Biomedical subjects
C C Capen
Publications and source records attributed to C C Capen.
Light- and electron-microscopic evaluation of the effects of 1,25-dihydroxyvitamin D3 on bone of thyroparathyroidectomized rats.
1,25-Dihydroxyvitamin D3 (1,25-[OH]2D3) was administered in doses of 1 (65 picomoles) or 5 (325 picomoles) units daily for 7 days to adult thyroparathyroidectomized rats fed a normal rodent diet. Both dose levels significantly increased serum calcium, decreased serum phosphorus, and increased urinary calcium and phosphorus concentrations. Numbers of osteoblasts were significantly increased in rats given 5 units 1,25-(OH)2D3. Ultrastructurally, these osteoblasts were larger and interpreted to be more active in bone matrix synthesis and mineralization, compared with osteoblasts in control rats. The number of osteoblasts in rats given 1 unit 1,25-(OH)2D3 was not increased, compared with controls, but they were morphologically similar to the osteoblasts in rats given 5 units 1,25-(OH)2D3. A granular electron-dense material, interpreted to be mineral, was present in the pericellular space of osteocytes in rats given 1 and 5 units 1,25-(OH)2D3. The size of osteocytes, organellar development, and contour of osteocytic lacunae were not affected by 1,25-(OH)2D3. The number of osteoclasts was not significantly elevated in 1,25-(OH)2D3-treated rats and their morphology was similar to that of osteoclasts in controls. It is concluded that in metaphyseal bone 1,25-(OH)2D3 increased the number and synthetic activity of osteoblasts without significantly enhancing osteoclasis or osteocytic osteolysis. This response was independent of parathyroid hormone and calcitonin in rats fed a normal diet.
Effect of dichloromethylene diphosphonate on morphology, enzyme activity, and ash content of bones of thyroparathyroidectomized rats.
Dichloromethylene diphosphonate (Cl2MDP) was given at doses of 4 mg/kg and 10 mg/kg daily for 7 days to adult thyroparathyroidectomized rats fed a low calcium diet. Primary metaphyseal trabeculae in Cl2MDP-treated rats were more numerous and longer than in controls. The light and electron microscopic appearance of osteoblasts, osteocytes and osteoclasts were unaltered by Cl2MDP. Bone alkaline phosphatase was significantly elevated in rats given Cl2MDP but adenosine triphosphatase activity was unchanged. Bone fat-free weight, fat-free minus ash weight, and bone calcium and phosphorus concentration were reduced significantly in rats given 10 mg/kg Cl2MDP compared to controls. Bone magnesium concentration was significantly elevated in rats given 10 mg/kg Cl2MDP. Serum calcium and phosphorus concentration were lower in Cl2MDP-treated rats. These results suggest that Cl2MDP is capable of altering bone remodeling, enzyme activity and mineral content, without significantly altering bone cell morphology, independent of the effects of parathyroid hormone, calcitonin, and dietary calcium.
Chronic cardiotoxicity of doxorubicin (adriamycin) in the rat: morphologic and biochemical investigations.
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Chemoresponsiveness of Moloney sarcoma virus-induced osteosarcoma to adriamycin in the rat.
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Lymphocytic thyroiditis in the dog.
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Ultrastructural evaluation of the effects of 1,25-dihydroxyvitamin D3 on bone of thyroparathyroidectomized rats fed a low-calcium diet.
Thyroparathyroidectomized rats fed a low-calcium-normal-phosphorus diet were administered 1 or 5 units of 1,25-dihydroxyvitamin D3-(1,25-[OH]2D3) or placebo daily for 7 days. 1,25-(OH)2D3 elevated serum and urine calcium and decreased serum phosphorus. Rats given 1 unit of 1,25-(OH)2D3 had increased numbers of osteoclasts in metaphyseal trabeculae, Ultrastructurally, osteoclasts, osteoblasts, and osteocytes in rats given 1 unit of 1,25-(OH)2D3, were similar to those in rats given placebo. In rats given 5 units of 1,25-(OH)2D3, osteoclasis was markedly increased. Osteoblasts were more numerous and interpreted to be active in matrix production and mineralization. Lamellated electron-dense bodies were observed adjacent to the plasma membranes of less active osteoblasts and were interpreted to be modified matrix. Most osteocytes in rats given 5 units of 1,25-(OH)2D3 were indistinguishable from osteocytes in rats given placebo. However,the pericellular space of some osteocytes in rats given 5 units of 1,25-(OH)2D3 contained electron-dense granular deposits that were interpreted to be calcium phosphate. It is concluded that 1,25-(OH)2D3 is able to significantly elevate serum calcium independent of dietary calcium, parathyroid hormone, and calcitonin primarily by increasing ostoeclasis with minimal dependence on osteocytic osteolysis.
