Cellular and molecular events associated with the bone-protecting activity of the noncalcemic vitamin D analog Ro-26-9228 in osteopenic rats.
We have examined several analogs of 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] in an animal model of osteoporosis (ovariectomized rats) to identify a compound with a greater therapeutic range than 1,25-(OH)(2)D(3) 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)(2)D(3) 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)(2)D(3) 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)(2)D(3) and Ro-26-9228 up-regulated TGF beta1 and beta2 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.
Peleg
Sara
S
Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. speleg@mail.mdanderson.org
Uskokovic
Milan
M
Ahene
Ago
A
Vickery
Brian
B
Avnur
Zafrira
Z
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D018938:Caco-2 Cells; D002117:Calcitriol / Q000627:therapeutic use; D002118:Calcium / Q000097:blood / Q000652:urine; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D010024:Osteoporosis / Q000517:prevention & control; D010052:Ovariectomy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection; D014807:Vitamin D / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000502:physiology / Q000627:therapeutic use* / Q000633:toxicity; D014809:Vitamin D-Binding Protein / Q000378:metabolism
D012333:RNA, Messenger; C453744:Ro 26-9228; D014809:Vitamin D-Binding Protein; D014807:Vitamin D; D002117:Calcitriol; D002118:Calcium