on AGE action. In conclusion, we have shown that SR could inhibit the deleterious action of AGE on osteoblastic proliferation and differentiation as well as proinflamatory cytokine secretion. We also demonstrated that SR action depends on the activation of calcium channels to exert its action.