Calcium metabolism and disorders of parathyroid glands.
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Effects of a low calcium prepartal diet on calcium homeostatic mechanisms in the cow: morphologic and biochemical studies.
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Intratibial Moloney sarcoma virus-induced osteosarcoma in the rat: tumor incidence and pathologic evaluation.
Osteosarcomas were induced in approximately 80% of young New Zealand Black rats by the intratibial inoculation of Moloney murine sarcoma virus from day 1 to day 5 after birth. The neoplasms were composed of a spectrum of well-differentiated to poorly differentiated osteoblasts, osteocytes, and osteoclasts. Budding of C-type viral particles was associated with tumor induction. Compared to rats inoculated on day 1 after birth, rats inoculated at 4 days of age developed consistently more osteoproliferative bone tumors that often were associated with hypercalcemia, increased serum alkaline phosphatase, and elevated urinary hydroxyproline.
Vitamin D-induced hypercalcemia in experimental renal failure.
Hypercalcemia was induced in 5/6 nephrectomized rats fed a low calcium diet by administering pharmacologic doses of vitamin D. The degree of hypercalcemia was greater in uremic rats than in sham-operated rats both of which were given vitamin D. Bone resorption was marked in both groups but differed in distribution. Increased osteoclasis in uremic rats was limited to diaphyseal cortical bone while metaphyseal trabeculae were relatively unaffected compared to sham-operated rats administered vitamin D. Ultrastructurally thyroid C cells were degranulated and in an active stage in both groups of rats receiving vitamin D. Urinary calcium excretion was greater in sham-operated rats given vitamin D than in uremic rats. The greater renal retention of calcium in uremic rats given vitamin D was felt to contribute to the development of hypercalcemia. These studies suggest that although trabecular bone was resistant to pharmacologic levels of vitamin D in renal failure, hypercalcemia developed due to selective resorption of cortical bone and impairment of renal calcium excretion.
Interaction of dichloromethylene diphosphonate and vitamin D on bone of thyroparathyroidectomized rats.
Dichloromethylene diphosphonate (Cl2MDP) antagonized the action of vitamin D on bone in thyroparathyroidectomized rats by reducing the metabolic activity of osteoblasts and osteocytes and decreasing the number of osteoclasts. Ultrastructurally, osteoblasts in Cl2MDP-treated rats were interpreted to be less active in bone matrix synthesis. Osteocytes in Cl2MDP-treated rats were interpreted ultrastructurally to be inactive; there was no evidence of bone resorption when compared to osteocytes in rats given vitamin D alone. Abnormal osmiophilic densities in the pericellular bone matrix of rats given vitamin D alone were not present in rats given vitamin D and Cl2MDP. The ultrastructure of osteoclasts was unaltered by Cl2MDT. These cellular changes were associated with a decrease in serum calcium and increase in bone ash and magnesium concentration in rats given high levels (10 mg/kg) of Cl2MDP. Bone adenosine triphosphatase and alkaline phosphatase activities were not affected by Cl2MDP. These results suggest that Cl2MDP may limit the hypercalcemia of hypervitaminosis D by directly inhibiting bone cells in addition to its physicochemical action.
Virus-induced animal model of osteosarcoma in the rat: Morphologic and biochemical studies.
