Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basic fibroblast growth factor (bFGF) stimulates bone formation in vitro and in vivo. The purpose of this study was to determine changes in gene expression for bone matrix proteins, growth factors, and cytokines associated with the stimulatory effects of bFGF on bone formation in aged ovariectomized (ovx) rats. At 3 months of age, female Sprague-Dawley rats were sham-operated (sham) or ovariectomized (ovx), then maintained untreated for 1 year. At 15 months of age, baseline (BSL) sham and ovx rats were killed. All other rats received daily intravenous injections of bFGF (200 microg/kg) or vehicle (veh) for 14 days. Lumbar vertebrae were processed for quantitative bone histomorphometry or molecular analyses. Ovariectomy decreased vertebral cancellous bone volume by approximately 33% and increased most indices of bone turnover. Treatment of aged ovx rats with bFGF for only 14 days significantly increased cancellous bone volume compared with vehicle treatment of ovx rats, but this variable remained lower than in sham + veh rats. Osteoid volume, osteoblast surface, and osteoid surface were markedly increased, and osteoclast surface was significantly decreased in ovx + bFGF rats compared with sham + veh and ovx + veh rats. Northern analyses revealed that mRNA levels for osteocalcin and type I collagen, relative to 18S RNA, were significantly higher in ovx + bFGF rats than in ovx + veh rats by a factor of >10. RNase protection assays revealed that insulin-like growth factor (IGF-I) mRNA levels, relative to L32 housekeeping gene, were also significantly higher, by nearly a factor of 3, in ovx + bFGF rats than in ovx + veh rats. Treatment of ovx rats with bFGF did not appear to affect message levels for transforming growth factor-beta (TGF-beta), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma). These in vivo results suggest that bFGF treatment upregulates gene expression for IGF-I, which may mediate, at least in part, the increased gene expression for bone matrix proteins and the bone anabolic effects of bFGF in aged ovx rats.
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PMID:Changes in gene expression associated with the bone anabolic effects of basic fibroblast growth factor in aged ovariectomized rats. 1211 Apr 27

We have observed a strong correlation between circulating levels of both interleukin-6 (IL-6) and interleukin-6 soluble receptor (IL-6sR) and rates of bone turnover in patients with primary hyperparathyroidism. Furthermore, we have found that serum levels of IL-6sR predict rates of bone loss in postmenopausal women with this disease. Estrogen modulates parathyroid hormone (PTH)-induced increases in serum IL-6/IL-6sR, such that, in the estrogen-deficient state, there is an exaggerated release of these cytokines. We therefore propose that the perimenopausal period represents a time when skeletal sensitivity to the resorbing actions of PTH increases because of augmented release of IL-6 and IL-6sR. To test this hypothesis, we retrospectively examined data from 91 women with primary hyperparathyroidism who were seen over the last 5 years at our institution. Women were categorized, based on their age, as premenopausal (n = 20, 41 +/- 2 years), perimenopausal (n = 17, 54 +/- 1 years), or postmenopausal (n = 54, 64 +/- 1 years). Despite having similar mean values for PTH, perimenopausal women had a mean serum IL-6 value that was significantly higher than that in the premenopausal group (13 +/- 2 vs. 8 +/- 2 pg/ml; p = 0.03). This difference in cytokine profile was mirrored by higher mean values for urine N telopeptides of type I collagen (NTX) in the perimenopausal group compared with premenopausal women (114 +/- 9 vs. 80 +/- 11 nM bone collagen equivalents (BCE)/mM creatinine, p = 0.01). Of the three groups of patients, values for IL-6 and urine NTX were highest in the postmenopausal group. We conclude that the perimenopausal period may be a time of increased risk for the skeletal complications of hyperparathyroidism. This is because of increased skeletal sensitivity to the resorbing actions of PTH, mediated in part, by the IL-6/IL-6sR cytokine system.
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PMID:Role of the interleukin-6/interleukin-6 soluble receptor cytokine system in mediating increased skeletal sensitivity to parathyroid hormone in perimenopausal women. 1241 87

