Strotium Ranelate prevents advanced glycation endproducts-induced deleterius effects on osteoblastic cells: role of MAP-kinase

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

Valencia

Congreso; European Congress on Osteoporosis & Osteoarthritis and 1st International Osteoporosis Foundation (ECCEO11-IOF); 2011

Type 2 Diabetes has been associated with alterations in bone tissue, possibly caused in part by an accumulation of advanced glycation end-products (AGEs). We have previously demonstrated that AGEs cause a deleterious effect on osteoblastic cells through induction of apoptosis, an increase in intracellular reactive oxygen species and a decrease in osteoblastic differentiation. Objectives: To evaluate the effect of strontium ranelate (SR) on the deleterious action of AGEs on osteoblasts in culture and the involvement of mitogen activated-protein kinases (MAPK) family as possible mechanisms of action. Material and Methods: AGEs were obtained as previously described [1]. Cell proliferation, alkaline phosphatase activity (ALP) and collagen production were determined by colorimetric assays as described in Gangoiti et al [1]. MC3T3E1 osteoblasts were cultured in the presence of glycated bovine serum albumin (AGEs) or control unmodified albumin (BSA), in the presence or absence of SR. Results: After 24h incubation, 0.1 mM of Strontium Ranelate (SR) increased osteoblastic proliferation (122 ± 5 % of BSA, p<0.05) while AGEs inhibited cell proliferation in a dose dependent manner, with a maximum effect at 200 ug/ml (63 ± 4 % of BSA, p<0.01). After 15 days of culture, AGEs also inhibited ALP (100 µg/ml AGEs: 60 ± 8 % of BSA, p<0.01) and collagen production (100 µg/ml AGEs: 79 ± 4 % of BSA, p<0.01). All these actions of AGEs were completely abolished by cotreatment with 0.1 mM SR. We found that AGEs but not SR action depends on p38 activation, because the p38 specific-inhibitor SB203580 was able to revert AGEs action. On the other hand, SR but not AGEs action involves activation of ERK, since its inhibitor PD98050 completely blocked the beneficial action of SR. Involvement of the MAPK cascade was confirmed by Western blot studies. Conclusion: SR reverts the deleterious action of AGEs on osteoblasts in culture. The balance between different components of the MAP kinase cascades seems to play a role in the action of both AGEs and SR. References: [1] Eur J Pharmacol 2008,600:140.