Growing giant-breed dogs are more susceptible to developing skeletal disorders than small-breed dogs when raised on diets with deficient or excessive Ca content. Differential hormonal regulation of Ca homeostasis in dogs with different growth rates was investigated in Great Danes (GD, n = 9) and Miniature Poodles (MP, n = 8). All animals were raised on the same balanced diet and under identical conditions. Calciotropic and growth-regulating hormones were measured. Production and clearance of 1,25-dihydroxycholecalciferol (1,25[OH]2D3) were investigated with the aid of [3H]-1,25(OH)2D3 and renal messenger RNA abundance of 1 alpha-hydroxylase and 24-hydroxylase. Intestinal, renal, and skeletal Ca handling were evaluated with the aid of 45Ca balance studies. Skeletal development was evaluated by radiology and histomorphometry. Great Danes had greater (P < 0.001) growth rates than MP, as indicated by the 17-fold greater body weight gain, by increased longitudinal growth reflected in the increased (P < 0.05) gain in length of the radius and ulna, and by increased (P < 0.001) growth plate thickness. These findings were accompanied in GD by greater (P < 0.05) plasma GH and IGF-I concentrations. Effects were observed for vitamin D3 metabolism, such as greater (P < 0.01) plasma 1,25(OH)2D3 concentrations due to decreased (P < 0.01) clearance rather than increased production of 1,25(OH)2D3, and decreased (P < 0.01) plasma 24,25-dihydroxycholecalciferol (24,25[OH]2D3) concentrations likely due to competitive inhibition of the production of 24,25(OH)2D3. These findings were accompanied in both breeds by a limited hormonal regulation of Ca and P absorption at the intestinal level, and in GD by increased (P < 0.05) renal reabsorption of inorganic P (Pi) compared with MP, resulting in greater (P < 0.01) Pi retention and greater (P < 0.01) plasma Pi concentrations. Bone turnover, resorption, and formation were greater (P < 0.01) in GD than in MP. In addition, GD had more irregular (P < 0.01) growth plates than MP, accompanied by disorders of endochondral ossification. It is suggested that in GD, increased calcitonin levels and/or a relative deficiency in 24,25(OH)2D3 at the growth-plate level may both be responsible for the retarded maturation of chondrocytes, resulting in retained cartilage cones and osteochondrosis, and this may be a pathophysiological factor for the increased susceptibility of large breed dogs to developing skeletal disorders.
Lamellar bodies isolated from rat lung contain all three classes of surfactant proteins, SP-A, SP-B and SP-C, as determined by immunoblot analysis. The amounts of the surfactant proteins present in lamellar bodies, determined by sandwich e.l.i.s.a. (SP-A) and fluorescamine assay (SP-B and SP-C) show that these organelles are highly enriched in the hydrophobic surfactant proteins SP-B and SP-C.
growth with a variety of target organs, including the skeleton, intestine, and kidney (7). 24,25(OH) 2 D 3 is a biologically active metabolite mainly directed to the skeleton (6, 56) but also with putative actions at the intestine (39,40,59,60).The rate of renal synthesis of 1,25(OH) 2 D 3 is directly responsive to plasma levels of P i , growth hormone (GH), insulin-like growth factor I (IGF-I), parathyroid hormone (PTH), and calcitonin (CT; see Refs. 24,36,and 41). Regulatory feedback on 1␣-hydroxylase is provided by 1,25(OH) 2 D 3 by induction of 24-hydroxylase activity and thus conversion of 1,25(OH) 2 D 3 into less biologically active metabolites in its target tissues, including intestine, kidney, and bone (7, 52). In the kidney, 24-hydroxylase activity is enhanced by 1,25(OH) 2 D 3 and downregulated by PTH (48, 62, 63), whereas in the intestine, 24-hydroxylase is enhanced by 1,25(OH) 2 D 3 and downregulated by CT (3).The period of rapid growth is a formidable challenge for vitamin D 3 metabolism in preserving skeletal mineralization. There are few investigations in young intact animals that have studied the hormonal regulation of excessive vitamin D 3 with respect to the activity of 1␣-hydroxylase and 24-hydroxylase (4, 47, 57, 58). However, these studies confined their measurements to single-moment observations, possibly because of technical limitations. Therefore, there is insufficient knowledge concerning the timedependent changes of vitamin D 3 metabolism during elevated dietary vitamin D 3 intake. Obtaining insight into the complexity of vitamin D 3 homeostasis in relation to its regulating hormones and enzymes requires large research animals for long-term studies on the effect of dietary vitamin D 3 supplementation. Dogs are of adequate size to allow for simultaneous and sequential sampling of blood and tissue material during the rapid growth period. Additional advantages are complete dependence on the dietary intake of vitamin D 3 (29) and thus easy regulation of the vitamin D 3 status without interpretation problems caused by seasonal variation of plasma vitamin D 3 metabolite concentrations.
Hormonal regulation of calcium (Ca) absorption was investigated in a cholecalciferol (vitamin D(3))-supplemented group (hVitD) vs. a control group (cVitD) of growing Great Danes (100 vs. 12.5 micro g vitamin D(3)/kg diet). Although Ca intakes did not differ, fractional Ca absorption was significantly lower in the hVitD group than in the cVitD group. There were no differences in plasma concentrations of Ca, inorganic phosphate, parathyroid hormone, growth hormone or insulin-like growth factor I between groups. Plasma 25-hydroxycholecalciferol [25(OH)D(3)] concentrations were maintained in the hVitD dogs at the same levels as in the cVitD dogs due to increased turnover of 25(OH)D(3) into 24,25-dihydroxycholecalciferol [24,25(OH)(2)D(3)] and 1,25-dihydroxycholecalciferol [1,25(OH)(2)D(3)]. In hVitD dogs, the greater plasma 24,25(OH)(2)D(3) concentration and the enhanced metabolic clearance rate (MCR) of 1,25(OH)(2)D(3) indicated upregulated 24-hydroxylase activity. The increased MCR of 1,25(OH)(2)D(3) decreased plasma 1,25(OH)(2)D(3) concentrations. In hVitD dogs, the greater production rate of 1,25(OH)(2)D(3) was consistent with the 12.9-fold greater renal 1alpha-hydroxylase gene expression compared with cVitD dogs and compensated to a certain extent for the accelerated MCR of 1,25(OH)(2)D(3). The moderately decreased plasma 1,25(OH)(2)D(3) concentration can only partially explain the decreased Ca absorption in the hVitD dogs. Intestinal vitamin D receptor concentrations did not differ between groups and did not account for the decreased Ca absorption. We suggest that 24,25(OH)(2)D(3) may downregulate Ca absorption.
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