Regulation Of Mineral Homeostasis Research Articles

Regulation of mineral homeostasis in osteopetrotic (op) rats

The osteopetrotic (op) rat is a lethal mutation characterized by severe skeletal sclerosis resulting from reduced bone resorption. Although the skeletal manifestations have been studied extensively, little is known about mineral homeostasis in this mutation. This paucity of data prompted us to undertake this study quantitating circulating levels of calcium, phosphorus, 1,25-dihydroxyvitamin D [1,25(OH)2D] and parathyroid hormone (PTH) in op mutants and normal rats between 2 and 8 wk of age. Calcium and phosphorus levels were significantly lower in op mutants at younger ages; both parameters normalized by 6 wk. Serum levels of 1,25(OH)2D were markedly elevated in op rats at all ages and showed no signs of normalization. Serum PTH levels were also elevated at most ages, with the greatest increase occurring when op mutants were severely hypocalcemic. These results demonstrate that, in op mutants, changes in circulating PTH and calcium levels were interdependent; however, levels of 1,25(OH)2D did not change despite normalization of serum calcium and phosphorus. The latter deserves further investigation and supports the hypothesis of a localized (skeletal) resistance to 1,25(OH)2D.

Cholecalciferol has no effect on calcium and inorganic phosphorus balance in a naturally cholecalciferol-deplete subterranean mammal, the naked mole rat (Heterocephalus glaber)

Naked mole rats, Heterocephalus glaber, have no obvious source of cholecalciferol (D3) available to them, given their underground habitat and tubiferous diet. They have undetectable levels of 25-OH-D3 and as such appear to be naturally deplete in D3. The effect of an oral D3 supplement on mineral balance and homeostasis was therefore investigated. This D3 treatment did not affect circulating levels of Ca2+ and inorganic phosphorus (P(i]. Nor did D3 treatment affect mineral intake and absorption. The Ca2+ and P(i) present in the food was efficiently extracted and absorbed, resulting in an apparent fractional absorption (AFA) efficiency exceeding 98%. Irrespective of D3 treatment, the amount of Ca2+ and P(i) absorbed was positively correlated with the amount ingested, suggesting that intestinal uptake is by a passive D3-independent process. After D3 supplementation urinary Ca2+ secretion was unchanged; however, the amount of P(i) excreted in the urine increased (P less than or equal to 0.05). This resulted in a concomitant decline in P(i) AFR (P less than or equal to 0.02 from 99.95 +/- 0.02% to 99.82 +/- 0.03%). Almost all the Ca2+ and P(i) in the glomerular filtrate were reabsorbed, facilitating AFR efficiencies that approach physiological maxima (greater than 99%). Changes in AFR efficiency with D3 supplementation are therefore of no biological significance. Net mineral flux of both elements, irrespective of D3 treatment, was positive. It is speculated that the ever-growing incisors of these animals act as mineral dumps and assist in the tight regulation of plasma Ca2+ and P(i). These data suggest that naked mole rats utilize mechanisms independent of D3 in regulating mineral homeostasis and are therefore well-adapted to an environment devoid of sunlight.

Emerging concepts on the biologic role and mechanism of action of 1,25-dihydroxyvitamin D 3

The biologic actions of 1,25-(OH)2D3 are diverse, ranging from a major role in the regulation of mineral homeostasis in intestine, kidney, and bone to the control of such fundamental processes as myeloid progenitor cell differentiation. The central character in this action is the 1,25-(OH)2D3 receptor, a protein whose activity is focused at the level of the genome. The function of this polypeptide, by analogy with other steroid receptors, is to interact in a sequence-specific manner with unique regulatory elements of DNA, which serve to modify the activity of their respective promoters. The exact manner in which receptor binding to these sequences precipitates promoter activity is unclear. It is, however, a direct result of the structural organization of the steroid receptors, which represent a class of transcriptional controlling proteins. The deduced primary sequences emanating from the molecular cloning of estrogen, progesterone, glucocorticoid, and 1,25-(OH)2D3 receptors has revealed several important structure-function relationships. These include the identification of a highly conserved cysteine-rich domain that may interact with DNA and a steroid-binding domain that is hydrophobic and is located at the carboxy terminus of the protein. The similarity of this domain among heterologous steroid receptor species implies that each of these proteins belongs to a common gene family whose functional activities are similar if not identical. It is this structure within the 1,25-(OH)2D3 receptor that provides conclusive evidence that 1,25-(OH)2D3 is a steroid hormone that via its receptor modifies the activity of hormone-sensitive genes.

Characterization of endosteal bone-lining cells from fatty marrow bone sites in adult beagles.

Bone-lining cells cover the majority of trabecular bone surfaces in adult long-lived mammals. The morphology, ultrastructure, and population density of bone-lining cells was investigated in several fatty marrow trabecular bone sites in adult beagles of different ages. Although there is a low population density of bone-lining cells on bone surfaces, their total numbers greatly exceed the numbers of osteoblasts and osteoclasts found on these bone surfaces. In one of the bone sites studied, there are significantly fewer bone-lining cells in very old beagles (12-16 years old) when compared to young adult beagles (1.5-3 years old), otherwise there are no differences in the cell population that could be attributed to aging. Bone-lining cells are flattened against bone surfaces and have flat or sometimes ovoid-shaped nuclei which are often located adjacent to areas in the fatty marrow where capillaries are found. When viewed in the electron microscope, bone-lining cells contain few organelles, and the attenuated cytoplasm of these cells is well extended over bone surfaces. The bone-lining cell cytoplasm does not appear to form a continuous layer over the bone surface, as numerous gaps and spaces are seen. Bone-lining cell processes are frequently joined by junctions morphologically similar to gap junctions. Between the lamina limitans of the bone matrix and the bone-lining cell, as well as between the bone-lining cell and the adjacent fat cells, there are layers of connective tissue containing collagenous fibers and other amorphous material. These findings are discussed in relation to the possible role of bone-lining cells in the regulation of mineral homeostasis.