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Biomedical subjects

S L Teitelbaum

Publications and source records attributed to S L Teitelbaum.

At least 127 records · Page 7Linked to original sources
PubMed1989

Podosome expression in osteoclasts: influence of high extracellular calcium concentration.

In this study the effect of high extracellular calcium concentration has been evaluated, by immunofluorescence, on podosome expression in chicken osteoclasts. Cells were cultured in presence of 0.2 and 4 mM calcium for 90 minutes and microfilaments were detected, after fixation and permeabilization, by decoration with rodhamine conjugated phalloidin. Results showed that increased extracellular calcium concentration induces the inhibition of podosome expression indicating that these close-contact areas are capable of calcium-mediated regulation.

Animals↗
PubMed1989

Spontaneous healing of jejunoileal bypass-induced osteomalacia.

We have previously reported that osteomalacia may develop in patients relatively soom after jejunoileal (JI) bypass surgery. The present study was designed to determine the course of JI bypass osteomalacia in an untreated group of patients. We performed serial iliac crest biopsies on nine patients at 46 and 79 months (mean) following operation. We found that the amount of osteoid (unmineralized bone matrix) decreased (P less than 0.05) with time, while trabecular bone mass increased (P less than 0.05). Although three patients were osteomalacic at the original biopsy, no patient had evidence of osteomalacia at the second bone biopsy. Based upon these patients, we conclude that the mineralization defect, when it occurs after JI bypass, does not cause clinically significant bone disease and does not persist late postoperatively.

Female↗
PubMed1989

Intracellular acidification induces decrease of cytosolic calcium in isolated osteoclasts.

In this study the effects of changes in intracellular pH on cytosolic Ca2+ were examined in single isolated osteoclasts. Alkalinization, performed by incubation in HCO3 containing buffer, induced increases in [Ca2+]. Conversely acidification, obtained by incubation in Na-butyrate-containing buffer induced a rapid and sustained decrease of [Ca2+]. The decrease of [Ca2+], during acidification with Na-butyrate was inhibited by VO4, an inhibitor of the Ca2+-ATPase. All these pieces of information indicate that changes in pH1 can modulate osteoclast activity together with modifications of [Ca2+], probably acting as intracellular signals.

Animals↗
PubMed1989

X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults.

Research and management of XLH have concentrated on the disease in childhood, and the natural history and morbidity of XLH in adult life are thus poorly understood. We have studied 22 adults (6 men) with XLH to clarify these aspects of this most common inherited form of rickets and osteomalacia. Most study participants had presented with rickets in early childhood and had undergone tibial osteotomies on at least 1 occasion. Seventeen individuals had genu varum, 1 had genu valgum, and 4 had straight legs, attributable to successful osteotomies in 2. Five subjects reported increasing lower limb deformity in the late teens or subsequently. Eight subjects complained of bone pain, 6 of whom had radiologic evidence of pseudofractures; pseudofractures were found in 4 additional asymptomatic individuals. None of 16 subjects who underwent transiliac bone biopsy had normal double tetracycline labeling; accordingly, all were considered to have osteomalacia. Bone pain was associated with a relative osteoid volume in excess of 25%. Relative osteoid volume was inversely related to serum 1,25(OH)2D concentration (r = -0.74, p less than 0.02), but unrelated to serum concentrations of calcium and phosphate or their product. Eighteen participants complained of joint pain, predominantly in the knees and ankles. The severity of joint pain correlated with the degree of lower limb deformity (p = 0.011) which, in turn, was related to fasting serum phosphate concentration (r = -0.56, p less than 0.025) and TmP/GFR (r = -0.70, p less than 0.005). Enthesopathy affected 33% of those younger than 30 years, and all those above this age. Nineteen individuals had experienced significant dental problems, most commonly abscess formation. Eight had required complete dental clearance. Twelve women from the group had a total of 22 live births. Fifteen of these were by cesarean section, although radiologic evidence of pelvic narrowing was not found in any subject. Serum ALP was elevated in all but 3 of the 18 untreated subjects. Levels correlated with those of other indices of bone turnover (BGP r = 0.82, p less than 0.005; urine total HP r = 0.60, p less than 0.025; urine free HPr = 0.78, p less than 0.005), but were not related to the degree of osteomalacia found on bone biopsy. Serum levels of iPTH, 25(OH)D, 1,25(OH)2D, and thyroid hormones were generally normal in the untreated patients. We conclude that adults with untreated XLH have osteomalacia that is frequently symptomatic. Even greater morbidity is caused by degenerative joint disease arising from lower limb deformities.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Arachidonic acid metabolism by a vitamin D3-differentiated human leukemic cell line.