Adhesion of bone cells to the extracellular matrix is a crucial requirement for osteoblastic development and function. Adhesion receptors connect the extracellular matrix with the cyto-skeleton and convey matrix deformation into the cell. We tested the hypothesis that sex hormones modulate mechanoperception of human osteoblastic cells (HOB) by affecting expression of adhesion molecules like fibronectin and the fibronectin receptor. Only dihydrotestosterone (DHT), but not 17beta-estradiol, stimulated fibronectin (137%) and fibronectin receptor (252%) protein expression. The effects of deformation strain on HOB metabolism were investigated in a FlexerCell strain unit. Cyclically applied strain (2.5% elongation) increased DNA synthesis (125%) and interleukin-6 (IL-6) production (170%) without significantly affecting alkaline phosphatase (AP) activity, type I collagen (PICP), or osteoprotegerin (OPG) secretion. 10 nM DHT pretreatment abolished the mitogenic response of HOB to strain and increased AP activity (119%), PICP (163%), and OPG production (204%). In conclusion, mechanical strain stimulates bone remodeling by increasing HOB mitosis and IL-6 production. DHT enhances the osteoanabolic impact of deformation strain by increasing bone formation via increased AP activity and PICP production. At the same time, bone resorption is inhibited by decreased IL-6 and increased OPG secretion into the bone microenvironment.
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PMID:Concerted action of androgens and mechanical strain shifts bone metabolism from high turnover into an osteoanabolic mode. 1243 30

Silk fibroin (SF)-based or -coated biomaterials are likely to be endowed with structural and surface properties that render them particularly apt for biomedical applications. In this work we investigated the behavior of four different strains of normal human adult fibroblasts that had been seeded onto membranes made up of poly(carbonate) urethane (PCU), the surfaces of which had or had not been homogeneously coated with SF. Cell adhesion within 3h to the SF-coated PCU films was 2.2-fold that to their uncoated homologues. After 30 days of incubation in vitro, 2.5-fold more cells had grown on the SF-coated specimens than on the uncoated ones. This enhanced cell adherence and hence growth on the SF-coated surfaces was coupled with higher cumulative rates of D-glucose (but not L-glutamine) uptake and of both lactate and interleukin-6 (IL-6) cumulative secretion. Conversely, human fibroblasts cultured on either type of PCU scaffolds never secreted any ELISA-assayable amount of three main proinflammatory cytokines, namely interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1). Finally, when the metabolic activities were compared on a per 10(5) cells basis, it became clear that the adhesion to SF favored an initially higher consumption of D-glucose, a late higher release of IL-6, and an at-first more intense, but declining, extracellular assembly of type I collagen fibers. Overall, these results show that SF-coated PCU membranes represent a novel type of biomaterial that favors the adhesion, the growth and performance of specific metabolic tasks by normal human adult fibroblasts without eliciting any concurrent secretion of some of the chief proinflammatory cytokines.
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PMID:Silk fibroin/poly(carbonate)-urethane as a substrate for cell growth: in vitro interactions with human cells. 1248 97

Essential amino acids, such as L-Arginine (Arg) and L-Lysine (Lys), are involved in bone metabolism and growth. Our previous studies analyzed the effect of these amino acids on rat osteoblast cultures and in experimental animals. In this study, we evaluated the effect of L-Arg and L-Lys on cultured human osteoblasts. Primary human osteoblast cultures were divided into four groups: the Arg Group received 0.625 mg/ml per day of Arg, the Lys Group 0.587 mg/ml per day of Lys, the Arg-Lys Group received both amino acids, whereas the Control Group was sham-treated. After 7 days, the following parameters were tested in all groups: alkaline phosphatase (ALP), nitric oxide (NO), calcium (Ca), phosphorus (P), osteocalcin (OC), type I collagen (PICP), interleukin-6 (IL-6), transforming growth factor-beta 1 (TGF-beta 1) on culture supernatant, platelet derived growth factor (PDGF), insulin-like growth factor-I (IGF-I), and MTT proliferation test on cells. Arg administration significantly increased ALP, NO, PICP and IGF-I production and reduced the level of IL-6. Lys administration over the same time interval mainly affected cell proliferation, as evidenced by the MTT test and immunostaining for PDGF. The same positive effects evidenced by the single administrations of the two amino acids resulted from their simultaneous administration. However, synergism could be demonstrated only for the decrease in the level of IL-6. Arg and Lys show a positive effect on human osteoblasts, which is related partly to the production of those factors required for matrix synthesis, and partly to the direct or mediated activation of cell proliferation.
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PMID:L-arginine and L-lysine stimulation on cultured human osteoblasts. 1250 70

