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R Baron

Publications and source records attributed to R Baron.

At least 235 records · Page 13Linked to original sources
PubMed1987

Animal model of primary hyperparathyroidism.

An experimental model of hyperparathyroidism was developed in the rat to simulate primary hyperparathyroidism in humans. In this model thyroparathyroidectomized (TPTX) or parathyroidectomized (PTX) animals were infused for 6 days with an amount of bovine synthetic parathyroid hormone (PTH)-(1-34) fragment to restore plasma calcium levels to normal (0.7 U X h-1) or with PTH at twofold (1.4 U X h-1) or threefold (2.1 U X h-1) this basal level. Animals infused with 2.1 U X h-1 of bovine PTH-(1-34) exhibited hypercalcemia, hypophosphatemia, a reduction in theoretical renal threshold for phosphate and an increase in 1,25-dihydroxyvitamin D plasma levels that were approximately threefold the control value. In addition, these animals demonstrated nephrocalcinosis and changes of bone histology that were typical of the findings in patients with primary hyperparathyroidism. In contrast, in animals infused at 1.4 U X h-1, plasma calcium, phosphate, and theoretical renal threshold for phosphate remained within normal limits, but plasma 1,25-dihydroxyvitamin D was increased above control, suggesting that increased activity of 1 alpha-hydroxylase may be the most sensitive index of increased PTH levels. This animal model permits sustained elevation of PTH plasma levels at basal or pathologically elevated levels and should provide an effective means by which to evaluate the consequences of chronic hyperparathyroidism on epithelial function, bone, and other organ systems.

Acid-Base Equilibrium↗
PubMed1986

Evidence for a high and specific concentration of (Na+,K+)ATPase in the plasma membrane of the osteoclast.

During bone resorption, the osteoclast actively acidifies a limited extracellular compartment. We hypothesized that, like other cells engaged in ion transport and proton translocation, the osteoclast's membrane might be highly enriched in sodium pumps. Using monoclonal antibodies to both the alpha and the beta subunits, immunoblot analysis, and [3H]ouabain binding, we have demonstrated that the osteoclast plasma membrane is both highly and specifically enriched in (Na+,K+)ATPase, compared with other bone cells, monocytes, macrophages, and other blood and bone marrow cells. The density of binding sites on the osteoclast is equivalent to that of kidney tubule cells. This observation is consistent with the hypothesis that the (Na+,K+)ATPase plays a role in the mechanism of bone resorption, possibly coupled with secondary active calcium and/or proton transport. Monoclonal antibodies against the (Na+,K+)ATPase can therefore be used as specific markers for the osteoclast in bone and bone marrow preparations.

Animals↗
PubMed1986

Kinetic and cytochemical identification of osteoclast precursors and their differentiation into multinucleated osteoclasts.

Positive identification of osteoclast percursors has not yet been possible. The authors have, in the present report, used a model system in the rat in which it is possible to induce the formation of multinucleated osteoclasts at a predictable and reproducible site and time (Tran Van P, Vignery A, Baron R. Anat Rec 1982, 202:445-451; Cell Tissue Res 1982, 225:283-292). This system allowed the investigation of the cellular events occurring locally during the recruitment and differentiation of osteoclast precursors. Prior to the formation of multinucleated osteoclasts, mononuclear cells positive for fluoride-inhibitable nonspecific esterase and cells positive for tartrate-resistant acid phosphatase increase in number locally. Double staining procedures demonstrated the presence of both enzymes in a number of cells, thereby suggesting that they are steps in the differentiation of a single cell population. Ultrastructural studies show that lysosomal enzymes are present in every compartment of the biosynthetic pathway, in small primary lysosomes and various forms of storage granules. As these precursors arrive at the bone surface, the storage granule lysosomes are markedly depleted. It is concluded that mononuclear precursors of the osteoclast are members of the mononuclear-phagocyte lineage and differentiate early to synthesize, store, and later secrete large quantities of lysosomal enzymes. The mature osteoclast, which, as its precursor, is positive for the mononuclear-phagocyte marker enzyme nonspecific esterase, results from the fusion of these mononuclear precursors, which occurs only after their attachment to the bone surface to be resorbed.

Acid Phosphatase↗
PubMed1985

The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. I. The hypogastric nerve.

