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Accelerated resolution of AA amyloid in heparanase knockout mice is associated with matrix metalloproteases.

ABSTRACT: AA-amyloidosis is a disease characterized by abnormal deposition of serum A amyloid (SAA) peptide along with other components in various organs. The disease is a complication of inflammatory conditions that cause persistent high levels of the acute phase reactant SAA in plasma. In experimental animal models, the deposited amyloid is resolved when the inflammation is stopped, suggesting that there is an efficient clearance mechanism for the amyloid. As heparan sulfate (HS) is one of the major components in the amyloid, its metabolism is expected to affect the pathology of AA amyloidosis. In this study, we investigated the effect of heparanase, a HS degradation enzyme, in resolution of the AA amyloid. The transgenic mice deficient in heparanase (Hpa-KO) produced a similar level of SAA in plasma as the wildtype control (Ctr) mice upon induction by injection of AEF (amyloid enhancing factor) and inflammatory stimuli. The induction resulted in formation of SAA amyloid 7-days post treatment in the spleen that displayed a comparable degree of amyloid load in both groups. The amyloid became significantly less in the Hpa-KO spleen than in the Ctr spleen 10-days post treatment, and was completely resolved in the Hpa-KO spleen on day 21 post induction, while a substantial amount was still detected in the Ctr spleen. The rapid clearance of the amyloid in the Hpa-KO mice can be ascribed to upregulated matrix metalloproteases (MMPs) that are believed to contribute to degradation of the protein components in the AA amyloid. The results indicate that both heparanase and MMPs play important parts in the pathological process of AA amyloidosis.

SUBMITTER: Wang B

PROVIDER: S-EPMC3393718 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Accelerated resolution of AA amyloid in heparanase knockout mice is associated with matrix metalloproteases.

Wang Bo B Tan Ying-Xia YX Jia Juan J Digre Andreas A Zhang Xiao X Vlodavsky Israel I Li Jin-Ping JP

PloS one 20120710 7

AA-amyloidosis is a disease characterized by abnormal deposition of serum A amyloid (SAA) peptide along with other components in various organs. The disease is a complication of inflammatory conditions that cause persistent high levels of the acute phase reactant SAA in plasma. In experimental animal models, the deposited amyloid is resolved when the inflammation is stopped, suggesting that there is an efficient clearance mechanism for the amyloid. As heparan sulfate (HS) is one of the major com ...[more]

PMID: 22808071

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Project description:BackgroundStudies suggest that the collagen degeneration and disordered arrangement of collagen fibers in rotator cuff tears are associated with an increase in activity of matrix metalloproteases 1 and 3 (MMP-1 and MMP-3), and that MMP activity may be in part genetically mediated. The degree to which this might be clinically relevant in patients with rotator cuff tears has not been well characterized.Questions/purposes(1) Is genetic polymorphism of MMP-1 and MMP-3 associated with rotator cuff tears? (2) Are there haplotypes of MMP-1 and MMP-3 correlated with rotator cuff tears? (3) Compared with control subjects, do patients with rotator cuff tears have a higher proportion of relatives with the same disease?MethodsWe evaluated 64 patients with full-thickness rotator cuff tears and 64 asymptomatic control subjects. Patients younger 65 years, with nontraumatic tears, were included. The tear or integrity of the rotator cuff tear was evaluated by MRI or ultrasonography in all individuals. The patients and control subjects were paired by age. MMP-1 and MMP-3 genotypes were determined using the PCR-restriction fragment length polymorphism assays.ResultsGenetic polymorphisms in MMP-1 and MMP-3 are associated with rotator cuff tear, in which individuals with rotator cuff tears have associated genotypes 1G/2G (patients, 32 of 64 [50%], control subjects, 16 of 64 [25%]; odds ratio [OR], 4.8; 95% CI, 2.1-11.0; p < 0.001) and 2G/2G were at great risk (patients, 15 of 64 [23%], control subjects, seven of 64 [11%]; OR, 5.2; 95% CI,1.8-14.9; p < 0.001), and patients with rotator cuff tears were associated with a higher proportion of 2G allele distribution (62 of 128 [48%] versus 30 of 128 [23%]; p < 0.001). Patients with the 5A/5A genotype are at greater risk of rotator cuff tear (patients, 15 of 64 [23%]; control subjects, four of 64 [6%]; OR, 5.5; 95% CI, 1.4-20.9; p = 0.021), and there was higher 5A allele distribution in patients with rotator cuff tears (patients, 68 of 128 [53%]; control subjects, 52 of 128 [41%]; p = 0.045). Individuals with the haplotype 2G/5A were more likely to have rotator cuff tears develop (patients, 42 of 64 [66%]; control subjects, 17 of 64 [27%]; OR, 5.3; 95% CI, 2.5-11.3; p < 0.001). Patients with rotator cuff tears reported, in higher number, the existence of relatives who previously had treatment for rotator cuff tears (19 of 64 [30%] versus four of 64 [6%]; OR, 6.3; 95% CI, 2.0-19.9; p = 0.001).ConclusionsThe genetic polymorphism of MMP-1 and MMP-3 is associated with rotator cuff tear. Individuals with haplotype 2G/5A were more susceptible to rotator cuff tears in the population studied.Clinical relevanceKnowledge of the genetic markers related to rotator cuff tears can enable identification of susceptible individuals and increase understanding of the pathogenesis of tendon degeneration.

Dataset Information

Accelerated resolution of AA amyloid in heparanase knockout mice is associated with matrix metalloproteases.

Publications

Accelerated resolution of AA amyloid in heparanase knockout mice is associated with matrix metalloproteases.

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