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S L Teitelbaum

Publications and source records attributed to S L Teitelbaum.

At least 55 records · Page 3Linked to original sources
PubMed1997

Osteopetrosis in mice lacking haematopoietic transcription factor PU.1.

Osteoclasts are multinucleated cells and the principal resorptive cells of bone. Although osteoclasts are of myeloid origin, the role of haematopoietic transcription factors in osteoclastogenesis has not been explored. Here we show that messenger RNA for the myeloid- and B-cell-specific transcription factor PU.1 progressively increases as marrow macrophages assume the osteoclast phenotype in vitro. The association between PU.1 and osteoclast differentiation was confirmed by demonstrating that PU.1 expression increased with the induction of osteoclastogenesis by either 1,25-dihydroxyvitamin D3 or dexamethasone. Consistent with the participation of PU.1 in osteoclastogenesis, we found that the development of both osteoclasts and macrophages is arrested in PU.1-deficient mice. Reflecting the absence of osteoclasts, PU.1-/- mice exhibit the classic hallmarks of osteopetrosis, a family of sclerotic bone diseases. These animals were rescued by marrow transplantation, with complete restoration of osteoclast and macrophage differentiation, verifying that the PU.1 lesion is intrinsic to haematopoietic cells. The absence of both osteoclasts and macrophages in PU.1-mutant animals suggests that the transcription factor regulates the initial stages of myeloid differentiation, and that its absence represents the earliest developmental osteopetrotic mutant yet described.

Animals↗
PubMed1997

Osteoclasts, macrophages, and the molecular mechanisms of bone resorption.

The osteoclast is a physiological polykaryon and the major if not exclusive resorptive cell of bone. It participates in bone remodeling, repair, and growth and mobilization of mineral to meet homeostatic demands. Most importantly, osteoporosis, a disease endemic in Western society and Asia, is always a reflection of enhanced osteoclastic activity relative to bone formation by osteoblasts. In fact, all forms of anti-osteoporosis therapy proven successful involve inhibition of osteoclastic bone resorption. Bone resorption is regulated either by altering recruitment of osteoclast precursors into fully differentiated resorptive polykaryons or modulating the rate at which mature osteoclasts degrade bone. With this in mind, our laboratory has focused on the molecular mechanisms of osteoclast differentiation and the means by which the cell degrades bone matrix.

Animals↗
PubMed1997

Paget bone disease involving young adults in 3 generations of a Korean family.

Although the etiology of Paget bone disease (PBD) is unknown, increasing evidence implicates a "slow virus" infection of the skeleton, perhaps in genetically predisposed individuals. PBD is rare in Asia. We describe a Korean family with PBD. The propositus noticed bowed limbs at approximately 25 years of age. Radiologic studies made when he was 55 years old revealed essentially panostotic PBD. Serum alkaline phosphatase (ALP) activity and osteocalcin (OC) levels were markedly elevated. An iliac crest specimen showed classic histopathologic changes of PBD. Additionally, palpable swellings were first observed at age 45 years at his occiput, pubic ramus, ileum, and facial bones. They contained numerous multinucleated cells and were originally diagnosed as giant cell tumors. However, we found that, like osteoclasts, these cells expressed considerable tartrate-resistant acid phosphatase activity. These "extraskeletal osteoclastomas" resolved rapidly with dexamethasone treatment. Two daughters, 20- and 24-years-of-age, were discovered by study of his 5 children to have elevated serum ALP activity and OC levels and widespread PBD. Both women, however, are without palpable masses and are asymptomatic. The propositus' father, who died at age 55 years, had similar skeletal deformities beginning at age 20 years, but was not examined. Leukocytopenia was found in the 3 living family members with PBD. There was no evidence for linkage of the PBD to HLA loci. The condition appears to be transmitted as an autosomal dominant trait and is manifest in young adult life. Multicentric extraskeletal osteoclastomas with remarkable sensitivity to dexamethasone treatment appear to be another unusual feature of this family's disorder. In this family, the stimulus for PBD is so great that the PBD is apparent at an early age, affects essentially the entire skeleton, and leads to the formation or extension of osteoclast-like cells into nonosseous tissues (extraskeletal osteoclastomas). This 3-generation kindred in Korea, where PBD is rare, shows a strong clustering of PBD compatible with autosomal dominant inheritance. Leukocytopenia appears to distinguish affected family members, but any role for this abnormality in the pathogenesis of PBD is unclear. Our findings support a heritable diathesis for PBD, perhaps mediated by an immune deficiency.

