Vitamin D₃ supports osteoclastogenesis via functional vitamin D response element of human RANKL gene promoter

Abstract

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.

Differential modulation of RANKL isoforms by human osteoarthritic subchondral bone osteoblasts: Influence of osteotropic factors

“…Vitamin D3, IL-1β, and PGE 2 all significantly upregulated membranous RANKL levels. These data agree with the literature reports that these factors increase osteoclastogenesis by inducing RANKL [42,46,47]. The stimulatory effect of these factors on the membranous RANKL level seems to occur via the modulation of the RANKL1 isoform, since a significant increase was found upon treatment, and the RANKL3 expression level was not modulated.…”

Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis

“…We did find, in the present studies, that average osteoclast size was decreased in the mutants with secondary hyperparathyroidism on the high calcium diet and in the 1,25(OH) 2 D 3 -treated VDR Ϫ/Ϫ and double mutants. Furthermore, levels of RANKL, the transcription factor stimulated by 1,25(OH) 2 D 3 that is required for the normal differentiation and maintenance of osteoclasts (44), were also decreased in the mutants. Consequently, the 1,25(OH) 2 D/ VDR system appears necessary for maximal PTH-induced osteoclast production, and the increase in bone volume appeared to reflect enhanced osteoblastic activity due to PTH that was dissociated from an increase in bone resorption.…”

Bone Health and Renal Replacement Therapies: Which are the Best?

“…103 diyaliz hastası (35 periton diyalizi, 68 hemodiyaliz) üzerinde yapılan bir çalışmada diyaliz hastalarının büyük bir kısmında serum FGF23 düzeyinin; diyaliz süresi, Kt/V, diyetteki fosfor oranı, aktive vitamin D tedavisi, serum kalsiyum ve fosfor seviyesinden bağımsız olarak rezidüel renal fonksiyonlarla ters ilişkili olduğu gös-Kemik Sağlığı ve Renal Replasman Tedavileri; En İyisi Hangisi? tesini inhibe eder (25). Diğer bir değişle, osteoblastik kemik yapımı ve osteoklastik kemik yıkımı gibi kemik aktiviteleri çok sayıda metabolik faktörün aktivitesiyle yakından ilişkilidir.…”