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" The relative competitive index (RCI) is a measure of the ability of a nonradioactive ligand to compete, under in vitro conditions, with radioactive la,25(OH)2D3 for binding to the nuclear la,25(OH)2D3 receptor (nVDR). [Data taken from Bouillon, R., Okamura, W. H., and Norman, A. W. (1995). Structure-function relationships in the vitamin D endocrine system. Endocr. Rev. 16, 200-257.]

" The relative competitive index (RCI) is a measure of the ability of a nonradioactive ligand to compete, under in vitro conditions, with radioactive la,25(OH)2D3 for binding to the nuclear la,25(OH)2D3 receptor (nVDR). [Data taken from Bouillon, R., Okamura, W. H., and Norman, A. W. (1995). Structure-function relationships in the vitamin D endocrine system. Endocr. Rev. 16, 200-257.]

sis, vitamin D metabolism, extracellular matrix proteins, cell differentiation and proliferation, oncogenes, chromosomal proteins, growth factors, signal transduction proteins, peptide hormones, and energy metabolism. The list of genes shown to be specifically regulated by the VDR now exceeds 70. Furthermore, in some cells the presence of a second putative membrane receptor for la,25(OH)2D3 is operative, generating biological responses via other signal transduction pathways.

Three distinct vitamin D-induced calcium-binding proteins have been isolated and biochemically characterized. These proteins are all produced de novo in target tissues as a consequence of the l,25(OH)2D3 receptor complex selective genome activation. The two proteins with a Kd for Ca2+ of 10~ 7 M are termed calbin-dins and belong to a family of tight calcium-binding proteins; other members of this family include the muscle proteins troponin C and parvalbumin and the widely distributed calmodulin. All of these proteins are believed to have a high degree of structural similarity in their calcium-binding sites. The third vitamin D-induced calcium-binding protein is an extracellular protein found associated with bone; it is termed osteocalcin or the bone Gla protein (BGP), since it has many y-carboxyglutamic acid residues and binds Ca2+ with a Kd~ 10"3 M.

A detailed biochemical function for the vitamin D-dependent calbindins (CaBP) has not yet been elucidated. Both the 9000- and the 28,000-Da CaBP species are soluble proteins found exclusively inside the intestinal and kidney cells, and they constitute 1-3% of the soluble cellular proteins. There is some evidence to implicate these CaBPs in some of the steps involved in the translocation of calcium ions across the cell. Normally, in all cells the intracellular concentration of "free" Ca2+ is maintained at 1CT7 M or lower. It has been suggested that calbindin may function in the intestinal and kidney cells, which are actively involved in calcium translocation, as well as in the pancreatic B cell as an intracellular calcium buffer to prevent the adverse effects of a high free Ca2+ concentration.

The principal classical biological effects of vitamin D (mediated by its daughter metabolites) are as follows: at the intestine to stimulate the absorption of dietary calcium and phosphorus; at the skeleton to promote both the mineralization of bone matrix and to stimulate bone resorption; and at the kidney to reduce the urinary excretion of phosphate and calcium (i.e., to stimulate the renal tubular reabsorption of these two ions). Of these three systems, the most thoroughly studied biochemically is the intestine.

The mode of action of la,25(OH)2D3 in the target organ, intestinal mucosa, in stimulating intestinal calcium and phosphorus absorption is believed to involve the integrated actions of the nuclear and membrane receptors for la,25(OH)2D3.

The process of intestinal calcium translocation and the effects of la,25(OH)2D3 therein are complex. At least three steps are involved: (1) uptake of the Ca2+ ions across the brush border membrane and packaging into lysosomal-like vesicles; (2) translocation of the Ca2+-containing vesicles across the cell; and (3) efflux of the Ca2+ out of the cell across the basal lateral membrane. A vesicular model for the action of la,25(OH)2D3 in the intestine is given in Figure 9-11.

la,25(OH)2D3 increases the permeability of the brush border membrane to Ca2+ by altering the membrane protein composition and topology, which may include the induction of a membrane-bound ATPase.