HL-60 is a human promyelocytic cell line that differentiates along the granulocytic pathway when incubated with dimethylsulfoxide and along the monocytic pathway when incubated with 1,25-(OH)2D3. We compared arachidonic acid metabolism in undifferentiated, DMSO-differentiated, and 1,25-(OH)2D3-differentiated cells. DMSO- and 1,25-(OH)2D3-differentiated cells metabolized exogenous arachidonic acid to both cyclo-oxygenase products (predominantly thromboxane B2 and prostaglandin E2) and 5-lipoxygenase products, including leukotriene B4. Undifferentiated cells produce these metabolites in much smaller amounts. DMSO-differentiated cells released a large percentage of phospholipid-bound arachidonic acid in response to stimulation with the ionophore A23187, zymosan, or formylmethionylleucylphenylalanine (FMLP). DMSO-differentiated cells stimulated with A23187 converted released arachidonate to LTB4 and TxB2. In contrast, 1,25-(OH)2D3-differentiated cells released a smaller percentage of phospholipid-bound arachidonate in response to stimuli, and undifferentiated cells released none at all. The three cell types (undifferentiated, DMSO-differentiated, and 1,25-(OH)2D3-differentiated) were homogenized and the 10,000 X g supernatant incubated with [14C]arachidonic acid. The supernatants from the homogenates of the DMSO- and 1,25-(OH)2D3-differentiated cells metabolized [14C]arachidonic acid to cyclooxygenase and lipoxygenase products, but the supernatant from the homogenate of undifferentiated cells did not. These data indicate that differentiation of HL-60 cells with DMSO or 1,25-(OH)2D3 induces cyclooxygenase and 5-lipoxygenase and induces mechanisms for the release of arachidonate from phospholipids by soluble and particulate stimuli.

Arachidonic Acid↗
PubMed1988

Receptor-mediated uptake of a mannose-6-phosphate bearing glycoprotein by isolated chicken osteoclasts.

We have recently shown that degradation of bone collagen by osteoclasts occurs via proteolytic enzyme activity that depends on an acidic milieu. Since bone resorption occurs in an extracellular, acidic compartment located at the cell-matrix attachment site, the osteoclast must deliver the acid collagenolytic enzymes to the cell surface. These observations raise the possibility that the mannose-6-phosphate (M-6-P) receptor, known to sort acidic proteases in other cells, is involved in trafficking lysosomal enzymes to the plasmalemma of bone resorbing cells. To this end we studied receptor-mediated uptake, distribution and release, by isolated chicken osteoclasts, of 125I-hexosaminidase, a M-6-P bearing enzyme. We found that at 4 degrees C, the bone-resorbing polykaryons bind approximately 10,000 molecules of radioligand/cell with a Kd of 0.7 nM, which is endocytosed by osteoclasts at 37 degrees C by a calcium-independent process. Furthermore, 125I-hexosaminidase uptake is unaffected by mannosylated albumin, documenting specificity of the receptor-mediated event. Release of endocytosed enzyme from the cell is also much more rapid than its degradation, attesting to a pathway of uptake and secretion. By autoradiography, the M-6-P bearing ligand is concentrated at the site of osteoclast-bone attachment. Thus, osteoclasts also have the capacity to deliver M-6-P bearing degradative enzymes to their surface at the site of matrix degradation.

Animals↗
PubMed1988

Assessment of calcitriol and inorganic phosphate therapy before cure of oncogenous osteomalacia by resection of a mixed mesenchymal tumor.

A 57 year old white male with oncogenous osteomalacia due to a mixed mesenchymal tumor was evaluated by sequential histologic and metabolic studies over a period of 33 mos prior to identifying the location of the tumor. On the basis of these studies we conclude: (i) disorders of the enterohepatic circulation and/or acceleration of metabolism of calcitriol are not responsible for its diminished level in oncogenous osteomalacia, (ii) the Von Kossa stain is preferred to the modified Masson in evaluating osteomalacia, (iii) avascular necrosis of the femoral head may be part of the syndrome, (iv) heterogeneity may be the hallmark of the responsible mesenchymal tumor and account for the different histological interpretations in the literature, (v) in compliant patients with oncogenous osteomalacia, calcitriol and Pi therapy may be effective.

Bone Neoplasms↗
PubMed1988

Radiologic and pathologic patterns of end-plate-based vertebral sclerosis.

