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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines and growth factors are important in bone tissue as mediators of cell-to-cell and matrix-to-cell communication. Cytokines also locally mediate the effects of several hormones on bone cells. Indeed, calciotropic hormones modulate the bone-cell production rate of these factors and, conversely, can change the number of receptors for these hormones on bone cells. Most cytokines are active in bone, but the existence of a bone-specific cytokine is still questioned. Recent work has searched for estradiol modulation of osteoblastic cytokine acting on osteoclast differentiation. In mice, increased interleukin-6 production by osteoblasts is responsible for increased bone resorption occurring after ovariectomy. Interleukin-6 could also be an autocrine or paracrine factor in the pathogenesis of increased resorption occurring in giant cell tumor or in Paget's disease. During osteoporosis and age-related bone changes, modifications of the production of insulin-like growth factor I or of one of its binding proteins could be responsible for low bone formation. Interrelationships between cytokines and hormones can affect the action of parathyroid hormone-related peptide on bone cells. The field of implication of cytokines in metabolic bone disease is growing.
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PMID:Bone cytokines. 851 70

Parathyroid hormone and other agents that stimulate bone resorption function, at least in part, by inducing osteoblasts to secrete cytokines that stimulate osteoclast differentiation and activity. We previously demonstrated that parathyroid hormone induces expression by osteoblasts of interleukin-6 and leukemia inhibitory factor without affecting the 16 other cytokines that were examined. We also showed that stimulation of osteoclast activity by parathyroid hormone is dependent on activation of the cAMP signal transduction pathway and secretion of interleukin-6 by osteoblasts. In the current study, we demonstrate that the rapid and transient stimulation of interleukin-6 and leukemia inhibitory factor is inhibited by actinomycin D and superinduced by protein synthesis inhibitors, the classical characteristics of an immediate-early gene response. Moreover, activation of cAMP signal transduction by parathyroid hormone and parathyroid hormone-related protein is necessary and sufficient to induce both interleukin-6 and leukemia inhibitory factor. In addition, cAMP analogues as well as vasoactive intestinal peptide and isoproterenol, two neuropeptides that stimulate bone resorption by activating cAMP signal transduction in osteoblasts, also induce interleukin-6 and leukemia inhibitory factor in these cells. Taken together with our previous results, this study suggests that interleukin-6 is crucial for stimulation of bone resorption not only by parathyroid hormone, but also by parathyroid hormone-related protein, vasoactive intestinal peptide, and beta-adrenergic agonists, like isoproterenol.
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PMID:Stimulation by parathyroid hormone of interleukin-6 and leukemia inhibitory factor expression in osteoblasts is an immediate-early gene response induced by cAMP signal transduction. 863 18

The mechanism of bone loss following cessation of ovarian function is still unclear. Several studies have shown an increase in bone turnover following natural or surgical menopause which could be prevented by estrogen administration. However, a direct effect of estrogen on osteoclast-mediated bone resorption has been difficult to demonstrate in vitro. Recent evidence suggested that estrogen withdrawal stimulates the production of bone resorbing cytokines, (e.g., interleukin-6, IL-6), which regulate osteoclast formation in the bone marrow microenvironment. We studied the effects of 17beta-estradiol on osteoclastic resorption, measured as 45calcium release, in vitro using cultures of fetal mouse long bone explants in which different stages of osteoclast development and activity are represented. 17beta-estradiol (10(-12)-10(-8) M) had no effect on basal or parathyroid hormone (PTH)-stimulated resorption of bone explants in which mature osteoclasts (radii/ulnae) or osteoclast precursors/progenitors (metacarpals) are present. 17beta-estradiol, however, inhibited significantly the PTH-stimulated resorption of osteoclast-free metacarpals cultured together with mouse fetal liver as a source of early osteoclast progenitors; basal resorption was also not inhibited in this system. In ex vivo studies we further examined the effects of culturing bone marrow cells from ovariectomized (OVX) or sham-operated mice as an osteoclastic source together with osteoclast-free metacarpals on 45calcium release and bone histology. Cocultures of the bone marrow cells from OVX mice with osteoclast-free metacarpals increased significantly the osteoclast formation and subsequent osteoclastic resorption compared with control cocultures. This increase in resorption was prevented by either treatment of the OVX animals with estrogen for 1 week starting immediately after OVX or injection of the OVX animals with an IL-6 neutralizing antibody. We conclude that estrogens suppress the increased osteoclastic resorption induced by PTH or OVX through an effect on hematopoietic progenitor cells of the osteoclast lineage. Furthermore our data suggest that IL-6 is involved in the increase in osteoclastic resorption following OVX.
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PMID:In vitro and ex vivo evidence that estrogens suppress increased bone resorption induced by ovariectomy or PTH stimulation through an effect on osteoclastogenesis. 868 8