FIGURE 9-11 Schematic model describing the actions of la,25(OH)2D3 in the intestine in stimulating intestinal calcium transport. In this model, the nuclear VDR in the intestine in the presence of la,25(OH)2D3 is responsible for up-regulating the genes for proteins involved with the intestinal Ca2+ transport process, including brush border alkaline phosphatase and the cytosolic calbindin D. Occupancy of the putative membrane receptor by la,25(OH)2D3 results in the initiation of a series of signal transduction events involving PKC, DAG, and the opening of voltage-gated Ca2+ channels, which collectively results in the exocytotic event that releases Ca2+ outside the cell and adjacent to the capillary system. EV, endocytic vesicle; GA, Golgi apparatus; L2 = lysozomal vesicle; N, nucleus; (•) Ca2+; (□) calbindin^.

FIGURE 9-11 Schematic model describing the actions of la,25(OH)2D3 in the intestine in stimulating intestinal calcium transport. In this model, the nuclear VDR in the intestine in the presence of la,25(OH)2D3 is responsible for up-regulating the genes for proteins involved with the intestinal Ca2+ transport process, including brush border alkaline phosphatase and the cytosolic calbindin D. Occupancy of the putative membrane receptor by la,25(OH)2D3 results in the initiation of a series of signal transduction events involving PKC, DAG, and the opening of voltage-gated Ca2+ channels, which collectively results in the exocytotic event that releases Ca2+ outside the cell and adjacent to the capillary system. EV, endocytic vesicle; GA, Golgi apparatus; L2 = lysozomal vesicle; N, nucleus; (•) Ca2+; (□) calbindin^.

FIGURE 9-12 Flowchart of stem cell differentiation. A pluripotent stem cell can differentiate along one of four lineages toward (1) B and T lymphocytes, (2) erythrocytes, (3) monocytes and macrophages, and (4) granulocytes. An asterisk indicates cells that possess la,25(OH)2D3 receptors; # indicates cells that can produce small amounts of la,25(OH)2D3. See also Figure 15-21.

FIGURE 9-12 Flowchart of stem cell differentiation. A pluripotent stem cell can differentiate along one of four lineages toward (1) B and T lymphocytes, (2) erythrocytes, (3) monocytes and macrophages, and (4) granulocytes. An asterisk indicates cells that possess la,25(OH)2D3 receptors; # indicates cells that can produce small amounts of la,25(OH)2D3. See also Figure 15-21.

It is believed that the absorption of Ca2+ from the lumen of the intestine occurs via endocytic internalization of the Ca2+ across the brush border membrane. This is followed by fusion of the resulting vesicles with lyso-somes, which also contain the Ca2+-binding protein, calbindin; these vesicles then move across the cell to the basal lateral membrane. In a complex process involving the la,25(OH)2D3 putative membrane receptor-mediated opening of voltage-gated Ca2+ channels, the exocytosis of the Ca2+-bearing membrane vesicles is stimulated. A further detailed description remains to be provided.

A major new action of la,25(OH)2D3 has been described within the hematopoietic system (see Figure 9-12). Nuclear receptors for la,25(OH)2D3 exist in promonocytes, monocytes, and activated B and T lymphocytes. The principal biological effect of la,25(OH)2D3 is to promote cell differentiation along the lineage from the committed stem cell to promono-

TABLE 9-5 Modulators of Bone Cell Resorptive Activity

Stimulators of bone resorption Inhibitors of bone resorption

PTH PTHrP la,25(OH)2D3 Prostaglandins

PGE2 Interleukin-1 (IL-1) Tumor Necrosis Factors TNF-a TNF-/8 Thyroxine Retinol

Growth factors EGF (epidermal growth factor) FGF (fetal growth factor)

Calcitonin Glucocorticoids Estrogens Androgens

Insulin-like growth factor TGF-1

Fluoride (F")

Hormones, Second Edition

Hematopoietic stem cell

Quiescent bone surface covered by lining cells

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