Calcitriol receptors have been identified in a variety of tissues; in some of these, the effect of calcitriol is to induce the synthesis of calbindin-D; in others, it is regulation of cell proliferation and differentiation.
Calbindin-D9k has been identified in both the placenta and yolk sac of rats and mice, and increases in the later stages of gestation when there is considerable fetal uptake of calcium for mineralization of the skeleton. In both birds and mammals, calcitriol is also required for ovulation (Halloran, 1989).
Calbindin-D28k is found in both the central and peripheral nervous systems. In the central nervous system, it is apparently a constitutive, calcitriol-independent protein, whereas in peripheral nerves, it is induced by calcitriol.
126.96.36.199 Endocrine Glands Calcium is known to be important in the secretion of insulin; in vitamin D deficiency, there is impairment of secretion. Calbindin-D28k in the f-islet cells of the pancreas is believed to be calcitriol dependent, unlike similar calcium binding proteins in other pancreatic cells that are constitutive proteins and independent of calcitriol.
188.8.131.52 The Immune System Calcitriol has effects on the proliferation, differentiation, and immune function of lymphocytes and monocytes. Lymphocytes from vitamin D-deficient mice show impaired inflammatory and phagocytic responses. There is a correlation between plasma concentrations of calcidiol (and hence vitamin D status) and circulating concentrations of immunoglobulins (Sedrani, 1988). Peripheral monocytes and macrophages have a constitutive calcitriol receptor at all stages of development and activation. Calcitriol promotes the differentiation of monocyte precursor cells to form monocytes and macrophages, and enhances monocyte function (Manolagas et al., 1985). Activated macrophages have calcidiol 1-hydroxylase and can synthesize calcitriol from calcidiol, suggesting that, in addition to the endocrine role of calcitriol, it may have a paracrine role in the immune system (Casteels et al., 1995). Resting lymphocytes do not have calcitriol receptors, although the receptor is induced within 24 hours of activation. Calcitriol is a potent inhibitor of interleukin-2, and suppresses the effector functions of T and B lymphocytes; it is a potent inhibitor of immunoglobulin production by peripheral blood monocytes in culture, apparently as a result of its antiproliferative effect on immunoglobulin-producing B cells and/or T-helper cells (Lemire et al., 1984; Manolagas et al., 1985). Thus, calcitriol acts at the site of inflammation both to limit T-lymphocyte action and to enhance or activate macrophage cytotoxicity.
Rickets is a disease of young children and adolescents, resulting from a failure of the mineralization of newly formed bone. In infants, epiphyseal cartilage continues to grow, but is not replaced by bone matrix and mineral. The earliest sign of this is craniotabes - the occurrence of unossified areas in the skull, accompanied by late closure of the fontanelles. At a later stage, there is enlargement of the epiphyses, initially at the costachondral junction of the ribs, giving a beading effect - the rachitic rosary. This may lead to deformity of the chest, and in severe cases collapse of the rib cage, with consequent obstruction of respiration. Other epiphyseal junctions also become enlarged. When the child begins to walk, the weight of the body deforms the undermineralized long bones, leading to bow legs or knock knees and deformity of the pelvis. Similar problems may develop during the adolescent growth spurt. In severe deficiency, the plasma concentration of calcium may fall to the level at which intracellular calcium in nerves and muscles cannot be maintained, and tetany occurs.
Rickets was more or less eradicated as a nutritional deficiency disease during the 1950s, as a result ofwidespread enrichment of infant foods with vitamin D. The level of supplementation was reduced as a result of the development of hypercalcemia caused by vitamin D intoxication (Section 3.6.1) in a small number of especially susceptible infants. As a result, rickets has reemerged, especially in northern cities in temperate countries.
There have been a number of reports of rickets, especially among African-Americans in the southern United States. Rickets and osteomalacia are problems among Indians living in the United Kingdom and elsewhere. Although dietary and cultural factors may be involved, there is evidence of a genetic predisposition from high activity of calcidiol 24-hydroxylase (Section 3.2.5) (Dunnigan and Henderson, 1997; Awumey et al., 1998; Shaw and Pal, 2002).
Osteomalacia is the defective remineralization of bone during normal bone turnover in adults, so that there is a progressive demineralization, but with adequate bone matrix, leading to bone pain and skeletal deformities, with muscle weakness. Women with inadequate vitamin D status are especially at risk of osteomalacia after repeated pregnancies, as a result of the considerable drain on calcium reserves for fetal bone mineralization and lactation.
Elderly people are at risk of osteomalacia, because of both decreased synthesis of 7-dehydrocholesterol in the skin with increasing age and low exposure to sunlight. Plasma concentrations of calcidiol below 10 nmol per L are commonly seen in people over 75 years of age, not rising above 20 nmol per L at any time of the year. Histologically proven osteomalacia is observed in 2% to 5% of elderly people presenting to the hospital in Britain.
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