Strontium ranelate is a new anti-osteoporosis treatment. This study showed that strontium ranelate stimulated PGE 2 production and osteoblastic differentiation in murine marrow stromal cells, which was markedly reduced by inhibition of COX-2 activity or disruption of COX-2 gene expression. Hence, some anabolic effects of strontium ranelate may be mediated by the induction of COX-2 and PGE 2 production. Introduction: Strontium ranelate is an orally active drug that reduces vertebral and hip fracture risk by increasing bone formation and reducing bone resorption. Strontium ranelate effects on bone formation are the result of increased osteoblastic differentiation and activity, but the mechanisms governing these effects are unknown. Based on previous work, we hypothesized that strontium ranelate increases cyclooxygenase (COX)-2 expression and that, consequently, the prostaglandin E 2 (PGE 2 ) produced could mediate some effects of strontium ranelate on osteoblasts. Materials and Methods: Marrow stromal cells (MSCs) from COX-2 wildtype (WT) and knockout (KO) mice were cultured with and without low-dose dexamethasone. Osteoblastic differentiation was characterized by alkaline phosphatase (ALP) activity, real-time PCR for ALP and osteocalcin (OCN) mRNA expression, and alizarin red staining for mineralization. Medium PGE 2 was measured by radioimmunoassay or enzyme immunoassay. Results and Conclusions:In MSCs from COX-2 WT mice, strontium ranelate significantly increased ALP activity, ALP and OCN mRNA expression, and mineralization after 14 or 21 days of culture. A short treatment at the beginning of the culture (0-7 days) with strontium ranelate was as effective as continuous treatment. Strontium ranelate (1 and 3 mM Sr

Recent studies of rat and human calcitonin (CT) gene expression have uncovered a diversity of secretory peptides. Here we report the results of testing two such non-CT secretory peptides for CT-like action in live rats and in cultured fetal rat long bone. One peptide, the carboxyl-terminal CT-adjacent peptide that is cosynthesized with CT, has no hypocalcemic effect and no inhibitory action on bone resorption in vitro. The other peptide, CT gene-related peptide, lowers blood calcium and inhibits bone resorption. In vitro experiments are consistent with the idea that CT gene-related peptide is acting at CT receptors in bone.

We compared the bone-resorbing activity in the conditioned medium from phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear cell cultures with that of partially purified human monocyte-derived interleukin 1 (IL-1), human recombinant IL-1 alpha (pI 5) and IL-1 beta (pI 7), human recombinant tumor necrosis factor-alpha (TNF alpha), and PTH in fetal rat long bone cultures. An antiserum to the products of activated human mononuclear cells, including IL-1, completely blocked the bone-resorbing activity of all three forms of IL-1 and of unfractionated PHA-stimulated human peripheral blood mononuclear cell supernatants, but did not inhibit resorption stimulated by recombinant human TNF alpha. This antiserum also had no effect on the resorptive response to 3 nM PTH, but did decrease the response to 1 nM PTH slightly. These results imply that IL-1, but not TNF alpha, mediates the bone-resorbing activity found in the supernatants of PHA-stimulated human peripheral blood mononuclear cell cultures. It is not known whether the small inhibitory effect that the antiserum to IL-1 had on the response to 1 nM PTH resulted from a nonspecific action or an effect of PTH on local IL-1 synthesis in bone. Since cytokines are found in the circulation of normal individuals and are produced at local sites of pathology, these results suggest that they can influence both normal and abnormal skeletal metabolism.