Adult↗
PubMed1997

Extraskeletal osteoclastomas responsive to dexamethasone treatment in Paget bone disease.

Giant cell tumors (GCTs) of bone, also called osteoclastomas, complicate Paget bone disease (PBD), though infrequently. Giant cell reparative granulomas (GCRGs), which are histologically similar to GCTs, also occur rarely in pagetic patients. A 45-yr-old black woman with neurofibromatosis, type I, and polyostotic PBD developed slowly-growing masses in the right posterior iliac and left upper parasacral regions. She had multiple cutaneous neurofibromas and café-au-lait spots. Serum alkaline phosphatase activity and urine hydroxyproline levels were elevated. Skeletal radiographs and bone scintigraphy showed changes of widespread PBD. Computerized tomography and magnetic resonance imaging (MRI) delineated masses in the right gluteal and the left lower lumbar paraspinal regions. Five additional smaller masses were found in the abdomen and in the pelvis. Biopsy of the right gluteal mass revealed a GCT. However, we found that this lesion had several histologic features distinct from those of giant cell reparative granulomas or GCT. In our patient's tumor, the huge polykaryons, like osteoclasts, expressed abundant tartrate-resistant acid phosphatase activity, whereas those of GCRG lack this enzyme. Although the polykaryons in conventional GCTs and GCTs in PBD express tartrate-resistant acid phosphatase activity, the location of these tumors in bone differs from the extraskeletal masses encountered in our patient. Furthermore, the larger size of the polykaryons and the greater number of nuclei in our patient's GCT differ from conventional GCTs, but not GCTs in PBD. Her extraskeletal osteoclastoma rapidly shrunk to one third its original size during 2 weeks of oral dexamethasone treatment. Significant clinical improvement lasted about 5 months before additional courses of dexamethasone therapy were necessary. Injections of synthetic salmon calcitonin alone did not affect the tumor's size. Thus, PBD can be complicated by extraskeletal tumors that seem to contain osteoclasts and are responsive to dexamethasone treatment.

Bone Neoplasms↗
PubMed1996

Retinoic acid stimulates expression of the functional osteoclast integrin alpha v beta 3: transcriptional activation of the beta 3 but not the alpha v gene.

The capacity of osteoclasts to resorb bone depends, in part, on the surface expression of the integrin alpha v beta 3. We have investigated whether the steroid hormone retinoic acid, known to stimulate bone resorption, regulates the appearance of the alpha v beta 3 complex in avian osteoclast presursors. Using surface labeling, followed by immunoprecipitation with a alpha v beta 3-specific antibody, we show that retinoic acid increases surface expression of the heterodimer in a dose- and time-dependent manner. Northern analysis reveals that the high basal steady-state levels of alpha v mRNA do not change, while those for beta 3 rise significantly from their initially low levels. Nuclear run-on studies confirm that steroid treatment stimulates transcription of the beta 3, but not the alpha v gene. Osteoclast precursors treated with retinoic acid exhibit increased multinucleation and expression of the osteoclast marker enzyme tartrate-resistant acid phosphatase. However, the fused cells do not have an increased capacity to resorb bone. In summary, multinucleated cells generated in this study do not represent fully differentiated bone-resorbing polykaryons. These results suggest that treatment of osteoclast precursors with retinoic acid is necessary, but insufficient, for expression of the mature osteoclast phenotype.

Animals↗
PubMed1996

Competition for a unique response element mediates retinoic acid inhibition of vitamin D3-stimulated transcription.

We have identified a novel steroid hormone response element in the avian beta3 integrin promoter. This sequence, comprising three hexameric direct repeat half-sites separated by nine and three nucleotides binds vitamin D receptor (VDR)-retinoid X receptor (RXR) and retinoic acid receptor (RAR)-RXR heterodimers. VDR-RXR binds direct repeats separated by three base pairs, and RAR-RXR recognizes half-sites separated by nine bases, whereas the central half-site interacts with both heterodimers. Retinoic acid and 1, 25-dihydroxyvitamin D3 activate both a genomic fragment including the transcriptional start site and an oligonucleotide containing the three repeats, linked to a heterologous promoter. Co-addition of the steroids produces neither synergy nor an additive effect; rather the result equals that for retinoic acid alone. Scatchard analysis demonstrates that RAR-RXR has greater affinity than VDR-RXR for the composite element. Based on these findings we propose a model in which there is specific, polarity-defined binding of VDR-RXR and RAR-RXR to three half-sites, which form two overlapping steroid response elements, with the central half-site common to both. Our results identify a novel mechanism by which one steroid hormone can modulate the activity of a second, by competing for a shared half-site in a composite response element.