The interfollicular dermis of adult human skin is partitioned into histologically and physiologically distinct papillary and reticular zones. Each of these zones contains a unique population of fibroblasts that differ in respect to their proliferation kinetics, rates at which they contract type I collagen gels, and in their relative production of decorin and versican. Here, site-matched papillary and reticular dermal fibroblasts couples were compared to determine whether each population interacted with keratinocytes in an equivalent or different manner. Papillary and reticular fibroblasts grown in monolayer culture differed significantly from each other in their release of keratinocyte growth factor (KGF) and granulocyte-macrophage colony stimulating factor (GM-CSF) into culture medium. Some matched fibroblast couples also differed in their constitutive release of interleukin-6 (IL-6). Papillary fibroblasts produced a higher ratio of GM-CSF to KGF than did corresponding reticular fibroblasts. Interactions between site-matched papillary and reticular couples were also assayed in a three-dimensional culture system where fibroblasts and keratinocytes were randomly mixed, incorporated into type I collagen gels, and allowed to sort. Keratinocytes formed distinctive cellular masses in which the keratinocytes were organized such that the exterior most layer of cells exhibited characteristics of basal keratinocytes and the interior most cells exhibited characteristics of terminally differentiated keratinocytes. In the presence of papillary dermal fibroblasts, keratinocyte masses were highly symmetrical and cells expressed all levels of differentiation markers. In contrast, keratinocyte masses that formed in the presence of reticular fibroblasts tended to have irregular shapes, and terminal differentiation was suppressed. Furthermore, basement membrane formation was retarded in the presence of reticular cells. These studies indicate that site-matched papillary and reticular dermal fibroblasts qualitatively differ in their support of epidermal cells, with papillary cells interacting more effectively than corresponding reticular cells.
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PMID:Site-matched papillary and reticular human dermal fibroblasts differ in their release of specific growth factors/cytokines and in their interaction with keratinocytes. 1513 66

The study was made to evaluate bone turnover in systemic lupus erythematosus (SLE) patients undergoing long-term glucocorticoid therapy. Thirty-eight female patients with established SLE were compared with a control group consisting from 160 age-matched healthy women. Serum concentrations of proinflammatory cytokines: interleukin-1alpha, interleukin-6, tumor necrosis factor-alpha, granulocyte-macrophage colony stimulating factor (GM-CSF) and some biochemical markers of osteoporosis (osteocalcin, total and bone alkaline phosphatase, procollagen type I carboxyterminal propeptide, carboxyterminal telopeptides of type I collagen--CTx) were measured. Additionally, morning urine excretions of deoxypyridinoline and calcium/creatinin ratios were determined. The forearm densitometry (DXA) was performed in all patients. Bone mineral content (BMC) and bone mineral density (BMD) in the SLE group was not significantly different from the controls, and no relationship was found between the glucocorticoid exposure and the BMC/BMD. However, biochemical markers of bone resorption--CTx and calcium/creatinin ratio--were significantly increased in the patient group. Our results suggest that BMD/BMC is preserved in glucocorticoid-treated SLE patients despite accelerated bone turnover.
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PMID:The effect of long-term glucocorticoids on bone metabolism in systemic lupus erythematosus patients: the prevalence of its anti-inflammatory action upon bone resorption. 1536 31

Arg-gingipain (Rgp) and Lys-gingipain (Kgp) are Porphyromonas gingivalis cysteine proteinases implicated as major virulence factors in pathologies of periodontitis. We purified a 660-kDa cell-associated gingipain complex existing as a homodimer of two catalytically active monomers which comprises their catalytic and adhesin domains. Electron microscopy revealed that the complex was composed of a globular particle with a 10-nm external diameter possessing one or two electron-dense hole-like structures. Two-dimensional gel electrophoresis and immunoblot analyses revealed the association of lipopolysaccharide (LPS) with the catalytic domains and a hemagglutinin domain, Hgp44, of Rgp and Kgp in the complex. The complex significantly degraded human type I collagen and elastin and strongly disrupted viability of human gingival fibroblasts and umbilical vein endotherial cells with an efficiency which was higher than that of the monomeric gingipains. The native complex produced only a small amount of nitrogen dioxide, tumor necrosis factor alpha, and interleukin-6 by macrophages, whereas the heat-denatured complex resulted in increased production. Inhibition of the proteolytic activities of the gingipain complex did not up-regulate the cytokine production, indicating that the functional domains in LPS are structurally masked by the complex proteins. These results indicate the importance of the complex in evasion of host defense mechanisms as well as in host tissue breakdown.
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PMID:A functional virulence complex composed of gingipains, adhesins, and lipopolysaccharide shows high affinity to host cells and matrix proteins and escapes recognition by host immune systems. 1566 30