Interleukin-6 (IL-6) is produced by bone cells and has been shown to stimulate the proliferation of osteoclast progenitors. Which cells in bone produce IL-6 is controversial. This article tests the hypothesis that tartrate-resistant acid phosphatase-positive osteoclasts (TRAP + OC) in neonatal mouse parietal bones are the major source of IL-6. Bones were preincubated with indomethacin to decrease the number of TRAP + OC and the amount of IL-6 produced. Incubation with parathyroid hormone or prostaglandin E2 increased the number of TRAP + OC and the amount of IL-6 produced. Calcitonin and 17 beta-estradiol inhibited this increase in TRAP + OC but had no effect on IL-6 production. 1,25-dihydroxy-vitamin D3 also stimulated an increase in TRAP + OC number but did not cause increased IL-6 production. Both the endocranial and ectocranial membranes of these bones produced large amounts of IL-6. TRAP activity in extracts of endocranial membranes was 14-fold that of the ectocranial membrane and, histochemically, some TRAP + cells could be detected here. However, the ectocranial membranes produced more IL-6 than the endocranial membranes. We conclude that TRAP + OC are not a major source of IL-6 in this system.
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PMID:Osteoclasts are not the major source of interleukin-6 in mouse parietal bones. 870 76

We have previously reported that parathyroid hormone (PTH) and PTH related protein (PTHrP) stimulate expression of interleukin-6 (IL-6) and leukemia inhibitory factor (LIF) in osteoblasts in vitro. In the current study, we have developed a model of hormone injection into the subcutaneous space overlying mouse parietal bones to demonstrate that similar processes occur in osteoblasts in vivo. Specifically, PTH and PTHrP rapidly and transiently induce expression of the mRNAs encoding IL-6 and LIF. The effects are dose-dependent, with a maximal stimulation of approximately 50-fold for each cytokine. Although PTH and PTHrP activate both adenyl cyclase and phospholipase C-dependent signal transduction pathways, stimulation of IL-6 and LIF depends on adenyl cyclase since it is not reproduced by PTH(3-34), a partial agonist that only activates phospholipase C. These results confirm our previous in vitro studies and support the hypothesis that IL-6 and/or LIF are physiologically important mediators of at least some of the actions of PTH and PTHrP.
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PMID:In vivo demonstration that parathyroid hormone and parathyroid hormone-related protein stimulate expression by osteoblasts of interleukin-6 and leukemia inhibitory factor. 872 72

We examined the roles of interleukin-1 Type I receptor (IL-1R1) and tumor necrosis factor receptor 1 (TNFR1) in bone metabolism using mice rendered deficient in these receptors by gene targeting. Sections of decalcified paraffin-embedded calvariae and humeri from 11- to 12-week-old mice deficient in IL-1 Type I receptor (IL-1R1-/-) or TNF receptor 1 (TNFR1-/-) were examined by histomorphometry. Wild-type mice (C57BL/6J x 129/J, WILD) served as controls. Interleukin-6 (IL-6) production in primary osteoblastic and bone marrow stromal cell cultures in response to parathyroid hormone (PTH, 100 ng/ml), IL-1 alpha (10 ng/ml), and TNF-alpha (10 ng/ml) was also examined. IL-1R1-/- and TNFR1-/- mice were viable and appeared phenotypically normal. However, the body weights of the IL-1R1-/- mice were 30% less than WILD, while the TNFR1-/- mice weighed 30% more than WILD mice of equivalent age. Calvariae and humeri of IL-1R1-/- and TNFR1-/- mice were normal with respect to trabecular bone volume, osteoclast number, osteoclast surface, growth plate widths, and cortical thickness. Receptor deficiency was confirmed by determining the ability of PTH, IL-1 alpha, and TNF-alpha to stimulate IL-6 in the media of primary calvaria-derived osteoblastic cell cultures from CD-1 and cytokine receptor-deficient mice. After 24 h of treatment, IL-1 alpha and TNF-alpha did not stimulate IL-6 production in osteoblasts from IL-1R1-/- and TNFR1-/- mice, respectively. In contrast, PTH increased IL-6 levels in the cells from all mice. IL-6 protein levels in bone marrow supernatants and conditioned media from untreated bone marrow stromal cells were undetectable in WILD, IL-1R1-/-, and TNFR1-/- mice. PTH, IL-1 alpha and TNF-alpha increased IL-6 mRNA and protein production in the WILD bone marrow stromal cells. In contrast, PTH and TNF-alpha increased IL-6 mRNA and protein levels in IL-1R1-/- bone marrow stromal cells while IL-1 alpha had no effect. These findings demonstrate that normal bone development in mice can occur in the absence of IL-1R1 or TNFR1 expression.
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PMID:Interleukin-6 expression and histomorphometry of bones from mice deficient in receptors for interleukin-1 or tumor necrosis factor. 891 81

