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S Meghji

Publications and source records attributed to S Meghji.

At least 19 recordsLinked to original sources
PubMed1995

Surface-associated proteins from Staphylococcus aureus demonstrate potent bone resorbing activity.

Staphylococcus aureus infections are associated with rapid bone destruction in conditions such as osteomyelitis, bacterial arthritis, and infected orthopedic implant failure. How this bacterium induces bone destruction has not been defined. In studies of the role of oral Gram-negative bacteria in periodontal pathology, we have established that cell surface-associated proteins (SAPs) are potent stimulators of bone resorption. The surface-associated components from S. aureus have now been isolated and demonstrated to be extremely potent stimulators of bone resorption in the murine calvarial bone resorption assay. Bone resorption appears to be due to proteins, is not the result of contamination with lipoteichoic acid or muramyl dipeptide, and is potently inhibited by indomethacin and can be completely blocked by high concentrations of interleukin-1 receptor antagonist or TN3-19.12, a neutralizing monoclonal antibody to murine TNF. The SAP fraction can stimulate fibroblasts or monocytes to release osteolytic cytokines, but only at high concentrations. Fractionation of the SAPs by high performance liquid chromatography demonstrated that a number of fractions were osteolytically active. The most active contained a heterodimeric protein of molecular weight 32-36 kD. The presence of this osteolytically active surface-associated fraction may account for the bone resorption associated with local infection with S. aureus.

Animals↗
PubMed1995

Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.

Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recently, however, there have been reports that these compounds can exert actions other than those normally associated with protein gamma-carboxylation. These observations suggest that naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts. Compounds examined in this study include: phylloquinone (K1), menaquinone-4 (K2), menadione (K3), 2,3-dimethoxy-1,4-naphthoquinone (DMK) and a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT). All of these compounds are capable of inhibiting IL-6 production with a rank order of potency: KCAT > K3 > DMK > K2 > K1. The most potent compound, KCAT, inhibited IL-6 production with an IC50 of 3 x 10(-7)M. The mechanism of action of these naphthoquinones on fibroblast IL-6 production is unknown. Given that K3 and KCAT are inactive in the gamma-carboxylation reaction, we suggest that this activity is not essential for the inhibition of IL-6 production and that activity may be related to the redox capacity of these naphthoquinones.

Cells, Cultured↗
PubMed1995

Serum antibody response to surface-associated material from periodontopathogenic bacteria.

Saline extracts of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and Eikenella corrodens contain surface-associated components of these bacteria. It has been shown that these extracts are potent stimulators of bone resorption in vitro. The possibility that the components of these surface-associated materials (SAM) could contribute to the serum immune response in patients with juvenile or adult onset forms of rapidly progressive periodontitis were investigated by direct binding ELISA. Very high titres of serum IgG antibodies to SAM from A. actinomycetemcomitans were detected in patients with localized juvenile periodontitis (LJP). Patients with adult onset rapidly progressive periodontitis (RPP) had significantly raised antibody levels to SAM from P. gingivalis. Both groups of patients had significantly raised levels of antibodies to SAM from E. corrodens compared with control sera. Thus, not only does solubilized SAM have the capacity to induce bone resorption, but it also contributes to the antigenic load on the immune system in LJP and RPP.

Adult↗
PubMed1995

Lipid A-associated proteins from periodontopathogenic bacteria induce interleukin-6 production by human gingival fibroblasts and monocytes.

The aim of this study was to determine whether lipid A-associated proteins (LAP) from two periodontopathogenic species of bacteria were able to stimulate interleukin-6 (IL-6) release from human gingival fibroblasts and myelomonocytic cells. LAP and lipopolysaccharide (LPS) were extracted from Porphyromonas gingivalis and Prevotella intermedia and added to cultures of human gingival fibroblasts and mono-mac-6 monocytic cells. Release of IL-6 into the culture supernatants was determined by ELISA. LAP and LPS from Por. gingivalis, but not from Prev. intermedia, stimulated IL-6 release from both cell types in a dose-dependent manner although LPS was less potent than LAP in inducing IL-6 release from the fibroblasts. IL-6 was detectable in cultures of both cell types following stimulation with LAP from Por. gingivalis at a concentration as low as 10 ng/ml. In response to LAP from Prev. intermedia, IL-6 was produced by mono-mac-6 cells but not by fibroblasts. Our results show that bacterial cell wall components other than LPS can induce IL-6 release from cells of the periodontium in vitro. The production of such potent immunomodulatory agents in vivo may contribute to the connective tissue breakdown characteristic of chronic periodontitis.

Bacterial Proteins↗
PubMed1995

Comparison of the osteolytic activity of surface-associated proteins of bacteria implicated in periodontal disease.

