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Cellular and Molecular Events Associated with the Bone-Protecting Activity of the Noncalcemic Vitamin D Analog Ro-26-9228 in Osteopenic Rats

Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, M. D. Anderson Cancer Center (S.P.), Houston, Texas 77030; and Department of Musculoskeletal Research, Roche Bioscience (M.U., A.A., B.V., Z.A.), Palo Alto, California 94305

Address all correspondence and requests for reprints to: Sara Peleg, Ph.D., Department of Endocrine Neoplasia and Hormonal Disorders, Box 435, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. E-mail: . speleg{at}mail.mdanderson.org

We have examined several analogs of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] in an animal model of osteoporosis (ovariectomized rats) to identify a compound with a greater therapeutic range than 1,25-(OH)₂D₃ for treatment of this bone disease. Here, we report that one analog, Ro-26-9228, had a bone-protecting effect but did not induce hypercalcemia at a wide concentration range. Analysis of biochemical markers and the bone histomorphometry of analog-treated rats suggested that Ro-26-9228 acted by inhibiting bone resorption and increasing the number of differentiated osteoblasts. To determine the basis for the segregation between hypercalcemia and bone-protecting action, we examined gene expression in tissues that regulate calcium homeostasis. We found that 1,25-(OH)₂D₃ induced 24-hydroxylase mRNA expression in the duodena of ovariectomized rats, but Ro-26-9228 did not. Furthermore, in the duodena of intact animals, 1,25-(OH)₂D₃ induced a significant increase in calbindin D 9K and plasma membrane calcium pump 1 mRNAs, but Ro-26-9228 had no effect on these mRNAs. On the other hand, the osteoblast-specific gene products osteocalcin and osteopontin were significantly up-regulated in trabecular bone by both the natural hormone and Ro-26-9228. Further investigation of gene-regulatory events in trabecular bone revealed that both 1,25-(OH)₂D₃ and Ro-26-9228 up-regulated TGF ß1 and ß2 mRNAs. We concluded that the unique properties of Ro-26-9228 include preferential gene regulation in osteoblasts over duodenum and effective induction of growth factors in bone.

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