Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 89, Issue 4, Pages 771-777Publisher
WILEY-LISS
DOI: 10.1002/jcb.10567
Keywords
RANKL; osteoclasts; promoter; vitamin D-3; osteoblasts
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Receptor activator of NF-kappaB ligand (RANKL) has been identified as requisite for osteoclastogenesis. To elucidate the molecular mechanism that conducts its catabolic action on bone, the effect of 1alpha,25 dihydroxyvitamin D-3 (1alpha,25(OH)(2)D-3) on osteoclastogenesis and RANKL mRNA expression was examined by coculture, RT-PCR and nuclear run-on studies. By accelerating the transcription rate of the RANKL gene in SaOS2 osteoblastic cells, 1alpha,25(OH)(2)D-3 enhanced in vitro osteoclast formation from peripheral monocytes. Cloning and characterization of the 5'-flanking region of the human RANKL gene revealed that the basic promoter comprises inverted TATA- and CAAT-boxes flanked by RUNX2 binding sites. Both electrophoresis mobility shift assay (EMSA) and transfection studies demonstrated that 1alpha,25(OH)(2)D-3 activated human RANKL promoter through vitamin D responsive elements (VDRE) located at -1584/-1570 by binding VDR and RXRalpha heterodimers in a ligand-dependent manner. The results provide direct evidence that 1alpha,25(OH)(2)D-3 augments osteoclastogenesis by transactivating the human RANKL gene in osteoblastic cells through VDRE. (C) 2003 Wiley-Liss, Inc.
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