OBJECTIVES: To compare the osteolytic activity of surface-associated material (SAM) and lipid A-associated proteins (LAPs) from periodontopathogenic bacteria. MATERIALS AND METHODS: Surface-associated material was extracted from the surface and LAPs from the cell walls of a range of periodontopathic bacteria including Actinobacillus actinomycetemcomitans and Eikenella corrodens. These bacterial fractions were assayed to determine their composition and their capacity to induce bone resorption was determined by use of the neonatal murine calvarial bone resorption assay. RESULTS: The SAMs from E. corrodens and A. actinomycetemcomitans demonstrated bone-resorbing capacity at concentrations as low as 1 ng ml-1 which, given the molecular weights of the active components, is in the picomolar range of activity. In contrast, the SAMs from the other three bacteria were significantly less potent and showed a lower efficacy. The LAPs all showed significant, and similar, capacities to induce bone breakdown. CONCLUSIONS: This is the first demonstration that LAP from periodontopathic bacteria can stimulate bone degradation. The LAPs from diverse bacteria all produced similar levels of bone-resorbing activity. In contrast, the SAM showed significant differences in potency and in efficacy (maximal stimulation). This may mean that in vivo certain periodontopathic bacteria have significantly more bone-resorbing capacity than others and should be therapeutic targets.

Aggregatibacter actinomycetemcomitans↗
PubMed1995

The potent bone-resorbing mediator of Actinobacillus actinomycetemcomitans is homologous to the molecular chaperone GroEL.

Actinobacillus actinomycetemcomitans is a Gram-negative bacterium implicated in the pathology of localized juvenile periodontitis, a condition involving rapid destruction of alveolar bone. We have established that gentle extraction of this bacterium in saline releases a proteinaceous fraction (which we have termed surface-associated material [SAM] which has potent osteolytic activity in the murine calvarial bone resorption assay. Fractionation of the SAM has now revealed that activity is associated with a 62-kD protein. This bone-resorbing activity can be blocked by a monoclonal antibody (raised to the whole bacterium) that is claimed to recognize a protein homologous to the Escherichia coli molecular chaperone GroEL. Purification of this bone-resorbing protein to homogeneity has been achieved by a combination of anion exchange, gel filtration, and ATP-affinity chromatography and the NH2-terminal sequence shows > 95% homology to E. coli GroEL. This GroEL homologue is found in the SAM of A. actinomycetemcomitans but is not found in the osteolytically active SAM from other Gram-negative or Gram-positive bacteria. The GroEL protein from E. coli, but not from Mycobacterium tuberculosis and Mycobacterium leprae, also showed activity in the bone resorption assay. We believe this to be the first observation that a molecular chaperone has the capacity to stimulate the breakdown of connective tissue.

Aggregatibacter actinomycetemcomitans↗
PubMed1993

Immunocytochemical localization of inflammatory cytokines and vascular adhesion receptors in radicular cysts.

Odontogenic cysts are one of the commonest bone destroying lesions of the maxillofacial skeleton, with the inflammatory radicular cyst being the commonest jaw cyst. Explants of radicular cysts produce an interleukin-1-like activity which could explain the osteolysis seen with these tumours though the cellular source of this osteolytic activity is unknown. In the present study, cytokines with known inflammatory and osteolytic activity: interleukin-1 (IL-1), tumour necrosis factor (TNF), interleukin-6 (IL-6), and the chemotactic cytokine interleukin-8 (IL-8) have been localized immunocytochemically in radicular cysts. The cellular adhesion receptors ICAM-1 and ELAM-1 have also been immunolocalized. All specimens showed positive staining for IL-1 (alpha and beta) and IL-6, with these cytokines being located in epithelial and vascular endothelial cells. Only two specimens demonstrated TNF and IL-8 staining, which was located in macrophages. All specimens demonstrated ELAM-1 staining in endothelium and ICAM-1 staining in epithelium, endothelium and mononuclear cells. These findings show that radicular cysts contain two bone-modulating cytokines, IL-1 and IL-6, and that these appear to be synthesized mainly by the epithelial cells. Cysts also contain a proportion of activated blood vessels whose endothelial cells express the cellular adhesion receptors ICAM-1 and ELAM-1.

Alveolar Bone Loss↗
PubMed1992

Bone remodelling.