The cell bodies of the lumbar sensory and sympathetic pre- and postganglionic neurons that project to the pelvic organs in the hypogastric nerve of the cat have been labeled retrogradely with horseradish peroxidase applied to the central end of their cut axons. The numbers, segmental distribution, location, and size of these labeled somata have been determined quantitatively. Afferent and preganglionic cell bodies were located bilaterally in dorsal root ganglia and spinal cord segments L3-L5, with the maximum numbers in L4. Very few cells lay rostral to L3. Afferent cell bodies were generally very small in cross-sectional area relative to the entire population in the dorsal root ganglia. Most of the preganglionic cell bodies lay clustered just medial to the region of the intermediolateral column and extended caudally well beyond its usual limit in the upper part of L4. These neurons were, on the average, larger than the cells of the intermediolateral column itself, with the largest cells lying in the most medial positions. Most of the post-ganglionic somata were in the ipsilateral distal lobe of the inferior mesenteric ganglion, while some (usually less than 10%) lay in accessory ganglia along the lumbar splanchnic nerves and in paravertebral ganglia L3-L5. Postganglionic somata in the inferior mesenteric ganglion were larger than both labeled and unlabeled ganglion cells in the paravertebral ganglia. From the data, it is estimated that about 1,300 afferent neurons, about 1,700 preganglionic neurons, and about 17,000 postganglionic neurons project in each hypogastric nerve in the cat.

Animals↗
PubMed1985

The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. II. The lumbar splanchnic nerves.

The cell bodies of the lumbar sensory and sympathetic pre- and postganglionic neurons that project to the inferior mesenteric ganglion in the lumbar splanchnic nerves of the cat have been labeled retrogradely with horseradish peroxidase applied to the central end of their cut axons near the inferior mesenteric ganglion. The numbers, segmental distribution, location, and size of these labeled somata have been determined quantitatively. After all the lumbar splanchnic nerves on one side of an animal were labeled, most labeled cell bodies were situated ipsilaterally in dorsal root ganglia, ganglia of the lumbar sympathetic trunk, and spinal cord segments L2-L5, with the maximum numbers in L3 and L4. A few labeled somata lay contralaterally or rostral to L2. After labeling of only one lumbar splanchnic nerve, the majority of cell bodies were found in the labeled segment, but a few were also present up to three segments rostral or caudal. These variations could always be attributed to extraspinal connections usually via the lumbar sympathetic trunk. Cross-sectional areas of labeled afferent somata were small relative to those of the entire population of dorsal root ganglion cells. Preganglionic cell bodies were labeled in the intermediate gray matter extending from its lateral border ventrolaterally across to the central canal. Two regions of high density were observed: one laterally just medial to the edge of the white matter and the other lateral to the central canal. The dorsolateral group lay somewhat medial and caudal to the usual limits of the intermediolateral column. Labeled preganglionic neurons were on the average larger than the unlabeled cells in the inferior mesenteric ganglion, with the group lying medially being larger than those that were laterally positioned. From the data, it is estimated that about 4,600 afferent axons, about 4,600 preganglionic axons, and about 2,800 postganglionic axons travel in the lumbar splanchnic nerves to the inferior mesenteric ganglion of the cat.

Animals↗
PubMed1985

The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. III. The colonic nerves, incorporating an analysis of all components of the lumbar prevertebral outflow.

The cell bodies of the lumbar sensory and sympathetic pre- and postganglionic neurons that project to the colon along the inferior mesenteric artery of the cat have been labeled retrogradely with horseradish peroxidase applied to the central end of their cut axons. The numbers, segmental distribution, location, and size of these labeled somata have been determined quantitatively. Afferent cell bodies were symmetrically distributed bilaterally in dorsal root ganglia T13-L5, with the maximum number (about 80%) in L3 and L4 and most of the rest in L2. Labeled afferent somata were small relative to the entire population of DRG cells. Occasionally a few preganglionic somata were labeled in the intermediate zone of L3 and L4 spinal cord segments. Postganglionic cell bodies were labeled bilaterally in the proximal lobes of the inferior mesenteric ganglion (70-95%), in accessory ganglia of the intermesenteric nerve and of the lumbar splanchnic nerves, and in lumbar paravertebral ganglia. The segmental distribution in the lumbar sympathetic trunk was symmetrical on both sides and was the same as that of the afferent cells. Labeled postganglionic cell bodies in both the IMG and the accessory ganglia were larger than labeled and unlabeled ganglion cells in the paravertebral ganglia. From these data, it is estimated that about 2,100 afferent neurons and about 29,000 postganglionic neurons project in the lumbar colonic nerves. In conjunction with equivalent data for the hypogastric and lumbar splanchnic nerves, the results provide a quantitative and spatial description of the afferent and efferent components of the lumbar innervation of the colon and pelvic viscera.

Animals↗
PubMed1985

PGE2 stimulates both resorption and formation of bone in vitro: differential responses of the periosteum and the endosteum in fetal rat long bone cultures.

