TY - JOUR T1 - Osteoprotegerin increases in metabolic syndrome and promotes adipose tissue proinflammatory changes. JF - Mol Cell Endocrinol Y1 - 2014 A1 - Bernardi, Stella A1 - Fabris, Bruno A1 - Thomas, Merlin A1 - Toffoli, Barbara A1 - Tikellis, Christos A1 - Candido, Riccardo A1 - Catena, Cristiana A1 - Mulatero, Paolo A1 - Barbone, Fabio A1 - Radillo, Oriano A1 - Zauli, Giorgio A1 - Secchiero, Paola KW - Adipose Tissue KW - Adult KW - Animals KW - Blood Glucose KW - Body Mass Index KW - C-Reactive Protein KW - Case-Control Studies KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Diet, High-Fat KW - Female KW - Humans KW - Inflammation KW - Insulin KW - Insulin Resistance KW - Male KW - Metabolic Syndrome X KW - Mice KW - Mice, Inbred C57BL KW - Middle Aged KW - Obesity KW - Osteoprotegerin KW - Triglycerides AB -

BACKGROUND: Inflammation is believed to link obesity to insulin resistance, as in the setting of metabolic syndrome (MetS). Osteoprotegerin (OPG) is a soluble protein that seems to exert proatherogenic and prodiabetogenic effects. This study aims at determining OPG levels in MetS and whether OPG might contribute to MetS development and progression.

METHODOLOGY/PRINCIPAL FINDINGS: Circulating OPG was measured in 46 patients with MetS and 63 controls, and was found significantly elevated in those with MetS. In addition, circulating and tissue OPG was significantly increased in high-fat diet (HFD) fed C57BL6 mice, which is one of the animal models for the study of MetS. To evaluate the consequences of OPG elevation, we delivered this protein to C57BL6 mice, finding that it promoted systemic and adipose tissue proinflammatory changes in association with metabolic abnormalities.

CONCLUSIONS/SIGNIFICANCE: These data suggest that OPG may trigger adipose tissue proinflammatory changes in MetS/HFD-induced obesity.

VL - 394 IS - 1-2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24998520?dopt=Abstract ER - TY - JOUR T1 - Osteoprotegerin induces morphological and functional alterations in mouse pancreatic islets. JF - Mol Cell Endocrinol Y1 - 2011 A1 - Toffoli, Barbara A1 - Bernardi, Stella A1 - Candido, Riccardo A1 - Sabato, Nicoletta A1 - Carretta, Renzo A1 - Corallini, Federica A1 - Secchiero, Paola A1 - Zauli, Giorgio A1 - Fabris, Bruno KW - Animals KW - Apoptosis KW - Blood Glucose KW - Blood Pressure KW - Body Weight KW - Cell Lineage KW - Cell Movement KW - Chemokine CCL2 KW - Connective Tissue Growth Factor KW - Fibrosis KW - Gene Expression Regulation KW - Humans KW - Insulin KW - Islets of Langerhans KW - Macrophages KW - Mice KW - Monocytes KW - Organ Size KW - Osteoprotegerin KW - Peptidyl-Dipeptidase A KW - Receptor, Angiotensin, Type 1 KW - Systole KW - Transforming Growth Factor beta KW - Vascular Cell Adhesion Molecule-1 AB -

Although serum osteoprotegerin (OPG) is significantly increased in diabetic subjects, its potential role in beta cell dysfunction has not been investigated. This study aimed to assess the effect of full-length OPG administered in vivo in mice on pancreatic islet structure and function and its interaction with the renin-angiotensin system (RAS). OPG-treated mice showed increased islet monocyte/macrophage infiltration, fibrosis and apoptosis with reduction of islet function. The remodeling of islet architecture was associated with increased pancreatic expression of components of the RAS, growth factor genes (transforming growth factor β and connective tissue growth factor) and inflammatory molecules (monocyte chemotactic protein-1 and vascular adhesion molecule type 1). Prevention of these changes with improvement of insulin secretion was observed in ramipril treated animals. Our data suggest that OPG might play an important role in promoting beta cell dysfunction and that the upregulation of the local RAS represents one possible mechanism responsible for the OPG-induced beta cell dysfunction.

VL - 331 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20832449?dopt=Abstract ER - TY - JOUR T1 - Osteoprotegerin promotes vascular fibrosis via a TGF-β1 autocrine loop. JF - Atherosclerosis Y1 - 2011 A1 - Toffoli, Barbara A1 - Pickering, Raelene J A1 - Tsorotes, Despina A1 - Wang, Bo A1 - Bernardi, Stella A1 - Kantharidis, Phillip A1 - Fabris, Bruno A1 - Zauli, Giorgio A1 - Secchiero, Paola A1 - Thomas, Merlin C KW - Animals KW - Apolipoproteins E KW - Cell Proliferation KW - Collagen KW - Fibronectins KW - Fibrosis KW - Gene Expression Regulation KW - Humans KW - Mice KW - Mice, Inbred C57BL KW - Mice, Transgenic KW - Muscle, Smooth, Vascular KW - Myocytes, Smooth Muscle KW - Osteoprotegerin KW - Platelet-Derived Growth Factor KW - Transforming Growth Factor beta1 AB -

BACKGROUND: This study was designed to evaluate the potential role of osteoprotegerin (OPG) in arterial fibrosis.

METHODS: Aortic samples were analyzed after in vivo treatment of ApoE(-/-) mice with recombinant human OPG. Mouse vascular smooth muscle cells (VSMC) were exposed in vitro to recombinant OPG and analyzed for markers of inflammation and fibrosis, such as fibronectin, collagen I, III, IV and transforming growth factor-β1 (TGF-β1). Conversely, the potential modulation of endogenous OPG expression and release by VSMC was analyzed in response to different pro-atherosclerotic cytokines, TGF-β1, platelet derived growth factor (PDGF) and angiogensin II (Ang II).

RESULTS: In vivo treatment with human OPG induced signs of fibrosis and up-regulated the arterial expression of TGF-β1. Consistently, in vitro treatment of VSMC with human OPG induced the expression of fibronectin, collagen type I, III, IV, metalloprotein-2 (MMP-2) and MMP-9, as well as of TGF-β1. On the other hand, exposure to recombinant TGF-β1 promoted the expression/release of endogenous OPG and mediated the increase of OPG release induced by PDGF and Ang II in VSMC.

CONCLUSIONS: Taken together, these data support a pathogenic role for OPG in the development and progression of atherosclerotic lesions and suggest the existence of a vicious circle between TGF-β1 and OPG.

VL - 218 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21679949?dopt=Abstract ER -