Animals↗
PubMed1996

Phorbol myristate acetate transactivates the avian beta 3 integrin gene and induces alpha v beta 3 integrin expression.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3)transactivates the avian beta 3 integrin gene whose promoter contains at least two vitamin D response elements, one of which is in close proximity to a candidate AP1 site (TGACTCA). Since fos/jun and steroid hormones interact to regulate gene expression, we asked whether phorbol-12-myristate-13-acetate (PMA), which stimulates binding of fos/jun to AP1 sites, transactivates the avian beta 3 integrin gene and, if so, does the phorbol ester modulate 1,25(OH)2D3 induction of the gene. We find the candidate AP1 sequence comigrates with the consensus AP1 sequence on electromobility shift assay when incubated with recombinant c-jun protein. Furthermore, PMA prompts expression of beta 3 integrin mRNA in the avian monocytic line, HD11. The increase in message reflects transactivation of the beta 3 gene and is mirrored by plasma membrane appearance of the integrin heterodimer alpha v beta 3. Moreover, attesting to the functional significance of PMA-enhanced alpha v beta 3 expression, cells treated with concentrations of the phorbol ester that induce the beta 3 gene, spread extensively on plastic, an event blocked by an anti-alpha v antibody and a peptide mimetic known to inhibit alpha v beta 3-mediated cell attachment. Interestingly, co-addition of 1,25(OH)2D3 and PMA prompts greater expression of alpha v beta 3 than when the cells are exposed to either agent alone and PMA enhances 1,25(OH)2D3-induced beta 3 integrin mRNA expression. Thus, PMA and 1,25(OH)2D3 impact on the avian beta 3 integrin gene independently and in combination.

Animals↗
PubMed1996

Juvenile Paget disease: life-long features of a mildly affected young woman.

Unusually mild Juvenile Paget Disease (JPD) was extensively investigated in a mentally retarded 21-year-old white woman. Progressive bowing deformitity of her lower limbs began at age 1 1/2 years. Nontraumatic fractures of both femora and both tibias occurred between ages 9 and 14 years. During adulthood, cortical thickening, osteosclerosis, and bowing affected these bones. Serum alkaline phosphatase (ALP) activity was persistently elevated. We found her serum osteocalcin and urinary hydroxyproline and pyridinoline/deoxypyridinoline to also be increased. The iliac crest histology, at ages 14 and 21 years, showed wide cortices and enhanced skeletal remodeling yet the bone was exclusively lamellar. Features of classic Paget Bone Disease (PBD)--such as hypermultinucleated osteoclasts, peritrabecular fibrosis, and mosaic or woven bone--were absent. Electron microscopy revealed no cytoplasmic or nuclear inclusions. Her dermal fibroblasts in culture synthesized unremarkable levels of ALP with proper membrane topography and lipid anchoring; ALP released into the medium also appeared normal. Six months of synthetic human calcitonin therapy daily appeared to reduce here lower limb pain and warmth, but the radiographs, biochemical parameters of skeletal turnover, and bone scintigraphy were unaltered. Lamellar bone has been reported in JPD but accompanied by excessive amounts of woven bone. Our patient reveals that lamellar bone without features of PBD can characterize the skeletal histopathology of the especially rare case of mild JPD.

Adult↗
PubMed1996

Doubling skeletal mass during adult life: the syndrome of diffuse osteosclerosis after intravenous drug abuse.

A former intravenous substance abuser, seropositive for hepatitis C virus infection, was referred for diffuse osteosclerosis. There was no history of fracture or skeletal deformity. Cortical and trabecular bone density was approximately twice the mean value for controls. Skeletal histology revealed dense lamellar bone. Recognized causes of acquired generalized osteosclerosis or hyperostosis were excluded. This patient verifies the syndrome of painful diffuse osteosclerosis after intravenous drug abuse and shows that skeletal mass can be markedly increased with histologically normal, structurally sound bone during adult life. Elucidation of the etiology and pathogenesis could offer an effective treatment for osteoporosis.

Absorptiometry, Photon↗
PubMed1995

Renal osteodystrophy.

Explore the source record for details and available documents.

Chronic Kidney Disease-Mineral and Bone Disorder↗
PubMed1995

Macrophage-colony-stimulating factor regulates expression of the integrins alpha 4 beta 1 and alpha 5 beta 1 by murine bone marrow macrophages.