Osteosarcomas were produced by the intratibial inoculation of New Zealand black rats with Moloney sarcoma virus (MSV) at 1 day and 4 days of age. Radiographic evidence of osteosarcoma development was first demonstrated at 10 to 15 days postinoculation in both groups. Subsequent radiographic and light and electron microscopic evaluation of tumor-bearing rats demonstrated that osteosarcomas in rats inoculated at Day 4 of age were more osteoproliferative osteosarcomas than those in rats inoculated on Day 1. Rats inoculated at 4 days of age lived longer, had more slowly growing osteosarcomas, and developed a consistent tumor-associated cachexia compared to tumor-bearing rats inoculated at Day 1. Both groups of rats had a 93% metastasis rate involving either sublumbar lymph nodes, lungs, or both. Tumor-bearing rats inoculated at 4 days of age had consistent elevations in both urinary hydroxyproline excretion (HOP/CR) and serum alkaline phosphatase levels, and in serum calcium levels at some time points. The high tumor incidence after a short latent period and the morphologic and biochemical similarities between the MSV-induced murine osteosarcoma and the osteosarcoma in human beings makes this discrete tumor and a valuable animal model for the evaluation of new therapeutic regimens.
Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) on the ultrastructure of parathyroid glands and plasma immunoreactive parathyroid hormone in pregnant cows fed a low calcium diet.
The long term (70 days) effects of administering ethane-1-hydroxy-1,1-diphosphonate (EHDP) (4 mg. per kg. per day) on parathyroid function was investigated in pregnant cows fed a low calcium diet. Serum calcium and phosphorus were significantly lower at parturition and postpartum in EHDP-treated cows compared to pregnant control cows fed the low calcium diet. Plasma immunoreactive parathyroid hormone levels were similar prepartum, at parturition, and postpartum in cows administered EHDP and control cows. Immediately available calcium reserves were greater preparation in control cows than in cows receiving EHDP as indicated by a more rapid rate of return of serum calcium toward normal levels following ethylenediaminetetraacetic acid (EDTA)-induced hypocalcemia approximately 10 days prepartum. EHDP-treated cows responded to the hypocalcemic challenge with similar changes in plasma immunoreactive parathyroid hormone levels as in control cows; however, urinary hydroxyproline excretion increased at certain intervals only in control cows. Ultrastructurally, chief cells in parathyroid glands of both groups of cows were in an active stage of the secretory cycle with well developed organelles concerned with hormonela synthesis. Chief cells in cows administered EHDP were degranulated and contained fewer secretory granules in response to the hypocalcemia than those in control cows. Chief cells in EHDP-treated cows often had prominent perinuclear accumulations of microfilaments, scattered vacuolated mitochondria, and lysosomal bodies in the cytoplasm. Thyroid C-cells were densely granulated and thyroid calcitonin content was similar in both groups of cows. The principal defect in calcium homeostasis of EHDP-treated cows appeared to be an impairment both in bone calcium mobilization and bone matrix catabolism in response to the secretion of parathyroid hormone. In vitro uptake of 45Ca by duodenal mucosa and urinary excretion of cyclic adenosine monophosphate were similar in both groups of cows. The ability of the parathyroid glands to synthesize and secrete parathyroid hormone in response to hypocalcemia induced either by EDTA or associated with parturition was not impaired by the administration of EHDP.
Effect of dichloromethane diphosphonate on calcium homeostatic mechanisms in pregnant cows.
The administration of 4 mg/kg/day of dichloromethane diphosphonate (Cl2MDP) subcutaneously to pregnant cows fed a low-calcium diet significantly reduced bone resorption as indicated by microradiographic evaluation of endosteal surfaces of cross sections of ribs. Plasma parathyroid hormone levels were similar between Cl2MDP-treated and control cows prepartum, during EDTA infusions, and near parturition. Ultrastructurally, chief cells of the parathyroid glands of both groups of cows were in the active stage of the secretory cycle. The chronically stimulated chief cell from cows administered Cl2MDP had a large cytoplasmic area containing many lipofuscin granules and lysosomal bodies and a few secretory granules near the large Golgi apparatus or aligned along the plasma membrane. Uptake of calcium 45 by the duodenal mucosa incubated in vitro was greater in Cl2MDP-treated cows compared to control cows. The administration of Cl2MDP significantly reduced rapidly mobilization calcium reserves. Following an intravenous EDTA infusion and the spontaneous calcium drain associated with parturition and the beginning of lactation, Cl2MDP-treated cows developed severe hypocalcemia. The rapid mobilization of calcium reserves in cows administered Cl2MDP prepartum was impaired mainly because of diminished resorption of bone despite adequate parathyroid hormone secretion in response to severe postpartal or EDTA-induced hypocalcemia.
Effect of polychlorinated biphenyl (PCB) on the thyroid gland of rats. Ultrastructural and biochemical investigations.
