Related Experiment Videos
Extrarenal production of calcitriol
A Dusso1, A Brown, E Slatopolsky
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093.
Abstract:
Similar to the discovery of the VDR in nonclassical target tissues, the expression of 1 alpha-hydroxylase activity in immune cells, in the hematopoietic system, in tissues at early stages in development, in keratinocytes, and in the liver raises numerous questions about the physiological role of endogenous 1,25(OH)2D3 production. Extrarenal sources are regulated independently from the renal enzyme. The tight control of nonrenal 1 alpha-hydroxylase by physiological levels of calcitriol under normal circumstances and the total absence of regulation in several pathological states are consistent with 1,25(OH)2D3 synthesis having a local role rather than contributing to systemic calcitriol homeostasis. The simultaneous expression of vitamin D receptors, constitutive 1 alpha-hydroxylase, and inducible 24-hydroxylase activity in the same cell or in cells of the nearby environment suggests that they constitute a means for an in situ regulation of the response to vitamin D. Experimental evidence indicates that tissue-specific vitamin D microendocrine systems participate in transmural calcium transport, in normalizing serum calcitriol in chronic renal failure, in the control of hematopoiesis, in the modulation of the immune response, and in cellular growth and differentiation in a variety of cell types. A complete understanding of the physiological relevance of extrarenal calcitriol synthesis awaits cloning of the 1 alpha-hydroxylase and characterization of the molecular mechanisms modulating its expression.
Insights
The discovery of 1 alpha-hydroxylase in non-kidney tissues suggests local vitamin D production plays a role in immune function and cell growth. This extrarenal activity is regulated differently than kidney sources, indicating unique physiological functions.
Area of Science:
- Endocrinology
- Cell Biology
- Biochemistry
Background:
- The vitamin D receptor (VDR) is found in many tissues beyond classical targets.
- 1 alpha-hydroxylase activity, the enzyme responsible for activating vitamin D, is expressed in various non-renal cells, including immune cells, keratinocytes, and liver cells.
Purpose of the Study:
- To investigate the physiological role of endogenous 1,25(OH)2D3 (calcitriol) production in extrarenal tissues.
- To understand the regulation and function of extrarenal 1 alpha-hydroxylase activity.
Main Methods:
- The study discusses experimental evidence and observations regarding the expression and regulation of 1 alpha-hydroxylase and VDR in various cell types.
- It highlights the co-localization of VDR, 1 alpha-hydroxylase, and 24-hydroxylase within cells.
Main Results:
- Extrarenal 1 alpha-hydroxylase activity is regulated independently of the renal enzyme and is tightly controlled by calcitriol levels in normal conditions, but dysregulated in pathological states.
- Evidence suggests tissue-specific vitamin D microendocrine systems are involved in calcium transport, hematopoiesis, immune response modulation, and cellular differentiation.
Conclusions:
- Endogenous calcitriol synthesis in non-renal tissues likely serves local functions rather than contributing to systemic calcium homeostasis.
- Further research, including cloning the 1 alpha-hydroxylase and characterizing its regulatory mechanisms, is needed to fully elucidate the physiological significance of extrarenal calcitriol synthesis.