The ability of PGE2 to stimulate bone resorption in vitro and in vivo is well established but the effects of this compound on bone formation are still controversial. Recent clinical reports have suggested that long-term infusion of PGE in infants with cyanotic heart diseases led to a stimulation of periosteal bone formation and to hyperostosis. In the present report, we describe the effects of PGE2 (10(-5) M) in bone organ cultures on bone resorption, measured by the release of 45Calcium and the number of osteoclasts in sections of cultured bones, and bone volume, by measuring separately medullary and cortical areas. PGE2 induced a marked increase in 45Ca release and in cortical and medullary osteoclast numbers over 4 days in vitro; despite this increase in bone resorption, cortical bone volume remained constant, indicating a parallel increase in bone resorption and formation at this site. Morphological and quantitative data demonstrated a higher extent of osteoblastic surface along the periosteum of PGE2-treated bones when compared with control cultures. Medullary bone volume, on the other hand, decreased sharply during the culture period, demonstrating a lack of parallel increase in bone formation at this site. It is concluded that, under these experimental conditions, prostaglandin E2 stimulated both resorption and formation along the periosteum and only bone resorption along the endosteum of the cultured bones. The overall effect of PGE2 on bone as a whole, however, was net bone loss.

Animals↗
PubMed1985

On the anatomical organization of the lumbosacral sympathetic chain and the lumbar splanchnic nerves of the cat--Langley revisited.

The anatomy of the sympathetic nervous pathways from the spinal cord to the lumbosacral spinal nerves and to the inferior mesenteric ganglion has been studied systematically in a series of 37 cats. Details of the arrangements of white and grey rami communicantes and the lumbar splanchnic nerves are summarized, and similarities and differences between individuals noted. The description largely follows that of Langley [13] but differs in many ways from those of Harris [6] and Pick [21]. An alternative nomenclature for the segmental ganglia of the paravertebral sympathetic chain is defined, and its rationale presented.

Animals↗
PubMed1985

Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border.

The extracellular compartment where bone resorption occurs, between the osteoclast and bone matrix, is shown in this report to be actively acidified. The weak base acridine orange accumulates within this compartment but dissipates after incubation with ammonium chloride. Upon removal of ammonium chloride, the cells are able to rapidly reacidify this compartment. The highly convoluted plasma membrane of the osteoclast facing this acidic compartment (ruffled border) is shown to contain a 100-kD integral membrane protein otherwise present in limiting membranes of lysosomes and other related acidified organelles (Reggio, H., D. Bainton, E. Harms, E. Coudrier, and D. Louvard, 1984, J. Cell Biol., 99:1511-1526; Tougard, C., D. Louvard, R. Picart, and A. Tixier-Vidal, 1985, J. Cell Biol. 100:786-793). Antibodies recognizing this 100-kD lysosomal membrane protein cross-react with a proton-pump ATPase from pig gastric mucosae (Reggio, H., D. Bainton, E. Harms, E. Coudrier, and D. Louvard, 1984, J. Cell Biol., 99:1511-1526), therefore raising the possibility that it plays a role in the acidification of both intracellular organelles and extracellular compartments. Lysosomal enzymes are also directionally secreted by the osteoclast into the acidified extracellular compartment which can therefore be considered as the functional equivalent of a secondary lysosome with a low pH, acid hydrolases, the substrate, and a limiting membrane containing the 100-kD antigen.

Animals↗
PubMed1984

Evidence of sequential remodeling in rat trabecular bone: morphology, dynamic histomorphometry, and changes during skeletal maturation.

The occurrence of a sequential bone remodeling activity, similar to what is observed in human bone, is demonstrated in rat trabecular bone at the level of the secondary spongiosa. A complete dynamic histomorphometric analysis of the remodeling activity, using undecalcified sections and double fluorescent labels, has consequently been performed in young adults (220 g, 8 weeks old) and in more mature animals (320 g, 12 weeks old). The results showed that, despite a similar trabecular bone volume, younger animals had a five times higher bone formation rate and five times more osteoclasts than more mature animals. The higher bone formation rate was due in part to a threefold higher extent of double-labeled trabecular bone surface and in part to a 1.5-fold faster mineralization rate. These results therefore demonstrate a marked slowing down of bone turnover during skeletal maturation in the rat. The values obtained in this study have been compared with measurements made in other parts of the skeleton in the same species (Vignery and Baron 1978, 1980b; Tran Van et al., 1982a) or in humans. This comparison indicated that 12-week-old rats had a turnover rate very similar to values observed in iliac crest trabecular bone in adult humans. The rat is therefore a good experimental animal for the study of trabecular bone remodeling but since large variations occur during skeletal maturation, care should be taken in the selection of an age group relevant to the type of questions being asked.

Animals↗
PubMed1984

Vitamin D metabolism and bone histomorphometry in a patient with antacid-induced osteomalacia.

