Osteopontin gene and clinical severity of multiple sclerosis

Hensiek, Anke; Roxburgh, Richard; Meranian, M.; Seaman, Shaun; Yeo, Tai Wai; Compston, D. A. S.; Sawcer, Stephen

doi:10.1007/s00415-003-1120-2

Cited by 29 publications

(18 citation statements)

References 22 publications

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“…Similar to study of Caillier et al, no evidence of association between OPN variants and MS susceptibility and severity was observed in a study of Hensiek et al [58].…”

Section: Multiple Sclerosissupporting

confidence: 77%

Osteopontin (OPN) Gene Polymorphisms and Autoimmune Diseases

Kaleta¹

2017

Genetic Polymorphisms

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Osteopontin (OPN) is a pleiotropic protein, important in bone remodeling and immune system signaling. OPN is synthesized in a variety of cells and tissues. It can be found not only in bone cells but also in immune cells (B and T lymphocytes, natural killer (NK) cells, natural killer T (NKT) cells, macrophages, neutrophils, and dendritic cells). OPN regulates T-helper 1/T-helper 2 (Th1/Th2) balance, stimulates B cells to antibodies production, regulates macrophages and neutrophils function, and activates dendritic cells. A number of factors, including hormones, cytokines, and polymorphisms of promoter region of OPN gene, regulate protein expression. OPN and variants of the OPN gene have been associated with the pathogenesis of multiple disorders, including systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, systemic sclerosis, inlammatory bowel diseases, asthma, type 1 diabetes, and many other. However, some studies gave diferent or inconclusive results. Thus, the role of OPN polymorphic variants in autoimmune diseases needs to be beter deined and explored as a diagnostic and therapeutic target to monitor and treat immune-mediated conditions.

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“…Similar to study of Caillier et al, no evidence of association between OPN variants and MS susceptibility and severity was observed in a study of Hensiek et al [58].…”

Section: Multiple Sclerosissupporting

confidence: 77%

Osteopontin (OPN) Gene Polymorphisms and Autoimmune Diseases

Kaleta¹

2017

Genetic Polymorphisms

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“…15,16 However, there is little evidence for a genetic link between OPN and MS disease susceptibility and disease course. 11,13,[17][18][19][20] Elevated OPN levels have also been documented by immunohistochemistry around MS lesions 21,22 although this was not observed by others. 23 The role that OPN plays in EAE and MS remains uncertain, but a prevailing view is that OPN plays a destructive role during EAE since it reduces apoptosis of effector T cells and because the exogenous administration of recombinant OPN exacerbates EAE clinical disease.…”

mentioning

confidence: 87%

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

DaSilva

Liaw

Yong

2010

The American Journal of Pathology

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A role for osteopontin (OPN) in promoting disease activity of multiple sclerosis or its animal model experimental autoimmune encephalomyelitis (EAE) has recently been suggested. As the biological activity of OPN is heavily influenced by posttranslational processing, we investigated the capacity of matrix metalloproteinase (MMP)-12 to cleave OPN and determined whether this influenced disease activity. We found that OPN mRNA and protein expression in the spinal cord increased with EAE disease in C57BL/6 mice concurrently with MMP-12 expression. A Western blot of EAE and control spinal cords revealed different OPNimmunoreactive bands, with a pattern that was similar to MMP-12 cleavage of recombinant OPN in vitro. In addition, OPN fragments in the spinal cord of EAEafflicted mice were reduced in MMP-12 ؊/؊ mice compared with wild-type controls. However, examination of OPN ؊/؊ mice in short-and long-term experiments revealed no difference in EAE outcomes from wildtype animals. OPN/MMP-12 double null mice were generated, and it was revealed that MMP-12 ؊/؊ mice had a worsening of disease compared with wild-type mice, which returned to wild-type levels in the OPN/ MMP-12 double null mice. These results suggest that EAE disease activity may be modulated by the cleavage of OPN by

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“…Paradoxical as it could seem, this scenario is reminiscent of the situation found with osteopontin, one of the most frequently transcribed genes in MS lesions and the fifth most common transcript that was unique to the brains of patients with MS. 27 Furthermore, patients with relapsing-remitting MS have higher serum levels of osteopontin, specifically during relapses. 28,29 However, in terms of the genetic association with MS, most studies in independent populations failed to find a role of the osteopontin polymorphisms in disease susceptibility, [30][31][32] including the more recent GWA studies. 22,23 One possible explanation for these results might involve the synergistic interaction with some other gene(s), in such a way that the effect of one of them is masked when analyzed separately and awaits the discovery of epistatic companions.…”

Section: à5mentioning

confidence: 99%

STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility

Cénit¹,

Alcina

Márquez³

et al. 2010

Genes Immun

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STAT3 (signal transducer and activator of transcription 3) signaling is a critical component of Th17-dependent autoimmune processes. Genome-wide association studies (GWAS) have revealed the role of the STAT3 gene in inflammatory bowel disease (IBD) susceptibility, although confirmation in clinical subphenotypes is warranted. Mice with targeted deletion of Stat3 in T cells are resistant to experimental autoimmune encephalomyelitis, which is a multiple sclerosis (MS) model. Moreover, increased phosphorylated STAT3 was reported in T cells of patients evolving from clinically isolated syndrome to defined MS and in relapsing patients. These evidences led us to analyze the role of STAT3 in Crohn's disease (CD), ulcerative colitis (UC) and MS risk. Polymorphisms in the STAT3 region (rs3809758/rs744166/rs1026916/rs12948909) were genotyped and the inferred haplotypes were subsequently analyzed in 860 IBD and 1540 MS Spanish patients and 1720 ethnically matched controls. The haplotype conformed by the risk alleles of each polymorphism was significantly associated with both clinical phenotypes of IBD (CD: P ¼ 0.005, odds ratio 1.25, 95% confidence interval 1.06-1.46; and UC: P ¼ 0.002, odds ratio 1.19, 95% confidence interval 1.02-1.38). No evidence of association was detected for MS. The originally described association of IBD with STAT3 polymorphisms is corroborated for the two clinical phenotypes, CD and UC, in an independent population. A major role of this gene in MS seems unlikely.

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Osteopontin gene and clinical severity of multiple sclerosis

Cited by 29 publications

References 22 publications

Osteopontin (OPN) Gene Polymorphisms and Autoimmune Diseases

Osteopontin (OPN) Gene Polymorphisms and Autoimmune Diseases

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility

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