Regulation of calcitonin gene transcription by vitamin D metabolites in vivo in the rat.
Calcitonin is secreted by the C cells of the thyroid in response to a raised serum calcium, and acts on bone to lower serum calcium. The C cells have specific receptors for the dihydroxymetabolite of vitamin D3, 1,25(OH)2D3. Moreover, calcitonin stimulates the synthesis of 1,25(OH)2D3 in the kidney. Parathyroid hormone (PTH), the third calciotrophic hormone, is also trophic to the renal synthesis of 1,25(OH)2D3, and in turn 1,25(OH)2D3 inhibits PTH gene transcription and synthesis. We report here the marked inhibition of calcitonin gene transcription by the injection of physiologically relevant doses of 1,25(OH)2D3 to normal rats that did not raise serum calcium. Calcitonin mRNA levels after 100 pmol 1,25(OH)2D3 decreased to 6% of basal at 6 h and 4% at 48 h, and a dose response showed a marked effect even after 12.5 pmol 1,25(OH)2D3, with no appreciably greater effect with larger doses (up to 200 pmol). Control genes, actin, thyroglobulin (thyroid follicular cells), somatostatin (thyroid C-cells) were not affected by 1,25(OH)2D3. Gel blots showed that 1,25(OH)2D3 decreased calcitonin mRNA levels without any change in its size. In vitro nuclear transcription showed that 1,25(OH)2D3-treated (100 pmol) rats' calcitonin transcription was 10% of control, while thyroglobulin and actin were 100%. We propose that calcium is the major regulator of PTH and calcitonin secretion, while 1,25(OH)2D3 is an important regulator of PTH and calcitonin gene transcription. We believe this to be the first demonstration of an effect of 1,25(OH)2D3 on the C cells thereby establishing a new target organ and site of action of vitamin D. Calcitonin is trophic to 1,25(OH)2D3 synthesis, which in turn inhibits calcitonin synthesis, which are the components of a new endocrinological feedback loop.
D000199:Actins / Q000235:genetics; D000818:Animals; D002116:Calcitonin / Q000235:genetics* / Q000378:metabolism; D004100:Dihydroxycholecalciferols / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010281:Parathyroid Hormone / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013004:Somatostatin / Q000235:genetics; D013954:Thyroglobulin / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
D000199:Actins; D004100:Dihydroxycholecalciferols; D010281:Parathyroid Hormone; D011498:Protein Precursors; D012333:RNA, Messenger; D013004:Somatostatin; C019056:preproparathormone; D002116:Calcitonin; D013954:Thyroglobulin