On the History of Vitamin D Targets:
Their Discoveries, Localization and Related Functions
Walter E. Stumpf – University of North Carolina, Chapel Hill
(www.walterstumpf.com)
With the histochemical approach of high resolution receptor microscopic autoradiography, we discovered target cells in the brain, spinal cord, pituitary, thymus and skin in 1979 (Science), and elsewhere during the 1980s and early 1990s. Over 50 identified target tissues were reviewed in 1995 (Stumpf WE, Histochem. Cell Biol. 104, 417-427), most of them unrelated to systemic calcium regulation.[1] This was in contrast to the five “classical targets” of bone, intestine, kidney, liver, and parathyroid, under the Procrustian calcium concept that stifled vitamin D research.
A new paradigm evolved: Vitamin D is primarily about the adaptation of vital functions to the seasonal solar environment, a primary biological role that is broader than mere calcium regulation (Stumpf WE, 2007. Europ. J. Drug Metab. Pharmacokin. 32, 1-6). In addition to bone growth and repair, effects on other vital functions (such as cell proliferation, differentiation, secretion) are equally or more important, depending on the situation. These other functions are not as easily monitored as bone conditions, but indicated by the strong nuclear receptor binding of 3H-1,25(OH)2 vitamin D3 on an array of targets that include:
· skin epidermis, hair follicles, sebaceous and sweat glands; myoepithelial cells;
· certain brain and spinal cord neurons;
· specific cells in anterior (esp. thyrotropes) and posterior pituitary;
· thymus reticular cells; adrenal medullary cells;
· stomach gland isthmus cells, entero-endocrine cells, and pyloric muscle cells;
· pancreas beta cells;
· heart atrial myocytes;
· special cells in salivary glands;
· cell population in female and male reproductive organs[2].
In the liver, there is accumulation and retention of radiolabel in cytoplasm of sinus littoral cells, probably Ito cells. These cells, known to store vitamin A, apparently are also storing 1,25(OH)2 vitamin D3 as well as 25(OH) vitamin D3 (Stumpf WE, 2008. Eur. J. Drug Metab. Pharmacokinet.3, 85-100). We did not, however, find evidence for receptor binding of either 24,25(OH)2 vitamin D3 and 25(OH) vitamin D3 or of specific plasma membrane associations with 1,25(OH)2 vitamin D3, contrary to claims by some biochemical reports..[3] Furthermore, no nuclear uptake of vitamin D was seen in mammalian skeletal muscle cells, and no evidence for storage of vitamin D in fat cells, both also occasionally claimed in biochemical reports. However, we noted uptake and retention in the ground substance of mucosae, probably a secondary storage site in addition to plasma protein.
Target-related structures and functions were characterized through combined autoradiography- immunocytochemistry with antibodies to receptor or secretory products. Biochemical and clinical follow-up confirmed and extended these findings. A number of vitamin D target cell populations have not yet received attention. These include pyloric muscle, stomach isthmus
neck cells, hair sheath keratinocytes, testis Sertoli cells, epididymis epithelial cells, certain brain, spinal cord, and spinal ganglion target cells, placenta, oviduct fimbriae, ovarian germinal epithelial cells, and others – the list is too long to discuss here.
Considering the current status of vitamin D targets and related functions, it is evident that histochemical discoveries preceded recent developments by 20 to 30 years. Vitamin D research is now at a stage similar to that of estradiol research during the 1960s. Back then, both biochemistry and histochemistry interacted fruitfully at the University of Chicago. Soon it became apparent that target tissues of estradiol, “the hormone of reproduction,” are not
limited to reproductive organs. Instead they exist throughout the body at specific sites, as is now also accepted for vitamin D. Much of the increased vitamin D appreciation in recent years can also be credited to improved blood assays of vitamin D metabolites and the related revision of salubrious dosing of 25(0H) vitamin D3. But the full recognition of vitamin D targets and actions is still to come.
While the complete significance of Vitamin D is yet to be revealed, it is clear that both scientific methods and the related mindset of the scientific community underlie our changing understanding of nature.
[1]At the time, non-calcitropic targets were ignored or downgraded (a typical Ca-expert comment: “These are a few cells, it does not matter.”). A few biochemists followed up with pituitary and skin cell lines, providing supportive data, without acknowledging the original discovery. Such omissions are not uncommon in science (Kuhn, T.S., 1962.The structure of scientific revolutions).
[2]Is Vitamin D another “hormone of reproduction,” like estradiol? See later discussion of estradiol.
[3]Such negative findings do not exclude possible actions under certain conditions, which points to the merits of further study.
