Osteogenic activity of vanadyl(IV)-ascorbate complex: Evaluation of its mechanism of action

We have previously shown that different vanadium(IV) complexes regulate osteoblastic growth. Since vanadium compounds are accumulated in vivo in bone, they may affect bone turnover. The development of vanadium complexes with different ligands could be an alternative strategy of use in skeletal tissue engineering. In this study, we have investigated the osteogenic properties of a vanadyl(IV)-ascorbate (VOAsc) complex, as well as its possible mechanisms of action, on two osteoblastic cell lines in culture. VOAsc (2.5-25 mu M) significantly stimulated osteoblastic proliferation (113-125% basal, p < 0.01) in UMR106 cells, but not in the MC3T3E1 cell line. VOAsc (5-100 mu M) dose-dependently stimulated type-I collagen production (107-156% basal) in osteoblasts. After 3 weeks of culture, 5-25 mu M VOAsc increased the formation of nodules of mineralization in MC3T3E1 cells (7.7-20-fold control, p < 0.001). VOAsc (50-100 mu M) significantly stimulated apoptosis in both cell lines (170-230% basal, p < 0.02-0.002), but did not affect reactive oxygen species production. The complex inhibited alkaline and neutral phosphatases from osteoblastic extracts with semi-maximal effect at 10 mu M doses. VOAsc induced the activation and redistribution of P-ERK in a time- and dose-dependent manner. Inhibitors of the mitogen activated protein kinases (MAPK) pathway (PD98059 and U0126) partially blocked the VOAsc-enhanced osteoblastic proliferation and collagen production. In addition, wortmanin, a PI-3-K inhibitor and type-L channel blocker nifedipine also partially abrogated these effects of VOAsc on osteoblasts. Our in vitro results suggest that this vanadyl(IV)-ascorbate complex could be a useful pharmacological tool for bone tissue regeneration. (c) 2005 Elsevier Ltd. All rights reserved.