We observed that when monocyte/macrophage precursors derived from murine bone marrow were treated with macrophage-colony-stimulating factor (M-CSF), there was a dose-dependent increase in both the number of adherent cells and the degree to which the cells were highly spread. Attachment was supported by fibronectin, but not by vitronectin or laminin, suggesting that the integrins alpha 4 beta 1 and/or alpha 5 beta 1 might mediate this event. Binding to fibronectin was blocked partially by antibodies to either integrin, and inhibition was almost complete when the antibodies were used in combination. By a combination of surface labeling with 125I and metabolic labeling with [35S]methionine and [35S]cysteine, we demonstrated that M-CSF treatment led to increased synthesis and surface expression of the two beta 1 integrins. Since attachment to fibronectin and/or stromal cells plays an important role in the maturation of other hematopoietic lineages, we propose that the action of M-CSF in the differentiation of immature monocytes/macrophages includes stimulated expression of the integrins alpha 4 beta 1 and alpha 5 beta 1, leading to interactions with components of the marrow microenvironment necessary for cell maturation.

Animals↗
PubMed1995

Interleukin-4 induces expression of the integrin alpha v beta 3 via transactivation of the beta 3 gene.

Osteoclastic bone resorption is dependent upon cell-matrix recognition. This process is mediated by the integrin alpha v beta 3 whose expression is enhanced, in avian osteoclast precursors, by bone-seeking steroids. The purpose of this study was to determine if bone-modulating cytokines impact on alpha v beta 3 expression by mouse marrow macrophages (BMMs), known to differentiate into osteoclasts. Of the cytokines tested. Interleukin-4 (IL-4) is most effective in increasing beta 3 mRNA levels by a mechanism involving transactivation of the beta 3 gene. Moreover, IL-4 augmented beta 3 mRNA is mirrored by plasma membrane appearance of alpha v beta 3. As IL-4 induces beta 3 and not alpha v mRNA, the beta 3 chain appears to regulate surface expression of the heterodimer. The functional significance of IL-4-induced alpha v beta 3 is underscored by the fact that, while attachment to fibronectin is unaltered, treatment of BMMs with the cytokine enhances alpha v beta 3-mediated binding to vitronectin 5-fold. Expression of this heterodimer by BMMs driven along a non-osteoclastic lineage suggests alpha v beta 3 may play a role in the inflammatory response of macrophages.

Animals↗
PubMed1995

Molecular mechanisms of bone resorption.

This review focuses on osteoclast ontogeny and function, emphasizing three aspects. We describe how a combination of laboratory models available to study the cell plus examination of the osteopetroses, a family of sclerotic diseases of the skeleton, have yielded major insights into osteoclast ontogeny and function. We proceed to describe the cell and molecular machinery enabling osteoclasts to resorb bone. The final, and most speculative, aspect of the review addresses possible mechanisms by which the osteoclast assumes its characteristic morphology, that of a polarized cell on bone. Since little direct information has been forthcoming as to how the osteoclast polarizes, we draw on other polarized cells. In particular, we examine the role of microtubules and members of the small GTPase family, the latter mediating polarized targeting of intracellular vesicles. In the case of the osteoclast, such vesicles probably represent the origin of the highly convoluted ruffled membrane, the cell's characteristic bone resorptive organ.

Animals↗
PubMed1995

Modulation of renal osteodystrophy by extrarenal production of calcitriol.

We report a patient with severe chronic renal failure who developed spontaneous bone fractures. He was found to have hypercalcemia, normal calcitriol levels (probably due to extrarenal production by noncaseating granulomas), and functional hypoparathyroidism. The bone biopsy showed low bone turn-over and the presence of noncaseating granulomas. Treatment with corticosteroids decreased the calcium and calcitriol levels and the parathyroid hormone levels rose. No further fractures occurred. A repeat bone biopsy revealed the presence of osteitis fibrosa. Renal osteodystrophy may be modulated by extrarenal production of calcitriol. In this case, excessive suppression of parathyroid hormone by endogenous calcitriol presumably caused an adynamic bone lesion and spontaneous fractures.

Adult↗
PubMed1995

1,25 dihydroxyvitamin D3 stimulates differentiation of committed murine bone marrow-derived macrophage precursor cells.

