The Osteopontin Gene +1239A/C Single Nucleotide Polymorphism is Associated with Type 1 Diabetes Mellitus in the Italian Population

Chiocchetti, Annalisa; Orilieri, Elisabetta; Barizzone, Nadia; Lorini, Renata; Ravazzolo, Roberto; Cadario, Francesco; Martinetti, M.; Calcaterra,; Cerutti, Fránco; Bruno, Graziella; Larizza, Daniela; Dianzani, Umberto

doi:10.1177/039463201002300124

Cited by 20 publications

(15 citation statements)

References 21 publications

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“…Associations with polymorphisms in the distal SPP1 region including 3′UTR were also reported [e.g. 40,41]. Collectively, the results of these studies imply that polymorphisms in both proximal and distal segments of SPP1 have the potential to affect phenotypic variability.…”

Section: Discussionsupporting

confidence: 52%

Quantitative genetic study of the circulating osteopontin in community-selected families

et al. 2010

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Section: Discussionsupporting

confidence: 52%

Quantitative genetic study of the circulating osteopontin in community-selected families

et al. 2010

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“…On the other hand, osteopontin was also shown to be proinflammatory and highly expressed in the islets toward the onset of diabetes in NOD mice. A single nucleotide polymorphism in the 3=-UTR of osteopontin gene, 1239C vs. A, was associated with elevated serum osteopontin level and risk of type 1 diabetes in an Italian cohort (4). Multiple low doses of streptozotocin (40 mg/kg, 5 days) caused autoimmune diabetes with elevated serum osteopontin level and islet inflammation and apoptosis.…”

Section: Discussionmentioning

confidence: 97%

Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

Xiong

Wang

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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. Pancreatic islet-specific overexpression of Reg3␤ protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus. Am J Physiol Endocrinol Metab 300: E669 -E680, 2011. First published January 18, 2011; doi:10.1152/ajpendo.00600.2010.-Reg family proteins have been implicated in islet ␤-cell proliferation, survival, and regeneration. The expression of Reg3␤ (pancreatitis-associated protein) is highly induced in experimental diabetes and acute pancreatitis, but its precise role has not been established. Through knockout studies, this protein was shown to be mitogenic, antiapoptotic, and anti-inflammatory in the liver and pancreatic acinars. To test whether it can promote islet cell growth or survival against experimental damage, we developed ␤-cell-specific overexpression using rat insulin I promoter, evaluated the changes in normal islet function, gene expression profile, and the response to streptozotocin-induced diabetes. Significant and specific overexpression of Reg3␤ was achieved in the pancreatic islets of RIP-I/Reg3␤ mice, which exhibited normal islet histology, ␤-cell mass, and in vivo and in vitro insulin secretion in response to high glucose yet were slightly hyperglycemic and low in islet GLUT2 level. Upon streptozotocin treatment, in contrast to wild-type littermates that became hyperglycemic in 3 days and lost 15% of their weight, RIP-I/Reg3␤ mice were significantly protected from hyperglycemia and weight loss. To identify specific targets affected by Reg3␤ overexpression, a whole genome DNA microarray on islet RNA isolated from the transgenic mice revealed more than 45 genes significantly either up-or downregulated. Among them, isletprotective osteopontin/SPP1 and acute responsive nuclear protein p8/NUPR1 were significantly induced, a result further confirmed by real-time PCR, Western blots, and immunohistochemistry. Our results suggest that Reg3␤ is unlikely an islet growth factor but a putative protector that prevents streptozotocin-induced damage by inducing the expression of specific genes.pancreatitis-associated protein; DNA microarray; real-time polymerase chain reaction; Western blot; immunofluorescence; Reg family proteins; transgenic mice A NORMAL ␤-CELL MASS is a crucial element against the development of diabetes mellitus and is determined by at least four independent parameters, i.e., mitogenic replication, cell size expansion, neogenesis (from other pancreatic cells), and apoptosis (42). The net rate of ␤-cell growth is the balance among the rates of ␤-cell replication, hypertrophy, neogenesis, and apoptosis (10). Various growth factors such as hepatocyte growth factor and glucagon-like peptide-1 (GLP-1) have been reported to stimulate islet cell expansion (12, 13, 43). For a therapeutic purpose, ␤-cell mass could also be supplemented by islet cell transplantation where growth factors were shown to promote the survival and/or expansion of transplanted cells in rodents (8,43). Unfortunately, very few of these factors have been pr...

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“…Thus far, OPN SNPs have been associated with a number of disease conditions including kidney stone disease [94–97]. Some SNPs are located in the coding region with others in the regulatory (promoter) region.…”

Section: Osteopontin Knockout Micementioning

confidence: 99%

Interstitial calcinosis in renal papillae of genetically engineered mouse models: relation to Randall’s plaques

2014

Urolithiasis

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Genetically engineered mouse models (GEMMs) have been highly instrumental in elucidating gene functions and molecular pathogenesis of human diseases, although their use in studying kidney stone formation or nephrolithiasis remains relatively limited. This review intends to provide an overview of several knockout mouse models that develop interstitial calcinosis in the renal papillae. Included herein are mice deficient for Tamm-Horsfall protein (THP; also named uromodulin), osteopontin (OPN), both THP and OPN, Na+-phosphate cotransporter Type II (Npt2a) and Na+/H+ exchanger regulatory factor (NHERF-1). The baseline information of each protein is summarized, along with key morphological features of the interstitial calcium deposits in mice lacking these proteins. Attempts are made to correlate the papillary interstitial deposits found in GEMMs with Randall’s plaques, the latter considered precursors of idiopathic calcium stones in patients. The pathophysiology that underlies the renal calcinosis in the knockout mice are also discussed wherever information is available. Not all the knockout models are allocated equal space because some are more extensively characterized than others. Despite the inroads already made, the exact physiological underpinning, origin, evolution and fate of the papillary interstitial calcinosis in the GEMMs remain incompletely defined. Greater investigative efforts are warranted in order to pin down the precise role of the papillary interstitial calcinosis in nephrolithiasis using the existing models. Additionally, more sophisticated, second-generation GEMMs that allow gene inactivation in a time-controlled manner and “compound mice” that bear several genetic alterations are urgently needed, in light of mounting evidence that nephrolithiasis is a multifactorial, multi-stage and polygenic disease.

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The Osteopontin Gene +1239A/C Single Nucleotide Polymorphism is Associated with Type 1 Diabetes Mellitus in the Italian Population

Cited by 20 publications

References 21 publications

Quantitative genetic study of the circulating osteopontin in community-selected families

Quantitative genetic study of the circulating osteopontin in community-selected families

Pancreatic islet-specific overexpression of Reg3β protein induced the expression of pro-islet genes and protected the mice against streptozotocin-induced diabetes mellitus

Interstitial calcinosis in renal papillae of genetically engineered mouse models: relation to Randall’s plaques

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