In 70 patients with stage III multiple myeloma (MM) the authors studied spontaneous and lipopolysaccharide-induced production of interleukin-1 (IL-1) and interleukin-6 (IL-6) by blood and bone marrow mononuclear cells, concentration of parathyroid hormone and vitamin D3 in the serum. Bone marrow density was measured at photon absorption (Gambro), in patients treated with osteoprotectors bonefos and oxidevit before and after therapy (3.5-6 month course). It is shown that in MM there is a pathogenetic association between production of osteotropic IL-1, IL-6 and bone demineralization. The cases with reduced concentration of Ca and P ions in the serum (4 and 5.7% of patients, respectively) and increased PTH concentration (7%) suggest the existence of new, extratumor mechanisms of osteolysis. It is found that biphosphonates are optimal osteoprotectors. Bonefos (chlodronat, Lieras, Finland) arrests osteolysis proved by a significant increase of bone marrow density and clinical effect.
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PMID:[The extratumor mechanisms of osteolysis in multiple myeloma and the means for their correction]. 892 74

Interleukin-6 (IL-6) is known to enhance osteoclast recruitment, and thereby bone resorption. Thus, IL-6 has been proposed to mediate hypercalcemia in multiple myeloma and the enhanced osteoclastic activity seen in postmenopausal osteoporosis. We recently reported that the calcium concentration in plasma affects IL-6 secretion from mononuclear blood cells. To investigate the underlying mechanism, we have studied the effect of calcium on IL-6 formation in mononuclear blood cells ex vivo and in vitro. Thirteen healthy volunteers were given 1 g of calcium orally after overnight fasting. Plasma levels of ionized calcium (pCa2+) and serum levels of parathyroid hormone (sPTH) were measured after 2 and 4 h, with all subjects still fasting. After 2 h, pCa2+ was increased and sPTH decreased in all 13 persons. IL-6 secretion ex vivo from mononuclear blood cells drawn 4 h after calcium intake was increased 185% as compared with IL-6 secretion from cells drawn just before calcium intake. In control experiments without calcium intake, there was no alteration in pCa2+ and no effect on IL-6 secretion from mononuclear blood cells. In vitro studies revealed that stimulation of isolated mononuclear blood cells with physiological concentrations of calcium dose-dependently increased IL-6 secretion with an estimated EC50 at 1.2 mM Ca2+. No effect on the IL-6 secretion was seen following treatment of the isolated mononuclear blood cells with PTH or calcitonin. These observations demonstrate that the plasma calcium concentration affects IL-6 secretion from mononuclear blood cells. The in vitro data indicate the involvement of a direct calcium sensing mechanism. These findings might have implications in hypercalcemia and should also be borne in mind when considering the role of cytokines in osteoporosis.
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PMID:Regulation of interleukin-6 secretion from mononuclear blood cells by extracellular calcium. 904 Oct 54

