Up until the publication of this article (1), the prevailing concept was that the kidney was the only source of the active metabolite of vitamin D, 1,25(OH)2D (1,25 dihydroxyvitamin D). There were 2 exceptions to this concept. The placenta was recognized as a source of 1,25(OH)2D during pregnancy (2), and an anephric patient with sarcoidosis was discovered to have elevated 1,25(OH)2D levels indicating that certain granulomatous diseases had this capability as well (3). Other than those examples, extrarenal production of 1,25(OH)2D was not recognized to occur in normal nonpregnant individuals (see Figure 1). Littledike and Horst (1) performed 2 related experiments with nephrectomized pigs that challenged this idea. In the first experiment, 2 pigs were nephrectomized, and 2 served as controls. All pigs were given 8 × 105 IU vitamin D3 the day of nephrectomy, then 5 × 106 IU on days 4 and 6. In the second experiment, the nephrectomized pigs underwent peritoneal dialysis to extend their life span. The vitamin D was given on day 0 and 7, and the animals followed for 10 days with daily blood sampling for vitamin D metabolite measurements. The rise in 1,25(OH)2D after vitamin D injections was substantially higher in the nephrectomized pigs than in the controls, reaching a peak of 300 pg/mL. Moreover, this was associated with a large increase in serum calcium, rising to 16 mg/mL, suggesting that unlike renal production of 1,25(OH)2D, extrarenal production was not regulated by either calcium or 1,25(OH)2D itself. A potential source for this extrarenal production of 1,25(OH)2D in pigs came from studies with perfusion of isolated skin preparations demonstrating that the skin could make 1,25(OH)2D (4). These results in pigs were confirmed by results in anephric humans that same year in a study by Lambert et al (5). In this study of 8 patients, 3 of whom were given 50 000- or 100 000-IU vitamin D per day, the patients not receiving vitamin D had low vitamin D metabolite levels, including 25OHD with mean 1,25(OH)2D levels of 5.8 pg/mL. In the patients that were receiving vitamin D, the mean 1,25(OH)2D level was 14.1 pg/mL, correlating with the higher 25OHD levels. With the cloning of CYP27B1 (6), the enzyme that makes 1,25(OH)2D, and the subsequent availability of sequences for quantitation of mRNA levels and antibodies for Western blot analyses and immunohistochemical localization, extrarenal CYP27B1 expression is now known to be widely distributed (7). As predicted by the observations of Littledike and Horst, regulation of extrarenal 1,25(OH)2D production differs from that of the kidney and may be more geared to providing for local tissue needs for 1,25(OH)2D than systemic needs. Thus, the article by Littledike and Horst had a profound effect on knowledge about vitamin D signaling within tissues, coinciding with the appreciation that most cells had the vitamin D receptor. This finding has significantly enhanced our understanding that many cells can produce the ligand for this receptor, namely 1,25(OH)2D, enabling the cells to tailor the levels of 1,25(OH)2D to their own local needs.
Figure 1.
This Centennial Paper was critical for demonstrating in a normal nonpregnant animal the extrarenal production of 1,25(OH)2D. This article demonstrated that in a nephrectomized pig, the administration of large doses of vitamin D caused a huge increase in levels of 1,25(OH)2D that could only have come from nonrenal sources.
Acknowledgments
Disclosure Summary: The author has nothing to disclose.
Abbreviations
- 1,25(OH)2D
1,25 dihydroxyvitamin D.
References
- 1. Littledike ET, Horst RL. Metabolism of vitamin D3 in nephrectomized pigs given pharmacological amounts of vitamin D3. Endocrinology. 1982;111:2008–2013. [DOI] [PubMed] [Google Scholar]
- 2. Gray TK, Lester GE, Lorenc RS. Evidence for extra-renal 1 α-hydroxylation of 25-hydroxyvitamin D3 in pregnancy. Science. 1979;204:1311–1313. [DOI] [PubMed] [Google Scholar]
- 3. Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Me. 1981;305:440–443. [DOI] [PubMed] [Google Scholar]
- 4. Bikle DD, Halloran BP, Riviere JE. Production of 1,25 dihydroxyvitamin D3 by perfused pig skin. J Invest Dermatol. 1994;102:796–798. [DOI] [PubMed] [Google Scholar]
- 5. Lambert PW, Stern PH, Avioli RC, et al. Evidence for extrarenal production of 1 α ,25-dihydroxyvitamin D in man. J Clin Invest. 1982;69:722–725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Fu GK, Lin D, Zhang MY, et al. Cloning of human 25-hydroxyvitamin D-1 α-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol Endocrinol. 1997;11:1961–1970. [DOI] [PubMed] [Google Scholar]
- 7. Bikle DD. Vitamin D: newly discovered actions require reconsideration of physiologic requirements. Trends Endocrinol Metab. 2010;21:375–384. [DOI] [PMC free article] [PubMed] [Google Scholar]