Resveratrol prevents CsA inhibition of proliferation and osteoblastic differentiation of mouse bone marrow-derived mesenchymal stem cells through an ER/NO/cGMP pathway

The purpose of this study was to investigate the in vitro effects of resveratrol (RSVL) and cyclosporin A (CsA) on proliferation and osteoblastic differentiation of mouse bone marrow-derived mesenchymal stem cell (BMSC) cultures. Application of RSVL (10(-8)10(-6) mol 1(-1)) resulted in a dose-dependent increase in [H-3]-thymidine incorporation, alkaline phosphatase (ALP) activity and calcium deposition of BMSCs cultures, which was accompanied with the increase of NO production and cGMP content. Concurrent treatment with the estrogen receptor antagonist ICI182,780 (10(-7) Mol 1(-1)) or the NO synthase inhibitor, N-omega-nitro-L-arginine methyl ester (6 x 10(-3) mol 1(-1)) abolished the RSVL (10(-6) mol 1(-1))-induced increase in NO production and cGMP content and eliminated the RSVL-induced increase in proliferation and osteoblastic differentiation of BMSCs. In contrast, CsA (10(-6)-10(-5) mol 1(-1)) dose-dependently decreased [H-3]-thymidine incorporation, ALP activity and calcium deposition of BMSCs cultures, which was accompanied with the reduction of NO production in the conditioned media. Concurrent treatment with RSVL (10(-6) Mol 1(-1)) significantly reversed the CsA (3 x 10(-6) mol 1(-1))-mediated decrease in NO production and restored the proliferation and differentiation potential of BMSCs. Our data suggest that (1) the NO/cGMP pathway may play an important role in both RSVL-induced and CsA-inhibited proliferation and osteoblastic differentiation of mouse BMSCs, and (2) RSVL may act through an ER/NO/cGMP pathway to reverse the inhibitory effect of CsA on BMSC cultures. Taken together, the data suggest that RSVL may prevent osteoporosis induced by CsA. (c) 2006 Elsevier Ltd. All rights reserved.