The etiology of primary osteoporosis in young and middle-aged men is unknown. We have studied osteoblast function in cells derived from men with idiopathic osteoporosis and in control cells from age-matched men with osteoarthrosis. Osteoblasts were isolated from transiliac bone biopsies. Osteoblast function was measured as vitamin D-stimulated osteocalcin production and production of cytokines and factors involved in osteoclast activation and bone formation. Cell proliferation was measured as (3)H-thymidine incorporation. Parathyroid hormone-related peptide (PTHrP) mRNA was measured using reverse-transcriptase polymerase chain reaction. In osteoporotic men, bone mineral density at the femoral neck was correlated to in vitro production of osteocalcin. Osteoblasts from osteoporotic men produced significantly less osteocalcin after vitamin D stimulation but had increased production of macrophage colony-stimulating factor (M-CSF) compared to controls. The osteocalcin response was negatively correlated to production of M-CSF, interleukin-6, and C-terminal propeptide of type I collagen. Basal (3)H-thymidine incorporation was similar in cells from osteoporotic patients and controls. PTHrP (10(-9 )M) significantly increased cell proliferation in control cells but not in osteoporotic cells. Basal PTHrP mRNA levels were significantly higher in osteoporotic cells than in cells from controls. The results are in agreement with previous histomorphologic studies indicating that men with idiopathic osteoporosis have an osteoblast dysfunction with decreased osteocalcin production and increased production of factors stimulating osteoclast activation. This indicates a catabolic cellular metabolic balance leading to negative bone turnover, resulting in osteoporosis. The cause of such cellular dysfunction needs further evaluation.
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PMID:Osteoblast dysfunction in male idiopathic osteoporosis. 1646 76

4-Hydroxynonenal (HNE), a lipid peroxidation end product, is produced abundantly in osteoarthritic (OA) articular tissues, but its role in bone metabolism is ill-defined. In this study, we tested the hypothesis that alterations in OA osteoblast metabolism are attributed, in part, to increased levels of HNE. Our data showed that HNE/protein adduct levels were higher in OA osteoblasts compared to normal and when OA osteoblasts were treated with H2O2. Investigating osteoblast markers, we found that HNE increased osteocalcin and type I collagen synthesis but inhibited alkaline phosphatase activity. We next examined the effects of HNE on the signaling pathways controlling cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) expression in view of their putative role in OA pathophysiology. HNE dose-dependently decreased basal and tumour necrosis factor-alpha (TNF-alpha)-induced IL-6 expression while inducing COX-2 expression and prostaglandin E2 (PGE2) release. In a similar pattern, HNE induces changes in osteoblast markers as well as PGE2 and IL-6 release in normal osteoblasts. Upon examination of signaling pathways involved in PGE2 and IL-6 production, we found that HNE-induced PGE2 release was abrogated by SB202190, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Overexpression of p38 MAPK enhanced HNE-induced PGE2 release. In this connection, HNE markedly increased the phosphorylation of p38 MAPK, JNK2, and transcription factors (CREB-1, ATF-2) with a concomitant increase in the DNA-binding activity of CRE/ATF. Transfection experiments with a human COX-2 promoter construct revealed that the CRE element (-58/-53 bp) was essential for HNE-induced COX-2 promoter activity. However, HNE inhibited the phosphorylation of IkappaBalpha and subsequently the DNA-binding activity of nuclear factor-kappaB. Overexpression of IKKalpha increased TNF-alpha-induced IL-6 production. This induction was inhibited when TNF-alpha was combined with HNE. These findings suggest that HNE may exert multiple effects on human OA osteoblasts by selective activation of signal transduction pathways and alteration of osteoblastic phenotype expression and pro-inflammatory mediator production.
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PMID:Alterations of metabolic activity in human osteoarthritic osteoblasts by lipid peroxidation end product 4-hydroxynonenal. 1704 56


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