Degenerative spondyloarthropathy is the result of a number of related pathologic processes, including loss of disc elasticity, repetitive mild trauma, and osteoporosis. The effects are manifested microscopically in a number of patterns reflecting alterations in stress, healing microfractures, and bone-cartilage interactions along the vertebral end-plate. The microscopic changes lead in turn to radiographically evident vertebral body sclerosis. The resultant sclerosis is not always in the classic band-like pattern along the vertebral end-plate, and the atypical patterns may be difficult to recognize as degenerative in origin. In a detailed analysis of clinical and postmortem material, we have categorized both the pathologic and radiographic patterns of benign non-Pagetic vertebral body sclerosis. This radiographic classification provides a unified framework for clinical recognition of the various patterns of degenerative sclerosis.

Adult↗
PubMed1988

Effects of hypervitaminosis A on the bone and mineral metabolism of the rat.

Vitamin A toxicity has been associated with alterations in mineral metabolism and may result in osteopenia, fractures, deformities, and growth arrest. The pathogenesis of the bone lesions that occur in vitamin A toxicity is, however, ill defined and was examined in the present study. The administration of pharmacological doses of vitamin A to growing male rats resulted in weakness and spontaneous fractures. Undecalcified bone histology of vitamin A toxic animals was characterized by increased bone resorption, osteoclastosis, a paucity of trabecular surfaces covered with osteoid, and lesions which appear to be pathognomonic of hypervitaminosis A. The serum calcium and magnesium levels of vitamin A-toxic animals were unremarkable, but serum phosphate levels were significantly higher than control values. Urinary hydroxyproline excretion reflected bone histology and was significantly increased in experimental rats. Circulating levels of the potent bone resorbers, PTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D, were, however, comparable in vitamin A-toxic and control animals, suggesting a possible direct effect of vitamin A on bone. Subsequently, the effects of vitamin A (retinol) on in vitro collagen synthesis (incorporation of [3H]proline into collagen) and bone resorption (45Ca release from bone) were examined using a fetal rat calvarial culture. Retinol added to the culture medium for 20-24 h in concentrations ranging from 0.5-10 micrograms/ml selectively inhibited collagen synthesis in a dose-dependent fashion. Higher concentrations of retinol were toxic and resulted in a general inhibition of protein synthesis. Bone resorption was stimulated by 0.5 and 2.5 micrograms/ml retinol. We conclude that vitamin A toxicity in rats causes bone lesions, the genesis of which can be explained, at least in part, by a direct effect of the vitamin on skeletal tissue.

Alkaline Phosphatase↗
PubMed1987

1,25-Dihydroxyvitamin D3 modulates bone marrow macrophage precursor proliferation and differentiation. Up-regulation of the mannose receptor.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3), the biologically active form of vitamin D3, has been shown to inhibit proliferation and promote monocytic differentiation of leukemic cell lines. In the present communication, we extend these observations to normal bone marrow macrophage precursors, and 1) identify the stage of monocytic maturation wherein the steroid exerts its antiproliferative effect, and 2) demonstrate that 1,25-(OH)2D3 promotes bone marrow macrophage differentiation as manifest by specific up-regulation of the lineage-specific membrane protein, the mannose-fucose receptor. In these experiments, the 1,25-(OH)2D3-mediated inhibitory effect on colony formation was shown to be independent of attendant levels of colony stimulating factor-1 and targeted through the adherent bone marrow macrophage precursor. Examination of this steroid-sensitive adherent precursor population demonstrates that its specific binding of 125I-mannose bovine serum albumin spontaneously and progressively increases with time in culture. Whereas adherent bone marrow macrophages cultured for 2 days express 3 X 10(4) mannose receptors/cell, the number of binding sites increases to 7 X 10(4)/cell by day 4. When bone marrow macrophage precursors are exposed to 1,25-(OH)2D3, an additional stepwise enhancement of 125I-mannose bovine serum albumin obtains with time. Four days of culture with the steroid results in 1.6 X 10(5) mannose receptors/cell, a 100% increase as compared to control cells. Neither duration of culture nor exposure to 1,25-(OH)2D3 alters the KD of 125I-mannose bovine serum albumin which approximates 3-5 X 10(-9) ml-1. Finally, the "specificity" of vitamin D-mediated up-regulation of the mannose receptor was established by demonstrating that the steroid does not alter binding of 125I-alpha-thrombin by bone marrow-derived macrophage precursors.

Animals↗
PubMed1987

Interleukin 1 stimulates proliferation of a nontransformed T lymphocyte line in the absence of a co-mitogen.