Bone is a specialised connective tissue that, together with cartilage, makes up the skeleton. These tissues serve three functions: (a) mechanical support and site of muscle attachment for locomotion; (b) protection for vital organs and bone marrow and (c) a metabolic reserve of ions for the entire organism, especially calcium and phosphate. The fundamental constituents are the cells and a calcified extracellular matrix. The latter is particularly abundant and is composed of collagen fibres and a ground substance rich in glycosaminoglycans. The osteoclasts and osteoblasts have evolved to regulate the growth and turnover of bone and mediate ion fluxes between the bone and blood. The osteoclasts solubilise the mineralised organic matrix, and the osteoblasts are capable of forming bone and synthesising the various structural proteins and growth factors. Except during growth, a balance between bone resorption and formation is maintained. The activities of the bone formation and resorbing cells are regulated by local and systemic humoral factors, such as parathyroid hormone, cytokines, 1,25,dihydroxy vitamin D3 and the eicosanoids. Any dysfunction of either the local or systemic regulatory systems will lead to pathological changes in the rate of bone formation or resorption and ultimately a clinical disease of the skeleton.

Bone Remodeling↗
PubMed1992

Interleukin-1: the principal osteolytic cytokine produced by keratocysts.

Fragments of keratocysts removed at operation were maintained in explant culture and the media were assayed for the biological activity of the potent osteolytic cytokines--interleukin (IL)-1, interleukin (IL)-6 and tumour necrosis factor (TNF). Media were also assayed for their ability to stimulate bone resorption. All six cysts examined released IL-1 and IL-6 bioactivity but TNF bioactivity was unmeasurable. Dialysed cyst media stimulated bone resorption and this could be completely inhibited by a monospecific antibody which neutralized IL-1 alpha and IL-1 beta. Immunohistochemical staining of cryostat sections of keratocysts revealed the presence of IL-1 alpha and IL-6 in cyst epithelial cells but not in other cell types. Sections did not react with antibodies to IL-1 beta or TNF. It is therefore proposed that IL-1 alpha is the major osteolytic cytokine produced by keratocysts and that IL-6 and IL-1 may contribute to keratocyst growth by promoting epithelial cell proliferation and bone resorption, respectively.

Adult↗
PubMed1992

Anti-proliferative and cytotoxic activity of surface-associated material from periodontopathogenic bacteria.

The easily solubilized surface-associated material from three bacterial species associated with periodontal diseases, Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and Eikenella corrodens, produced dose-dependent inhibition of thymidine incorporation by human fibroblasts, the human monocytic cell line U937 and guinea pig epidermal cells. In contrast, lipopolysaccharides from A. actinomycetemcomitans and P. gingivalis were either inactive or substantially less active over the dose range tested. One of the constituents of surface-associated material from a 'non-leucotoxic' strain of A. actinomycetemcomitans was highly cytotoxic to human peripheral blood polymorphonuclear cells, with 50% killing from less than 1 ng/ml. A constituent of the surface-associated material from P. gingivalis was approximately one log order less active. The lipopolysaccharides from these bacteria were at least three log orders less active in neutrophil killing. These findings add weight to the hypothesis that easily solubilized exopolymers from periodontopathogens play a major part in the pathology of periodontal diseases.

Aggregatibacter actinomycetemcomitans↗
PubMed1992

Stimulation of bone collagen and non-collagenous protein synthesis by products of 5- and 12-lipoxygenase: determination by use of a simple quantitative assay.

The influence of 5- and 12-lipoxygenase products on the rate of collagen and non-collagenous protein (NCP) synthesis by murine calvarial explants has been investigated using a new assay based on the resistance of native collagen to degradation by pepsin. The reproducibility and simplicity of this assay allows the quantitative estimation of the rate of bone formation in large numbers of cultures. Hydroxyeicosatetraenoic acids (HETEs) stimulated both the rate of collagen and NCP synthesis with maximal stimulation occurring at 10-100 pM. All leukotrienes stimulated collagen synthesis. LTB4, C4 and D4 showed similar dose-responses with maximal activity occurring at 100 pM. LTE4 was less potent only showing activity at 1-10 nM. Only LTD4 demonstrated the capacity to stimulate NCP synthesis with significant stimulation being seen at 10 nM. The extreme sensitivity of bone collagen and NCP synthesis to lipoxygenase products suggests that these mediators may play a physiological role in bone remodelling.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1992

Inhibition of bone DNA and collagen production by surface-associated material from bacteria implicated in the pathology of periodontal disease.

Gentle extraction of oral bacteria implicated in the pathogenesis of periodontal disease, Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, or Eikenella corrodens, with saline removes the extracellular components while leaving the bacteria intact. This readily-solubilized surface-associated material (SAM) has been demonstrated to significantly inhibit DNA and collagen synthesis by murine calvaria at concentrations as low as 10 ng/ml. DNA and collagen synthesis in isolated calvarial osteoblasts were also inhibited by these SAM preparations with similar dose responses. The inhibitory effect of these bacterial expolymers was blocked by 1 microM indomethacin. The potent inhibitory actions on bone synthesis of the SAM from these bacteria may contribute to the alveolar bone loss found in patients with periodontal disease.

