Cellular and molecular events associated with the bone-protecting activity of the noncalcemic vitamin D analog Ro-26-9228 in osteopenic rats.

Abstract

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.

• Authors: Sara Peleg, Milan Uskokovic, Ago Ahene, Brian Vickery, Zafrira Avnur
• Journal: Endocrinology (Endocrinology) Vol. 143 Issue 5 Pg. 1625-36 (May 2002) ISSN: 0013-7227 [Print] United States
• PMID: 11956143 (Publication Type: Journal Article)

Chemical References

• RNA, Messenger
• Ro 26-9228
• Vitamin D-Binding Protein
• Vitamin D
• Calcitriol
• Calcium

Topics

• Animals
• Binding, Competitive (drug effects)
• Bone Density (drug effects)
• Bone Diseases, Metabolic (drug therapy, metabolism, pathology)
• Caco-2 Cells
• Calcitriol (therapeutic use)
• Calcium (blood, urine)
• Female
• Gene Expression (drug effects)
• Humans
• Osteoporosis (prevention & control)
• Ovariectomy
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription, Genetic (genetics)
• Transfection
• Vitamin D (analogs & derivatives, pharmacokinetics, physiology, therapeutic use, toxicity)
• Vitamin D-Binding Protein (metabolism)