Although interleukin (IL) 2-responsive T cell lines provide an opportunity to study the cellular effects of this lymphokine on homogeneous T lymphocyte populations, T cell clones which proliferate in response to IL-1 alone have not been available. We have isolated from cultures of the nontransformed murine T helper cell line, D10 . G4 . 1, a variant (MD10 cells) which proliferates (no lectin or antigen needed) in response to IL-1 alone. The MD10 cells are markedly sensitive to either murine or human recombinant IL-alpha (HrIL-1 alpha) with half-maximal responses observed at monokine concentrations as low as 0.4 X 10(-12) M or 0.8 U/ml, respectively. MD10 cells show the maximal IL-1 effect at 72 hr where the response exceeds the base line by 100-fold (approximately 3,000----300,000 cpm of [3H]thymidine). Whereas both HrIL-2 and purified murine B cell-stimulatory factor 1 (MpBSF-1) induce MD10 proliferation, the maximal response to either is much lower (HrIL-2: 50X baseline; MpBSF-1: less than 20X base line) than to IL-1. Conditioned media from control, concanavalin A-, or IL-1-treated MD10 cells fail to stimulate CTLL or HT-2 cell proliferation alone or inhibit CTLL mitogenesis in the presence of added HrIL-2. Furthermore, monoclonal antibodies to BSF-1 fail to inhibit IL-1-stimulated MD10 replication, and neither HT-2 nor CTLL cells proliferate despite direct cell-to-cell contact with IL-1-treated MD10 cells. When combined, IL-1 (10(-13), 10(-12) M) and IL-2 (10(-13) to 10(-10) M) act synergistically in their MD10 cell growth-promoting effects. MD10 proliferation induced by either IL-1 or IL-2 is relatively resistant to cyclosporine A, with the ID50 of cyclosporine for both IL-1- and IL-2-exposed MD10 cells (ID50 5000 ng/ml) exceeding that for concanavalin A-activated splenocytes (ID50 20 ng/ml) by 2 to 3 orders of magnitude. Finally, MD10 cells bear the L3T4 antigen, IL-2 receptors, and the same clonotypic antigen receptor as the parent clone as recognized by monoclonal antibody 3D3. These data suggest that, in respect to this particular T cell line, IL-1 is directly growth-promoting or, alternatively, induces the production of undetectable, intermediate growth factor(s) resistant to inhibition by cyclosporine A.

Animals↗
PubMed1987

Vitamin D affects proliferation of a murine T helper cell clone.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active form of vitamin D3, has been shown to inhibit the activation of T cell hybridomas and heterogeneous populations of mononuclear leukocytes. Because the response of various clones to 1,25(OH)2D3 may differ, we have examined the proliferative effects of the steroid on an antigen-specific cloned, nontransformed T helper cell line (D10.G4.1 [D10 cells]), and find that in contrast to these previous studies, the steroid is a potent stimulator of lectin-induced proliferation. In these experiments, D10 cells were incubated with concanavalin A and 1,25(OH)2D3, and although the lectin or steroid alone has minimal proliferative effects, their co-addition prompts up to a 50-fold increase in 3H-TdR incorporation at a concentration of 2.5 to 5 X 10(-9) M 1,25(OH)2D3, with significant mitogenesis occurring at 0.1 to 0.3 X 10(-9) M 1,25(OH)2D3. 25-Hydroxyvitamin D3 and 24,25(OH)2D3 have similar activity, but at concentrations two to three times greater than that of 1,25(OH)2D3, reflecting their relative affinities for the 1,25(OH)2D3 receptor. In addition, lectin treatment enhances 1,25(OH)2D3 receptor capacity fourfold to fivefold, an event coupled with the appearance of positive cooperativity. Although the steroid does not affect the quantity of bioassayable T cell growth factors as assessed by HT-2 cell proliferation, the expression of immunoreactive IL 2 receptors by lectin-activated D10 cells exposed to 1,25(OH)2D3 is enhanced. In contrast to its proliferative effect in the absence of IL 1, 1,25(OH)2D3 exerts biphasic effects on D10 replication when this monokine is present. Specifically, this steroid augments D10 proliferation at low concentrations of recombinant IL 1, but as the abundance of the monokine increases in the presence of 10(-10) to 10(-8) M 1,25(OH)2D3, the peak response of D10 cells to optimal IL 1 concentrations is diminished. Therefore, in this clone, 1,25(OH)2D3 presents itself as a regulator of T helper cell proliferation.

Animals↗
PubMed1987

Hypercalcemic hyperparathyroidism complicating oncogenic osteomalacia. Effect of successful tumor resection on mineral homeostasis.