Polychlorinated biphenyls (PCB) produced ultrastructural lesions in thyroid follicular cells and reductions in serum thyroxine levels in rats that were time- and dose-dependent. The acute effects (4 week) of PCB (50 and 500 ppm) consisted of an accumulation of lysosomal bodies and colloid droplets in follicular cells with abnormalities of microvilli on the luminal surface. The chronic administration (12 week) of PCB (50 and 500/250 ppm) resulted in a striking distention of many follicular cells with large lysosomal bodies with strong acid phosphatase activity and colloid droplets, blunt and abnormally branched microvilli, and mitochondrial vacuolation. These ultrastructural alterations in follicular cells were associated with a highly significant reduction in serum thyroxine with both the low and the high dose of PCB. Follicular cells remained responsive to the lowered thyroxine level after feeding PCB for 4 and 12 weeks and underwent moderate compensatory hypertrophy and hyperplasia. Thyroid follicles were smaller than in controls and were lined by more columnar cells that occasionally formed papillary projections into the colloid. Residual ultrastructural alterations persisted for 12 weeks following cessation of feeding the compound, and serum thyroxine levels were significantly lower than in control rats. However, 35 weeks after discontinuing PCB, thyroid follicular cells were similar to those in controls and serum thyroxine levels had returned to normal. The striking ultrastructural lesions in follicular cells produced by feeding PCB to rats appeared to contribute to the lowering of serum thyroxine levels, in combination with the known stimulation of peripheral thyroxine metabolism by these compounds. Certain metabolic alterations produced by PCB intoxication in experimental animals and human beings may be related to an alteration in thyroid function.
The ultrastructural effect of estrogens on bone cells in thyroparathyroidectomized rats.
To determine the direct effect of estrogen on bone cells, female rats were thyroparathyroidectomized and given either 200 microng of estradiol cypionate or placebo treatment for 4 to 30 days. After 8 days, an osteosclerosis of the tibial metaphysis developed in rats treated with estrogens. Osteoblasts in estrogen-treated rats were interpreted ultrastructurally to be less active in bone formation than controls. Osteocytes in estrogen-treated rats were inactive compared to osteocytes in control rats which were continuing the process of bone formation. Osteoclasts were decreased in numbers in rats treated with estrogen; however, the electron microscopic characteristics of osteoclasts did not differ from controls. These cellular changes were associated with a severe hypocalcemia in both estrogen-treated and control rats. Serum phosphorus and urinary hydroxyproline were lowered significantly by the administration of estrogen. It is concluded that metaphyseal osteosclerosis develops in estrogen-treated rats independent of parathyroid hormone and calcitonin. The osteoclerosis is due to an effect of estrogens to reduce osteoclast-numbers and a lesser inhibitory effect on the bone-forming activity of osteoblasts and osteocytes. (Am J Pathol 87:311-322, 1977).
Ultrastructural evaluation of parathyroid glands and thyroid C cells of cattle fed Solanum malacoxylon.
Fine structural alterations of thyroid C cells and parathyroid chief cells were evaluated after feeding dried leaves of the calcinogenic plant, Solanum malacoxylon, to cattle for 1, 6 and 32 days. Thyroid C cells initially were degranulated in response to the hypercalcemia, and parathyroid chief cells accumulated secretory granules. There was hypertrophy of thyroid C cells with well-developed secretory organelles but few secretory granules in the cytoplasm after 6 days of feeding S. malacoxylon. Inactive chief cells with dispersed profiles of endoplasmic reticulum and increased lysosomal bodies predominated in the parathyroid glands. Multiple foci of soft tissue mineralization were present in the heart, lung, and kidney. Thyroid C cells underwent hypertrophy and hyperplasia after 32 days of S. malacoxylon, and parathyroid chief cells were inactive or atrophic in response to the long-term hypercalcemia. Severe soft tissue mineralization was present throughout the cardiovascular system, lung, kidney, and spleen. These ultrastructural changes in thyroid C cells and parathyroid chief cells plus the widespread soft tissue mineralization observed after feeding cattle small amounts of S. malacoxylon are consistent with the recent evidence that leaves of this plant are a potent source of the active metabolite, 1,25-dihydroxycholecalciferol, of vitamin D.