Aggregatibacter actinomycetemcomitans↗
PubMed1991

Hypercalcaemia and the synthesis of interleukin-1 by an ameloblastoma.

A case of hypercalcaemia secondary to a long-standing solitary ameloblastoma is presented with evidence to suggest that the raised plasma calcium was the result of the secretion of interleukin-1 and a parathyroid hormone-like substances by the tumour. The aetiology of humoral hypercalcaemia of malignancy is discussed in relation to the role played by these substances.

Ameloblastoma↗
PubMed1989

Dual elevation of cyclic AMP and inositol phosphates in response to mechanical deformation of murine osteoblasts.

Mechanical deformation of bone cells was thought to be mediated via prostaglandin production and the cyclic AMP pathway. We present evidence that the phosphoinositide pathway is also activated by mechanical stress. We find that inositol phosphate production, but not glycerophosphoinositol production, is elevated, and the activation of adenylate cyclase is relatively small. These results are not compatible with the proposal that mechanical deformation of bone cells acts solely via prostaglandin synthesis.

Animals↗
PubMed1989

Murine osteoblasts release bone-resorbing factors of high and low molecular weights: stimulation by mechanical deformation.

Murine calvarial osteoblasts in monolayer culture were found to constitutively produce bone-resorbing factors; mechanical deformation significantly increased the synthesis and/or release of these factors. In short-term cultures (2 h) the resorptive activity was largely dialysable, indicating a relative molecular mass (Mr) less than 2000. Intermittent mechanical deformation stimulated the synthesis of these low Mr factors irrespective of serum conditions. Continuous deformation, however, was without effect. When the culture period was extended to 24 h, bone resorptive activity was stimulated by both intermittent and continuous deformation in the presence of 10% serum. This activity was dialysable. Over this same period in cultures with 2% serum, intermittent deformation also produced a non-dialysable bone-resorbing factor. We also cultured osteoblasts for 72 h in serum-free conditions and deformed the cells intermittently. Fractionation of the medium by high pressure liquid chromatography (HPLC) resolved three peaks of bone resorptive activity: peak I (Mr 50-60,000); peak II (Mr 5-20,000); and peak III (Mr less than 1000). Only peaks II and III were stimulated by mechanical deformation. These bone-resorbing factors remain as yet poorly characterized, but none of the activity in the HPLC fractions was attributable to interleukin-1 or prostaglandin E2.

Animals↗
PubMed1989

Interleukin 1-like activity in cystic lesions of the jaw.

Odontogenic cyst capsules were cultured in vitro and the culture media analysed for bone-resorption and interleukin 1-like activity. Five cysts synthesised a non-dialysable bone resorbing factor with significant interleukin 1-like activity. One specimen thought to be a cyst with little interleukin 1 activity proved to be antral lining. The results indicate that interleukin 1 may play an important role in cyst expansion by its direct effects on fibroblast proliferation and bone resorption and by stimulating prostaglandin synthesis in stromal fibroblasts of the cyst capsule.

Adult↗
PubMed1989

Enhanced presynaptic facilitation of vascular adrenergic neurotransmission in spontaneously hypertensive rats.

1. The interaction between the vascular renin-angiotensin system and presynaptic beta-adrenoreceptors was examined in male and female normotensive and spontaneously hypertensive rats, using the in vitro perfused mesentery preparation. 2. Enhancement of the pressor response to periarterial nerve stimulation by isoprenaline was shown to be significantly greater in preparations from male and female spontaneously hypertensive rats compared to corresponding preparations from normotensive Wistar rats. 3. In preparations from normotensive and hypertensive animals, the potentiating effect of isoprenaline was prevented by pretreatment with propranolol or ICI 118 551, but not atenolol, implicating a beta 2-adrenoreceptor. 4. Angiotensin II enhanced the responses to peripheral nerve stimulation in preparation from normotensive and hypertensive animals. Enhancement was significantly greater in preparations from hypertensive animals. 5. The potentiation caused by isoprenaline was blocked by the angiotensin II receptor antagonist [Sar1-Ile8] angiotensin II, and by captopril. The potentiation following angiotensin II was unaffected by ICI 118 551. 6. These results suggest that stimulation of presynaptic beta 2-adrenoreceptors activates a localized angiotensin II system. No significant differences in this facilitatory system were observed between male and female animals, but the potentiation caused by activation of this system was considerably greater in the spontaneously hypertensive rats.

Adrenergic beta-Antagonists↗