Osteoblasts are established targets of estrogen action in bone. We screened 66 conditionally immortalized clonal human osteoblast cell lines for estrogen receptors (ERs) using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis for ER alpha mRNA and transactivation of adenovirus-estrogen response element (ERE)-tk-luciferase by 17 beta-estradiol (17 beta-E2) for functional ER protein. One of these cell lines, termed HOB-03-CE6, was chosen for further characterization. The cells, which were conditionally immortalized with a temperature-sensitive SV40 large T antigen, proliferated at the permissive temperature (34 degrees C) but stopped dividing at the nonpermissive temperature (> or = 39 degrees C). Alkaline phosphatase activity and osteocalcin secretion were upregulated by 1 alpha, 25-dihydroxyvitamin D3 in a dose-dependent manner. The cells also expressed type I collagen and other bone matrix proteins, secreted a variety of growth factors and cytokines, formed mineralized nodules based on alizarin red-S and von Kossa histochemical staining, and responded to dexamethasone, all-trans retinoic acid, and transforming growth factor-beta 1. This cell line expressed 42-fold less ER message than MCF-7 human breast cancer cells, as determined by quantitative RT-PCR. However, adenovirus-ERE-tk-luciferase activity was upregulated three- to fivefold in these cells by 17 beta-E2 with an EC50 of 64 pM. Furthermore, this upregulation was suppressed by co-treatment with the anti-estrogen ICI-182, 780. Cytosolic extracts of these cells specifically bound [125I]-17 beta-E2 in a concentration-dependent manner with a Bmax of 2.7 fmoles/mg protein (approximately 1,200 ERs/cell) and a Kd of 0.2 nM. DNA gel-shift analysis using a [32P]-ERE demonstrated the presence of ERs in nuclear extracts of these cells. Moreover, binding of the extracts to this ERE was blocked by a monoclonal antibody to the human ER DNA-binding domain. We evaluated these cells for 14 of 20 reported endogenous responses to 17 beta-E2 in osteoblasts. Although most of these responses appeared to be unaffected by the steroid, 17 beta-E2 suppressed parathyroid hormone-induced cAMP production, as well as basal interleukin-6 mRNA expression; conversely, the steroid upregulated the steady-state expression of alkaline phosphatase message in these cells. In summary, we have identified a clonal, conditionally phenotypic, human osteoblast cell line that expresses functional ERs and exhibits endogenous responses to 17 beta-E2. This cell line will be a valuable in vitro model for exploring some of the molecular mechanisms of estrogen action in bone.
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PMID:Functional properties of a conditionally phenotypic, estrogen-responsive, human osteoblast cell line. 913 93

Previous studies have suggested that increased secretion of bone active cytokines, such as interleukin-6 (IL-6) and interleukin-11 (IL-11), from osteoblasts and stromal cells play a pivotal role in the activation of osteoclasts and the genesis of osteoporosis. Various systemic and local factors can stimulate IL-6/IL-11 production, but the intracellular mechanism for such stimulation is largely unknown. In this study, we characterized the second messenger signaling in parathyroid hormone (PTH)- and IL-1-induced production of IL-6/IL-11 and studied the possible modulating effects of estrogen. rhPTH(1-34) and rhIL-1 alpha dose-dependently stimulated IL-6 and IL-11 production from human bone marrow stromal cells (hBMSCs). Agonists for protein kinase A (PKA) (forskolin), and protein kinase C (PKC) (phorbol 12-myristate 13-acetate; PMA) also stimulated IL-6/IL-11 production. Rp-diastereoisomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS) and H-8, inhibitors of PKA, significantly inhibited PTH-stimulated IL-6/IL-11 production, but did not inhibit IL-1-stimulated IL-6/IL-11 production. In contrast, staurosporine and calphostin C, inhibitors of PKC, suppressed IL-1-stimulated, but not PTH-stimulated, IL-6/ IL-11 production. Pretreatment of cells with 17 beta-estradiol (17 beta-E2) antagonized IL-1-stimulated IL-6 production. However, PTH-stimulated IL-6 production and IL-1- and PTH-stimulated IL-11 production were not affected by 17 beta-E2. Similarly, 17 beta-E2 inhibited PMA-stimulated IL-6 production, whereas neither forskolin-stimulated IL-6/ IL-11 production nor PMA-stimulated IL-11 production was affected by 17 beta-E2. These results indicate that different second messengers are involved in PTH- and IL-1-induced IL-6 and IL-11 production by hBMSCs: PTH and IL-1 stimulate IL-6/IL-11 production via a PKA-dependent and PKC-dependent pathway, respectively. Furthermore, our results suggest that regulation of cytokine production by estrogen in hBMSCs is selective; only the IL-1-induced IL-6 production, which is mediated by PKC pathway, is inhibited, but PTH-induced IL-6 production and PTH/IL-1-induced IL-11 production are not inhibited by estrogen.
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PMID:Involvement of different second messengers in parathyroid hormone- and interleukin-1-induced interleukin-6 and interleukin-11 production in human bone marrow stromal cells. 916 47


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