Novel regulation of 25‐hydroxyvitamin D₃ 24‐hydroxylase (24(OH)ase) transcription by glucocorticoids: Cooperative effects of the glucocorticoid receptor, C/EBPβ, and the Vitamin D receptor in 24(OH)ase transcription

Abstract

Glucocorticoid-induced bone loss has been proposed to involve direct effects on bone cells as well as alterations in calcium absorption and excretion. Since vitamin D is important for the maintenance of calcium homeostasis, in the present study the effects of glucocorticoids on vitamin D metabolism through the expression of 24(OH)ase, an enzyme involved in the catabolism of 1,25(OH)(2)D(3), were examined. Injection of vitamin D replete mice with dexamethasone (dex) resulted in a significant induction in 24(OH)ase mRNA in kidney, indicating a regulatory effect of glucocorticoids on vitamin D metabolism. Whether glucocorticoids can affect 24(OH)ase transcription is not known. Here we demonstrate for the first time a glucocorticoid receptor (GR) dependent enhancement of 1,25(OH)(2)D(3)-induced 24(OH)ase transcription. Dex treatment of GR and vitamin D receptor (VDR) transfected COS-7 cells and dex treatment of osteoblastic cells (in which VDR and GR are present endogenously) potentiated 1,25(OH)(2)D(3)-induced 24(OH)ase transcription. In addition, GR was found to cooperate with C/EBP beta to enhance VDR-mediated 24(OH)ase transcription. Using the rat 24(OH)ase promoter with the C/EBP site mutated, GR-mediated potentiation of 1,25(OH)(2)D(3)-induced 24(OH)ase transcription was inhibited. Immunoprecipitation indicated that that GR can interact with C/EBP beta and ChIP/re-ChIP analysis showed that C/EBP beta and GR bind simultaneously to the 24(OH)ase promoter. These findings indicate a novel mechanism whereby glucocorticoids can alter VDR-mediated 24(OH)ase transcription through functional cooperation between C/EBP beta and GR that results in an enhanced ability of C/EBP beta to cooperate with VDR in the regulation of 24(OH)ase.

Relationship Between Vitamin D Deficiency and Metabolic Syndrome in Renal Transplant Patients in Mashhad, Iran

“…Vitamin D could be absorbed not only through food but also via synthesis in the skin (mediated by ultraviolet radiation). In this group of patients, vitamin D deficiency could be more severe due to reduced exposure to sunlight, which alleviates increased risk of skin cancer in them, and also dietary restrictions that reduce the natural absorption of vitamin D through digestive system (23,24). An immunosuppressive medication like glucocorticoids also activates the genes involved with the vitamin D catabolism enzyme expressions and therefore exacerbates this deficiency (25).…”

Novel Mechanism of Negative Regulation of 1,25-Dihydroxyvitamin D3-induced 25-Hydroxyvitamin D3 24-Hydroxylase (Cyp24a1) Transcription

“…Thus it is possible that one factor involved in the age-related increase in renal Cyp24a1 may be decreased levels of renal PRMT5. Enhanced catabolism of 1,25(OH) 2 D 3 by glucocorticoids in bone cells has been suggested as one mechanism that contributes to glucocorticoid-induced bone loss (30,60). PRMT5, by inhibiting Cyp24a1 in bone cells, may also have a physiological role in protecting against glucocorticoid enhancement of 1,25(OH) 2 D 3 catabolism in osteoblastic cells.…”

“…Chromatin immunoprecipitation was performed as described previously (30). DNA fragments were purified using QIAquick PCR purification kits (Qiagen, Valencia, CA) and subjected to PCR using primers designed to amplify fragments of the Cyp24a1 promoter C/EBP motif at Ϫ395/Ϫ388 (forward, 5Ј-GAAATT-CTGCAAACCGCATT-3Ј; reverse, 5Ј-CCAGACTTCCCTT-GGATGAA-3Ј).…”

Dexamethasone Enhances 1α,25-Dihydroxyvitamin D3 Effects by Increasing Vitamin D Receptor Transcription

“…1␣,25-Dihydroxycholecalciferol (calcitriol), the most active metabolite of vitamin D, is a seco-steroid hormone that regulates calcium homeostasis, bone development, and bone maintenance (1,2). Calcitriol has potent anti-proliferative effects in a number of human and murine cancer cell types in vitro and in in vivo xenograft tumor models.…”