Osteoprotegerin induces morphological and functional alterations in mouse pancreatic islets.
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.
Toffoli
Barbara
B
Department of Morphology and Embryology, University of Ferrara, via Fossato di Mortara 64/b, 44100 Ferrara, Italy.
Bernardi
Stella
S
Candido
Riccardo
R
Sabato
Nicoletta
N
Carretta
Renzo
R
Corallini
Federica
F
Secchiero
Paola
P
Zauli
Giorgio
G
Fabris
Bruno
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D053244:Osteoprotegerin / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D013599:Systole / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; C526318:CCN2 protein, mouse; D018932:Chemokine CCL2; D007328:Insulin; D053244:Osteoprotegerin; D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D055513:Connective Tissue Growth Factor; D007703:Peptidyl-Dipeptidase A