Described herein is a case of oncogenic osteomalacia that ran a course of at least 16 years before curative resection of a mixed mesenchymal tumor. Hypercalcemic hyperparathyroidism developed in the patient, and review of the literature indicated that this occurs in about 10 percent of reported cases. Changes in serum parathyroid hormone levels with and without phosphate supplement therapy and before and after tumor resection suggested that both the high intake of phosphate and the effect of the neoplasm on vitamin D bioactivation engendered the parathyroid overactivity. Despite marked hyperparathyroidism, serum 1,25-dihydroxyvitamin D levels were subnormal preoperatively but showed a sevenfold increase within 48 hours of tumor resection. Thereafter, a gradual increase in the maximal tubular reabsorption of phosphate occurred during several months. Biopsy of the iliac crest confirmed that tumor removal was followed by resolution of osteomalacia, but there was no accompanying increase in vertebral mineral density as assessed by quantitative computed tomography or in total-body bone mineral as measured with dual-photon absorptiometry. The findings presented are consistent with secretion by the tumor of a factor with a short half-life that is potent enough to inhibit renal 25-hydroxyvitamin D-1 alpha-hydroxylase despite hyperparathyroidism. The resulting subnormal circulating 1,25-dihydroxyvitamin D levels may have secondarily contributed to decreased renal tubular reabsorption of phosphate.

Chronic Disease↗
PubMed1987

Hormonal regulation of the production of collagenase and a collagenase inhibitor activity by rat osteogenic sarcoma cells.

Collagenases that specifically cleave native collagen at neutral pH have been implicated in the maintenance and turnover of connective tissue. In bone, the origin of neutral collagenase has remained equivocal, although recent studies have indicated that it is synthesized by the osteoblast. In the present work, regulation of secretion of neutral collagenase and a collagenase inhibitory activity was investigated using the osteoblastic tumor cell line UMR 106-01 and a variety of bone-resorbing agents. Under basal conditions, UMR 106-01 cells produced very low levels of collagenase but substantial amounts of the inhibitory activity. Exposure to PTH and, to a lesser extent, 1,25-dihydroxyvitamin D3, prostaglandin E2, retinoic acid, and epidermal growth factor stimulated the release of collagenase, an effect not seen with interleukin-1 or heparin. The stimulation of collagenase by PTH was dose dependent, with a half-maximal response occurring at 10(-8) M. Inclusion of isobutylmethylxanthine decreased the concentration of PTH required to produce half-maximal stimulation to 2 X 10(-10) M, indicating action via cAMP. With respect to the inhibitory activity, PTH and epidermal growth factor were the only agents, among those tested, able to enhance its production. Both hormones caused a 50-100% increase over control levels 72 h after hormone administration. There were notable differences in the time courses of production of collagenase and the inhibitor. After treatment with PTH, the enzyme reached maximal concentrations between 12-48 h, but declined to undetectable levels by 96 h. In contrast, the inhibitory activity was secreted in a linear fashion, with the highest concentrations achieved around 72-96 h. These results suggest a complex pattern of regulation of collagenase and inhibitor secretion by the osteoblastic cell, with the steady accumulation of inhibitor perhaps being responsible for the ultimate curtailment of enzyme activity.

Animals↗
PubMed1986

Collagenase production by smooth muscle: correlation of immunoreactive with functional enzyme in the myometrium.

A monospecific antibody to rat uterine collagenase has been produced and employed to study the cell of origin and the time course of production of this enzyme in the involuting rat uterus. The specificity of the anti-collagenase antibody was confirmed by immunoprecipitation, Western analysis, and by its ability to inhibit the activity of collagenase. Parallel measurements of functional enzyme, both latent and active, bound to tissue collagen were also made in nonpregnant, gravid, and postpartum rat uteri. Immunohistochemical staining of collagenase in sections of rat uterus showed the enzyme to be present in the perinuclear region of the smooth muscle cells only of the involuting myometrium. No detectable collagenase was present in the prepartum or nonpregnant uterus. Identity of the smooth muscle cells was confirmed using an anti-smooth muscle actin antibody. In addition, the cultured uterine cells from which the immunizing antigen was obtained were also identified as smooth muscle cells. Specificity of the tissue staining was confirmed by the ability of pure rat uterine collagenase to block the reaction of the antibody with the tissue. These observations indicate that smooth muscle cells are capable of producing collagenase and are consistent with the hypothesis that this enzyme presides over the massive collagen degradation seen in postpartum uterine involution. Furthermore, measurement of collagenase bound to uterine collagen revealed that collagenase activity could be detected only at the time that the cells could be seen to be producing the enzyme by immunolocalization. These findings support the concept that collagenase is produced only as needed and not stored, either intra- or extra-cellularly.

Animals↗