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Raloxifene Concurrently Stimulates Osteoprotegerin and Inhibits Interleukin-6 Production by Human Trabecular Osteoblasts

Department of Obstetrics and Gynecology (V.V., C.G., B.N., G.E.), Division of Nephrology and Rheumatology (S.B.), Division of Gastroenterology and Endocrinology (H.S., D.R.), Department of Trauma Surgery, Plastic and Reconstructive Surgery (K.-H.F.), Georg-August-University of Goettingen, Goettingen, Germany D-37075; and Division of Gastroenterology and Endocrinology, Philipps-University of Marburg (L.C.H.), Marburg, Germany D-35033

Address all correspondence and requests for reprints to: Volker Viereck, M.D., Department of Obstetrics and Gynecology, University of Goettingen, Robert-Koch-Strasse 40, D-37075 Goettingen, Germany. E-mail: viereck{at}med.uni-goettingen.de.

Raloxifene reduces bone loss and prevents vertebral fractures in postmenopausal women. Its skeletal effects are mediated by estrogen receptors (ER) and their modulation of paracrine osteoblastic factors. Receptor activator of nuclear factor-B ligand is essential for osteoclasts and enhances bone resorption, whereas osteoprotegerin (OPG) neutralizes receptor activator of nuclear factor-B ligand. Here, we assessed the effects of raloxifene on OPG production in human osteoblasts (hOB). Raloxifene enhanced gene expression of ER- and progesterone receptor. Moreover, raloxifene increased OPG mRNA levels and protein secretion by hOB in a dose- and time-dependent fashion by 2- to 4-fold with a maximum effect at 10^-7 M and after 72 h (P < 0.001). Treatment with the ER antagonist ICI 182,780 abrogated the effects of raloxifene on OPG production. Moreover, raloxifene enhanced osteoblastic differentiation markers, type 1 collagen secretion, and alkaline phosphatase activity by 3- and 2-fold, respectively (P < 0.001). In addition, raloxifene inhibited expression of the bone-resorbing cytokine IL-6 by 25–45% (P < 0.001). In conclusion, our data suggest that raloxifene stimulates OPG production and inhibits IL-6 production by hOB. Because OPG production increases with osteoblastic maturation, enhancement of OPG production by raloxifene could be related to its stimulatory effects on osteoblastic differentiation.

This work was supported by grants from Eli Lilly International Foundation and Forschungsfoerderungsprogramm 2000 of the University of Goettingen (to V.V.) and from the Deutsche Forschungsgemeinschaft (Ho 1875/2-1) and the Deutsche Krebshilfe (10-1697-Ho 1, to L.C.H.). Raloxifene was kindly provided by Lilly Research Laboratories, Indianapolis, Indiana.

Abbreviations: AP, Alkaline phosphatase; cs-FCS, charcoal-stripped fetal calf serum; CV, coefficient(s) of variation; ER, estrogen receptor(s); GAPDH, glyceraldehyde-3-phosphate dehydrogenase; hOB, human osteoblasts; OPG, osteoprotegerin; PICP, carboxy-terminal peptide of procollagen I; PR, progesterone receptor; RANK, receptor activator of nuclear factor-B; RANKL, RANK ligand; SERM, selective estrogen receptor modulator; TBS, Tris-buffered saline.

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