TY - JOUR
T1 - Variable in vivo regulation of rat vitamin D-dependent genes (osteopontin, Ca,Mg-adenosine triphosphatase, and 25-hydroxyvitamin d3 24-hydroxylase)
T2 - Implications for differing mechanisms of regulation and involvement of multiple factors
AU - Matkovits, Theresa
AU - Christakos, Sylvia
PY - 1995/9
Y1 - 1995/9
N2 - In these studies, the regulation of renal osteopontin (OPN), intestinal calcium pump, and renal and intestinal 25-hydroxyvitamin D3 24-hydroxylase (24OHase) was compared to the regulation of calbindin by Northern blot analysis. The time course of induction of the calbindins and calcium pump messenger RNAs (mRNAs) in vitamin D-deficient rats in response to 1,25-hydroxyvitamin D3 [1,25-(OH)2D3] was similar [first induction 3 h after 1,25-(OH)2D3 (200 ng/100 g BW), reaching a maximum at 12-24 h]. However, the maximal induction of calbindin mRNA was greater (8.2 ± 1.2-fold) than that of intestinal calcium pump mRNA (2.3 ± 0.5-fold). 24-Hydroxylase mRNA showed a different time course of induction by 1,25-(OH)2D3. 24-Hydroxylase mRNA was undetectable in vitamin D-deficient rat intestine and kidney. In intestine, 24OHase mRNA was maximally induced early [3-6 h after 1,25-(OH)2D3] and did not accumulate long after 1,25-(OH)2D3 administration. Unlike the other vitamin D-regulated genes, OPN was uninduced by 1,25-(OH)2D3 in the kidney of D-deficient rats. However, in vitamin D-replete rats given 1,25-(OH)2D3 for 5 days, a significant induction in renal OPN was observed (6.0-fold; P < 0.01). Developmental studies indicated that renal 24OHase and intestinal calcium pump mRNAs, similar to calbindin-D9K mRNA, were induced at 3 weeks of age, the time of weaning when active intestinal calcium absorption is induced. A comparison of the effect of calcium status showed that low dietary calcium resulted in an induction of intestinal calcium pump as well as calbindin-D9k mRNA, consistent with the requirement for an increase in intestinal calcium absorption during dietary calcium restriction. We next examined gender- and age-related changes in the expression of these genes. Our results indicate that renal OPN mRNA increases markedly in males with aging (10-fold between 3-20 months; P < 0.01), whereas OPN mRNA levels are unchanged in females. In both males and females, significant increases (2.7- to 4.5-fold) in renal 24OHase mRNA were observed at 20 months compared to 3 months of age. In summary, 1) the most pronounced effect of 1,25-(OH)2D3 in vitamin D-deficient rats was increased synthesis of calbindin and 24OHase; 2) the lack of an effect of 1,25-(OH)2D3 on renal OPN mRNA in vitamin D-deficient rats and the induction in vitamin D-replete rats suggest that multiple factors may be involved in vitamin D-mediated OPN regulation; and 3) the increase in 24OHase mRNA with age suggests that increased renal metabolism of 1,25-(OH)2D3 may contribute to the decrease in serum 1,25-(OH)2D3 levels observed in both aging and postmenopausal osteoporosis.
AB - In these studies, the regulation of renal osteopontin (OPN), intestinal calcium pump, and renal and intestinal 25-hydroxyvitamin D3 24-hydroxylase (24OHase) was compared to the regulation of calbindin by Northern blot analysis. The time course of induction of the calbindins and calcium pump messenger RNAs (mRNAs) in vitamin D-deficient rats in response to 1,25-hydroxyvitamin D3 [1,25-(OH)2D3] was similar [first induction 3 h after 1,25-(OH)2D3 (200 ng/100 g BW), reaching a maximum at 12-24 h]. However, the maximal induction of calbindin mRNA was greater (8.2 ± 1.2-fold) than that of intestinal calcium pump mRNA (2.3 ± 0.5-fold). 24-Hydroxylase mRNA showed a different time course of induction by 1,25-(OH)2D3. 24-Hydroxylase mRNA was undetectable in vitamin D-deficient rat intestine and kidney. In intestine, 24OHase mRNA was maximally induced early [3-6 h after 1,25-(OH)2D3] and did not accumulate long after 1,25-(OH)2D3 administration. Unlike the other vitamin D-regulated genes, OPN was uninduced by 1,25-(OH)2D3 in the kidney of D-deficient rats. However, in vitamin D-replete rats given 1,25-(OH)2D3 for 5 days, a significant induction in renal OPN was observed (6.0-fold; P < 0.01). Developmental studies indicated that renal 24OHase and intestinal calcium pump mRNAs, similar to calbindin-D9K mRNA, were induced at 3 weeks of age, the time of weaning when active intestinal calcium absorption is induced. A comparison of the effect of calcium status showed that low dietary calcium resulted in an induction of intestinal calcium pump as well as calbindin-D9k mRNA, consistent with the requirement for an increase in intestinal calcium absorption during dietary calcium restriction. We next examined gender- and age-related changes in the expression of these genes. Our results indicate that renal OPN mRNA increases markedly in males with aging (10-fold between 3-20 months; P < 0.01), whereas OPN mRNA levels are unchanged in females. In both males and females, significant increases (2.7- to 4.5-fold) in renal 24OHase mRNA were observed at 20 months compared to 3 months of age. In summary, 1) the most pronounced effect of 1,25-(OH)2D3 in vitamin D-deficient rats was increased synthesis of calbindin and 24OHase; 2) the lack of an effect of 1,25-(OH)2D3 on renal OPN mRNA in vitamin D-deficient rats and the induction in vitamin D-replete rats suggest that multiple factors may be involved in vitamin D-mediated OPN regulation; and 3) the increase in 24OHase mRNA with age suggests that increased renal metabolism of 1,25-(OH)2D3 may contribute to the decrease in serum 1,25-(OH)2D3 levels observed in both aging and postmenopausal osteoporosis.
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M3 - Article
C2 - 7649106
SN - 0013-7227
VL - 136
SP - 3971
EP - 3982
JO - Endocrinology
JF - Endocrinology
IS - 9
ER -