Dose-dependent differential effects of risedronate on gene expression in osteoblasts.

Bisphosphonates have multiple effects on bone. Their actions on osteoclasts lead to inhibition of bone resorption, at least partially through apoptosis. Effects on osteoblasts vary, with modifications in the molecule and concentration both resulting in qualitatively different responses. To understand the mechanism of the differential effects of high and low bisphosphonate concentrations on osteoblast activity, we compared the effects of 10⁻⁸ M and 10⁻⁴ M risedronate on gene expression in UMR-106 rat osteoblastic cells. Two targeted arrays, an 84-gene signaling array and an 84-gene osteogeneic array were used. Gene expression was measured at 1 and 24 h. Although some genes were regulated similarly by low and high concentrations of the drug, there was also differential regulation. At 1 h, 11 genes (1 signaling and 10 osteogenesis) were solely regulated by the low concentration, and 7 genes (3 signaling, 4 osteogenesis) were solely regulated by the high concentration. At 24 h, 8 genes (3 signaling, 5 osteogenesis) were solely regulated by the low concentration and 30 genes (16 signaling and 14 osteogenesis) were solely regulated by the high concentration. Interestingly, the low, but not the high concentration of risedronate transiently and selectively upregulated several genes associated with cell differentiation. A number of genes related to apoptosis were regulated, and could be involved in effects of bisphosphonates to promote osteoblast apoptosis. Also, observed gene changes associated with decreased angiogenesis and decreased metastasis could, if they occur in other cell types, provide a basis for the effectiveness of bisphosphonates in the prevention of cancer metastases.