Physiologic and Pathophysiologic Roles of Extra Renal CYP27b1: Case Report and Review

Overview

Journal Bone Rep

Date 2018 Jul 3

PMID 29963603

Citations 52

Authors

Daniel D Bikle

Sophie Patzek

Yongmei Wang

Affiliations

Soon will be listed here.

Abstract

Although the kidney was initially thought to be the sole organ responsible for the production of 1,25(OH)D via the enzyme CYP27b1, it is now appreciated that the expression of CYP27b1 in tissues other than the kidney is wide spread. However, the kidney is the major source for circulating 1,25(OH)D. Only in certain granulomatous diseases such as sarcoidosis does the extra renal tissue produce sufficient 1,25(OH)D to contribute to the circulating levels, generally associated with hypercalcemia, as illustrated by the case report preceding the review. Therefore the expression of CYP27b1 outside the kidney under normal circumstances begs the question why, and in particular whether the extra renal production of 1,25(OH)D has physiologic importance. In this chapter this question will be discussed. First we discuss the sites for extra renal 1,25(OH)D production. This is followed by a discussion of the regulation of CYP27b1 expression and activity in extra renal tissues, pointing out that such regulation is tissue specific and different from that of CYP27b1 in the kidney. Finally the physiologic significance of extra renal 1,25(OH)D production is examined, with special focus on the role of CYP27b1 in regulation of cellular proliferation and differentiation, hormone secretion, and immune function. At this point the data do not clearly demonstrate an essential role for CYP27b1 expression in any tissue outside the kidney, but several examples pointing in this direction are provided. With the availability of the mouse enabling tissue specific deletion of CYP27b1, the role of extra renal CYP27b1 expression in normal and pathologic states can now be addressed definitively.

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References

Vantieghem K, Overbergh L, Carmeliet G, De Haes P, Bouillon R, Segaert S . UVB-induced 1,25(OH)2D3 production and vitamin D activity in intestinal CaCo-2 cells and in THP-1 macrophages pretreated with a sterol Delta7-reductase inhibitor. J Cell Biochem. 2006; 99(1):229-40. DOI: 10.1002/jcb.20910. View

Meyer M, Benkusky N, Kaufmann M, Lee S, Onal M, Jones G . A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene essential for vitamin D activation. J Biol Chem. 2017; 292(42):17541-17558. PMC: 5655528. DOI: 10.1074/jbc.M117.806901. View

Lee S, Clark S, Gill R, Christakos S . 1,25-Dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors, gene expression, and insulin secretion. Endocrinology. 1994; 134(4):1602-10. DOI: 10.1210/endo.134.4.8137721. View

Pittas A, Lau J, Hu F, Dawson-Hughes B . The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007; 92(6):2017-29. PMC: 2085234. DOI: 10.1210/jc.2007-0298. View

Sigmundsdottir H, Pan J, Debes G, Alt C, Habtezion A, Soler D . DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat Immunol. 2007; 8(3):285-93. DOI: 10.1038/ni1433. View

Stumpf W, Clark S, Sar M, DeLuca H . Topographical and developmental studies on target sites of 1,25 (OH)2 vitamin D3 in skin. Cell Tissue Res. 1984; 238(3):489-96. DOI: 10.1007/BF00219863. View

Garland F, Garland C, Gorham E, Young J . Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med. 1990; 19(6):614-22. DOI: 10.1016/0091-7435(90)90058-r. View

Milde P, Hauser U, Simon T, Mall G, Ernst V, Haussler M . Expression of 1,25-dihydroxyvitamin D3 receptors in normal and psoriatic skin. J Invest Dermatol. 1991; 97(2):230-9. DOI: 10.1111/1523-1747.ep12480255. View

Yokomura K, Suda T, Sasaki S, Inui N, Chida K, Nakamura H . Increased expression of the 25-hydroxyvitamin D(3)-1alpha-hydroxylase gene in alveolar macrophages of patients with lung cancer. J Clin Endocrinol Metab. 2003; 88(12):5704-9. DOI: 10.1210/jc.2003-030537. View

10.

Gyetko M, Hsu C, Wilkinson C, Patel S, Young E . Monocyte 1 alpha-hydroxylase regulation: induction by inflammatory cytokines and suppression by dexamethasone and uremia toxin. J Leukoc Biol. 1993; 54(1):17-22. DOI: 10.1002/jlb.54.1.17. View

11.

Delvin E, Arabian A, Glorieux F, Mamer O . In vitro metabolism of 25-hydroxycholecalciferol by isolated cells from human decidua. J Clin Endocrinol Metab. 1985; 60(5):880-5. DOI: 10.1210/jcem-60-5-880. View

12.

Kogawa M, Findlay D, Anderson P, Ormsby R, Vincent C, Morris H . Osteoclastic metabolism of 25(OH)-vitamin D3: a potential mechanism for optimization of bone resorption. Endocrinology. 2010; 151(10):4613-25. DOI: 10.1210/en.2010-0334. View

13.

Breves G, Harmeyer J . Role of 1,25-(OH)2D3 during pregnancy; studies with pigs suffering from pseudo-vitamin D-deficiency rickets, type I. Q J Exp Physiol. 1989; 74(6):875-81. DOI: 10.1113/expphysiol.1989.sp003358. View

14.

Ritter C, Haughey B, Armbrecht H, Brown A . Distribution and regulation of the 25-hydroxyvitamin D3 1α-hydroxylase in human parathyroid glands. J Steroid Biochem Mol Biol. 2012; 130(1-2):73-80. DOI: 10.1016/j.jsbmb.2012.01.010. View

15.

Hsu J, Feldman D, McNeal J, Peehl D . Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res. 2001; 61(7):2852-6. View

16.

Turner M, Barre P, Benjamin A, Goltzman D, Gascon-Barre M . Does the maternal kidney contribute to the increased circulating 1,25-dihydroxyvitamin D concentrations during pregnancy?. Miner Electrolyte Metab. 1988; 14(4):246-52. View

17.

Vidya M, Kumar V, Sejian V, Bagath M, Krishnan G, Bhatta R . Toll-like receptors: Significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol. 2017; 37(1):20-36. DOI: 10.1080/08830185.2017.1380200. View

18.

Hobaus J, Thiem U, Hummel D, Kallay E . Role of calcium, vitamin D, and the extrarenal vitamin D hydroxylases in carcinogenesis. Anticancer Agents Med Chem. 2012; 13(1):20-35. PMC: 3826118. View

19.

Adams J, Sharma O, Gacad M, Singer F . Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest. 1983; 72(5):1856-60. PMC: 370476. DOI: 10.1172/JCI111147. View

20.

WIELAND P, Fischer J, Trechsel U, Roth H, Vetter K, Schneider H . Perinatal parathyroid hormone, vitamin D metabolites, and calcitonin in man. Am J Physiol. 1980; 239(5):E385-90. DOI: 10.1152/ajpendo.1980.239.5.E385. View