Mechanism of 24,25-dihydroxyvitamin D3-mediated inhibition of rapid, 1,25-dihydroxyvitamin D3-induced responses: Role of reactive oxygen species

✍ Scribed by Ilka Nemere; Cody Wilson; Wendy Jensen; Marla Steinbeck; Ben Rohe; Mary C. Farach-Carson

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 209 KB
• Volume: 99
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.21008

✦ Synopsis

In intestine, 24,25(OH) 2 D 3 , which is made under conditions of calcium-, phosphate-, and 1,25(OH) 2 D 3 sufficiency, inhibits the stimulatory actions of 1,25(OH) 2 D 3 on phosphate and calcium absorption. In the current work, we provide evidence that 24,25(OH) 2 D 3 -mediated signal transduction occurs mechanistically through increased H 2 O 2 production which involves binding of 24,25(OH) 2 D 3 to catalase and resultant decreases in enzyme activity. Physiological levels of H 2 O 2 mimicked the action of 24,25(OH) 2 D 3 on inhibiting 1,25(OH) 2 D 3 -stimulated phosphate uptake in isolated enterocytes. Moreover, the molecular basis of such inhibition was suggested by the presence of two thioredoxin domains in the 1,25D 3 -MARRS protein/ERp57: Exposure of cells to either 24,25(OH) 2 D 3 or H 2 O 2 gradually reduced 1,25(OH) 2 D 3 binding to 1,25D 3 -MARRS protein, between 10 and 20 min of incubation, but not to VDR. Feeding studies with diets enriched in the antioxidants vitamins C and E showed that net phosphate absorption in vivo nearly doubled relative to chicks on control diet. Antioxidant diets also resulted in increased [ 3 H]1,25(OH) 2 D 3 binding to both 1,25D 3 -MARRS and VDR, suggesting benefits to both transcription-and membrane-initiated signaling pathways. Intriguingly, phosphorous content of bones from birds on antioxidant diets was reduced, suggesting increased osteoclast activity. Because mature osteoclasts lack VDR, we analyzed a clonal osteoclast cell line by RT-PCR and found it contained the 1,25D 3 -MARRS mRNA. The combined data provide mechanistic details for the 1,25(OH) 2 D 3 /24,25(OH) 2 D 3 endocrine system, and point to a role for the 1,25D 3 -MARRS protein as a redox-sensitive mediator of osteoclast activity and potential therapeutic target.