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Biomedical subjects

G R Mundy

Publications and source records attributed to G R Mundy.

At least 19 recordsLinked to original sources
PubMed1979

Monocytes regulate osteoclast-activating factor production by releasing prostaglandins.

Osteoclast-activating factor (OAF), a powerful stimulator of osteoclastic bone resorption, is released by peripheral blood mononuclear cells on exposure to phytohemagglutinin (PHA) or a specific antigen to which the leukocytes have been previously exposed. Both lymphocytes and monocytes are required in the leukocyte population for OAF release to occur. In this study we examined the relationship between the lymphocyte and monocyte in OAF production. Biological activity, as a result of OAF, was assessed by a bioassay based on the release of previously incorporated 45Ca from fetal rodent long bones in organ culture. We found that an enriched lymphocyte population depleted of monocytes by serial adherence does not release OAF after stimulation with PHA, although the cells are activated as assessed by [3H]thymidine and 3H-amino acid incorporation. When conditioned media harvested from adherent cells which did not contain OAF was added to the enriched lymphocytes, OAF release occurred. Media harvested from adherent cells which were cultured with indomethacin (10 microM), an inhibitor of prostaglandin synthesis, did not permit OAF release by activated lymphocytes. When PGE1 and PGE2 (0.1 microM) were added exogenously to the enriched lymphocyte population, OAF release occurred after stimulation with PHA. These results indicate that, (a) the activated lymphocyte is the cell or origin of OAF, (b) prostaglandins produced by monocytes are necessary for OAF production by activated lymphocytes, and (c) monocyte prostaglandins can influence bone resorption indirectly by regulating OAF production as well as directly by osteoclast activation. The interactions of OAF and prostaglandins at bone resorbing sites may be important in inflammatory and neoplastic diseases associated with bone destruction.

Bone Resorption↗
PubMed1979

Chemotactic responses of tumor cells to products of resorbing bone.

To explore possible mechanisms for the metastasis of malignant cells to bone, a model of tumor cell migration was developed, using Walker carcinosarcoma or malignant lymphoma cells. It was found that bone contains a factor that is strongly chemotactic for tumor cells. This factoor is released by a variety of agents that induce resorption of bone.

Animals↗
PubMed1979

Prostaglandins are necessary for osteoclast-activating factor production by activated peripheral blood leukocytes.

The production of osteoclast-activating factor (OAF) by normal human peripheral blood leukocytes stimulated by phytohemagglutinin was inhibited by a series of structurally unrelated inhibitors of prostaglandin synthetase. Inhibition of OAF production by these agents was reversed by adding prostaglandins of the E series back to the leukocyte suspension. These results indicate that prostaglandin synthesis is necessary for OAF production.

Bone Resorption↗
PubMed1978

Production of bone resorbing activity in poorly differentiated monocytic malignancy.

A patient with poorly differentiated monocytic malignancy had extensive lytic lesions of bone and hypercalcemia. The patient's bone margins showed little evidence of osteoclast activity. Serum parathormone concentrations were slightly increased relative to the degree of hypercalcemia, consistent with impaired renal function. Serum concentrations of the relevant prostaglandins were normal. Supernatant medium from cultured tumor cells caused prominent bone resorption in vitro. The studies on this patient provide evidence that malignant cells of the monocyte-macrophage line are capable of direct bone resorption.

Adult↗
PubMed1978

Pathogenesis of hypercalcemia in lymphosarcoma cell leukemia. Role of an osteoclast activating factor-like substance and a mechanism of action for glucocorticoid therapy.

The pathogenesis of hypercalcemia and mode of action of glucocorticoid therapy was examined in a patient with lymphosarcoma cell leukemia. Circulating neoplastic cells were cultured in vitro and secreted a bone-resorbing factor. The bone-resorbing factor was partially purified with the use of a bioassay for bone resorption, and was found to be chromatographically and pharmacologically similar to osteoclast activiating factor (OAF), which is produced by normal mitogen-activated peripheral blood lymphocytes. Other factors which stimulate bone resorption, such as parathyroid hormone, prostaglandins and the vitamin D metabolites, were excluded by criteria which included dose-response curves, radioimmunoassays, extraction in organic solvents and failure of glucocorticoids to inhibit bone-resorbing activity. The patient's hypercalcemia responded rapidly to prednisone therapy. The effects of the bone-resorbing factor secreted by the neoplastic cells on bone cultures to which cortisol was added were examined. Cortisol inhibited bone resorption directly at low doses (10(-8) M), which suggests that prednisone may have lowered the serum calcium in this patient by direct inhibition of bone resorption.