1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] and macrophage colony-stimulating factor (M-CSF) both accelerate differentiation of marrow macrophages from which osteoclasts are derived. Previously, we showed that the steroid's effect on early macrophage precursors may be mediated through M-CSF, as the steroid enhances cytokine receptor expression. In contrast, 1,25-(OH)2D3 blunts M-CSF receptor expression on more mature, yet still pluripotential, hematopoietic precursors. Extending these observations to marrow cells committed to macrophage differentiation, we found that 1,25-(OH)2D3 causes a marked decrease in cellular proliferation despite a 2- to 3-fold increase in [125I]M-CSF binding in a similar dose-dependent metabolite-specific manner. Scatchard analysis demonstrated that increased binding reflects increased receptor capacity without an alteration in affinity. Steroid-induced M-CSF receptor enhancement reflects acceleration of protein appearance rather than overexpression, as treated and untreated cells ultimately exhibit equivalent binding. Increased M-CSF receptor expression is mirrored by increased c-fms messenger RNA levels, and actinomycin D or cycloheximide experiments indicate that new receptor synthesis, rather than mobilization of intracellular pools, is required. Thus, 1,25-(OH)2D3 differentially impacts on M-CSF receptor expression throughout the spectrum of bone marrow macrophage differentiation.

Animals↗
PubMed1995

Interleukin 4, interferon-gamma, and prostaglandin E impact the osteoclastic cell-forming potential of murine bone marrow macrophages.

Interleukin 4 (IL-4) is an immune cytokine that inhibits bone resorption in mice and suppresses osteoclastic cell formation in vitro through an undefined mechanism. In this report, we have established the cellular identity of the IL-4 target cell using a variety of bone marrow/stromal cell coculture methods. Initially, we found that the majority of IL-4's inhibition of osteoclastic cell formation was due to its effect on bone marrow cells, not stromal cells. Consequently, bone marrow macrophages were used as osteoclastic cell progenitors after they had been transiently exposed to IL-4 (48 h), before the addition of stromal cells, 1,25-dihydroxyvitamin D3, and dexamethasone. In this circumstance, IL-4 impaired subsequent osteoclastic cell formation, suggesting that the macrophage may be potentially targeted by many factors known to influence osteoclast formation. Consequently, we discovered that interferon-gamma (IFN gamma), prostaglandin E (PGE), and cell-permeant cAMP analogs also impacted osteoclastic cell formation when used to selectively treat bone marrow macrophages. IFN gamma suppressed osteoclastic cell formation, whereas PGE and cAMP analog treatment led to the formation of significantly enlarged osteoclastic cells. Importantly, PGE antagonized the inhibitory effects of both IL-4 and IFN gamma on the osteoclastic cell-forming potential of bone marrow macrophages. Collectively, these findings establish bone marrow macrophages as osteoclastic cell precursors with the degree of their commitment to the osteoclast pathway sensitive to the effects of soluble mediators, including IL-4, IFN gamma, and PGE.

Animals↗
PubMed1995

Estrogen enhances alpha v beta 3 integrin expression by avian osteoclast precursors via stabilization of beta 3 integrin mRNA.

Although bone resorption is accelerated with menopause, the means by which diminished circulating 17 beta-estradiol (E2) promotes osteoclastic activity are unknown. We hypothesized that since the integrin alpha v beta 3 is essential to the resorptive process, reduced E2 levels may increase the integrin's expression by osteoclast precursors. Thus, avian osteoclast precursors (known to contain E2 receptors) were exposed +/- E2, surface iodinated, and lysed. The lysate was immunoprecipitated with an antibody recognizing the intact alpha v beta 3 heterodimer. We find E2 alone fails to impact on alpha v beta 3 expression. Most importantly, however, picomolar (i.e. post-menopausal), but not nanomolar (i.e. premenopausal) concentrations of E2, when added in conjunction with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], enhance alpha v beta 3 expression on the plasma membrane of avian osteoclast precursors relative to 1,25(OH)2D3 alone. Induction of alpha v beta 3 by picomolar levels of E2 is dose-dependent, maximizing at 10(-11)-10(-12) M, wherein the sex steroid enhances 1,25-(OH)2-D3-stimulated integrin expression approximately 2.5-fold. Northern analysis reveals that beta 3 mRNA levels parallel those of alpha v beta 3. E2 (10(-12) M) increases expression of beta 3 mRNA induced by a range of 1,25-(OH)2D3 concentrations extending from 10(-10) m-10(-8) M. The E2 + 1,25-(OH)2D3 additive effect on beta 3 mRNA appears as early as 1 day of treatment and progresses for at least 3 days. Consistent with evidence that the beta 3 subunit regulates heterodimer expression, the sex steroid does not impact alpha v mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