Strontium Ranelate Stimulates the Activity of Bone-specific Alkaline Phosphatase: Interaction with Zn(2+) and Mg (2+)

Strontium ranelate (SR) is an orally administered and bone-targeting anti-osteoporotic agent that increases osteoblast-mediated bone formation while decreasing osteoclastic bone resorption, and thus reduces the risk of vertebral and femoral bone fractures in postmenopausal women with osteoporosis. Osteoblastic alkaline phosphatase (ALP) is a key enzyme involved in the process of bone formation and osteoid mineralization. In this study we investigated the direct effect of strontium (SR and SrCl2) on the activity of ALP obtained from UMR106 osteosarcoma cells, as well as its possible interactions with the divalent cations Zn(2+) and Mg(2+). In the presence of Mg(2+), both SR and SrCl2 (0.05-0.5 mM) significantly increased ALP activity (15-66 % above basal), and this was dose-dependent in the case of SR. The stimulatory effect of strontium disappeared in the absence of Mg(2+). The cofactor Zn(2+) also increased ALP activity (an effect that reached a plateau at 2 mM), and co-incubation of 2 mM Zn(2+) with 0.05-0.5 mM SR showed an additive effect on ALP activity stimulation. SR induced a dose-dependent decrease in the Km of ALP (and thus an increase in affinity for its substrate) with a maximal effect at 0.1 mM. Co-incubation with 2 mM Zn(2+) further decreased Km in all cases. These direct effects of SR on osteoblastic ALP activity could be indicating an alternative mechanism by which this compound may regulate bone matrix mineralization.