A patient with hypophosphatemic osteomalacia secondary to ingestion of large amounts of phosphate-binding antacids is presented. Vitamin D metabolites were measured during the course of his illness and recovery and demonstrated an initially elevated concentration of 1,25-dihydroxyvitamin D, an undetectable level of 24,25-dihydroxyvitamin D, and a normal level of 25-hydroxyvitamin D. These metabolites returned to normal levels when the hypophosphatemia was corrected. Bone histomorphometry showed osteomalacia with increased resorption. The possible role of altered vitamin D metabolism in the pathogenesis of this disorder is discussed.

Aged↗
PubMed1984

Thymus-derived lymphocytes and their interactions with macrophages are required for the production of osteoclast-activating factor in the mouse.

A bone-resorbing factor, comparable to the osteoclast-activating factor (OAF) produced from peripheral blood leukocytes, is shown to be produced by murine spleen cells activated with the T-cell mitogen Con A. Murine OAF is demonstrated here as being a product of the interaction between thymus-derived T lymphocytes and macrophages. Activation of T cells in the presence of macrophages with Con A yields culture supernatants with OAF activity. This OAF activity is not dialyzable and is not extracted by lipid solvents. Purified B cells in the presence or absence of macrophages and cocultured with Con A or activated with the B-cell-specific mitogen lipopolysaccharide yield culture supernatants with no detectable OAF activity. Similarly, macrophages cocultured with Con A or activated with lipopolysaccharide fail to yield culture supernatants with bone resorbing activity. These types of immune cell interactions are similar to that required for the production of lymphokines. These data support the hypothesis that one aspect of regulation of bone remodeling is through cells of the immune system.

Animals↗
PubMed1984

Squamous carcinoma model of humoral hypercalcemia of malignancy.

Squamous carcinomas are the most common cause of humoral hypercalcemia of malignancy (HHM) in humans. To develop an animal model of this syndrome, CD-1 female mice were painted with dimethylbenzanthracene, which produced cutaneous squamous carcinomas in the majority of those painted. Greater than 90% of tumor-bearing mice developed a syndrome of hypercalcemia, hypophosphatemia, hypercalciuria, elevated plasma 1,25-dihydroxyvitamin D, normal immunoreactive PTH, elevated urinary cAMP, and accelerated bone resorption compared to control mice. Tumor excision reversed the hypercalcemia and hypophosphatemia, and autopsies revealed no evidence of skeletal or other metastases. Dietary calcium restriction did not affect the hypercalcemia in tumor-bearing mice. Extracts of tumor tissue contained potent bioactivity paralleling that of bovine (b) PTH in a PTH-sensitive canine renal cortical adenylate cyclase assay. The activity was trypsin sensitive and partially inhibitable by Nle, Tyr bPTH amide. The activity coeluted with chymotrypsinogen (mol wt, 25,700) on Sephacryl S-200 chromatography, well ahead of bPTH. This is the first description of an animal squamous carcinoma that produces HHM. With the exception of elevated plasma 1,25-dihydroxyvitamin D levels, the syndrome precisely mimics that seen in human HHM. The presence of a biologically active protein larger than PTH in tumor extracts, similar to that extracted from human tumors, suggests a common mode of pathogenesis. This model should be useful in further studying the pathophysiology of HHM.

Animals↗
PubMed1984

Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model.

UNLABELLED: Wistar-Lewis rats received therapeutic doses of doxorubicin or methotrexate daily for five days, were pulse-labeled with a fluorescent compound (calcein) on the seventh and thirteenth days, and were killed fourteen days after initiation of the protocol. Proximal tail vertebrae were then evaluated histomorphometrically, and the effects of the chemotherapeutic agents on trabecular bone were quantitated with respect to changes in total bone mass, new-bone formation, and resorption. Short-term administration of methotrexate caused a 26.9 per cent reduction in net trabecular bone volume and doxorubicin, an 11.5 per cent decrease. Both drugs significantly and profoundly diminished bone-formation rates by nearly 60 per cent. The toxic effect on osteoblasts was also reflected in reduced volume and thickness of osteoid, but the total numbers of osteoblasts and the per cent of trabecular surface covered by bone-forming cells were not affected. The numbers of osteoclasts and the extent of their activity were not clearly different from those in untreated rats, but rates of resorption were not determined. The effects of chronic treatment with these chemotherapeutic agents on intact, fractured, and transplanted bone and the biomechanical significance of these changes has not yet been evaluated. CLINICAL RELEVANCE: Chemotherapeutic agents have an adverse effect on normal physiological bone turnover, especially osteoblastic activity, and would also be expected to alter fracture-healing and bone-allograft incorporation by these same mechanisms. Knowledge of these changes and efforts to favorably affect the remodeling cycle must address these specific defects before bone allografts can be reliably used and fracture-healing can be improved concomitant with chemotherapy.

Animals↗