Aged↗
PubMed1978

Differential diagnosis of osteopenia.

Differentiating the demineralizing bone diseases, especially osteoporosis from osteomalacia, is difficult but clinically rewarding, since the latter is highly treatable. Bone biopsy can detect the 20% of osteoporotic patients who also have osteomalacia.

Adult↗
PubMed1978

Effects of glucocorticoids on osteoclast-activating factor.

Glucocorticoids lower the serum calcium in patients with hypercalcemia due to myeloma and related lymphoproliferative disorders. OAF is a potent bone-resorbing lymphokine which is probably responsible for the bone lesions and hypercalcemia which occur in patients with these hematological neoplasms. In this study, we have examined the effects of cortisol on the production of OAF and its biological activity in order to clarify the mechanism of action of glucocorticoids in lowering the serum calcium in these disorders. The effects of OAF-containing media on bone resorption were inhibited by cortisol at concentrations from 10-5M to 10-9M. In contrast, OAF production was not inhibited by cortisol at concentrations less than 10-5M. These data support the hypothesis that glucocorticoids inhibit the effects of OAF in vivo primarily by a direct effect on bone resorption.

Animals↗
PubMed1977

Role of the tubulin-microtubule system in lymphocyte activation.

The role of the tubulin-microtubule system was examined in human peripheral blood leukocytes after activation with phytohemagglutinin (PHA). Soluble tubulin and microtubules were measured with a [(3)H]colchicine-binding assay. It was found that the tubulin content of PHA-activated lymphocytes was consistently increased relative to total protein content after 36 h of culture. There was no increase in the proportion of total tubulin synthesis which was present as microtubules at 36 h. Nevertheless, as a result of increased tubulin synthesis, there was a two-to three-fold increase in total microtubular mass. Colchicine, which disrupts microtubles, was used to assess the role of microtubule assembly in the sequence of events which follow lymphocyte activation, namely lymphokine release, protein synthesis, RNA synthesis, and DNA synthesis. Colchicine consistently inhibited DNA synthesis but did not inhibit release of the lymphokine, osteoclast activating factor (OAF). Protein and RNA syntheses were inhibited much less than DNA synthesis. The fact that some effects of PHA on lymphocytes appear to require intact microtubules and at least one does not suggest that the microtubule dependent step in PHA-stimulated lymphocyte activation occurs at a stage after propagation of the signal from the membrane to the cell interior.

Blood Proteins↗
PubMed1977

Big and little forms of osteoclast activating factor.

We have further characterized osteoclast activating factor (OAF) using a bioassay for bone resorption which utilizes the release of previously incorporated (45)Ca from fetal rat long bones in organ culture. When supernatant media from activated leukocyte cultures were concentrated on Amicon PM10 membranes (assigned molecular weight cutoff 10,000 daltons) and chromatographed on Sephadex G-50 columns, the bone-resorbing activity eluted between the molecular weight markers chymotrypsinogen (25,000 daltons) and cytochrome c (12,500 daltons). This peak of biological activity has been called big OAF. When filtrates from the PM10 membranes were concentrated on Amicon UM2 membranes (assigned molecular weight cutoff 1,000 daltons) and chromatographed on Sephadex G-50 columns, some of the biological activity eluted between the molecular weight markers chymotrypsinogen and cytochrome c (big OAF), but there was a separate peak of biological activity which eluted with [(3)H]proline (140 daltons). This second peak has been called little OAF. Little OAF was eluted from Bio-Gel P6 columns between the molecular weight markers calcitonin (approximately 3,500 daltons) and vitamin B(12) (1,330 daltons), but was retained by Spectrapor dialysis tubing (nominal molecular weight cutoff 3,500 daltons). Big OAF was converted to little OAF by equilibration in 1 M NaCl or 2 M urea. Little OAF was self-associated back to big OAF by equilibration in buffers of low ionic strength (Tris-HCl 10-50 mM). Little OAF was extracted into the organic phase in ethyl acetate after acidification of the sample to pH 3.5. The biological activity remained in the aqueous phase after ethyl acetate extraction at pH 7.5-8.4. Little OAF has been purified more than 6,000-fold compared with the original material so that bone-resorbing activity is maximal in a sample with a protein concentration of 80 ng/ml.

Animals↗