Accelerated resolution of AA amyloid in heparanase knockout mice is associated with matrix metalloproteases.
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.
Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden.
Bo
B
Wang
Ying-Xia
YX
Tan
Juan
J
Jia
Andreas
A
Digre
Xiao
X
Zhang
Israel
I
Vlodavsky
Jin-Ping
JP
Li
D000686:Amyloidosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics; D006023:Glycoproteins; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000685:Serum Amyloid A Protein / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D012835:Silver Nitrate; D013154:Spleen / Q000201:enzymology* / Q000473:pathology; D015854:Up-Regulation; D000099175:Heparanase
D005966:Glucuronidase; D006023:Glycoproteins; D006497:Heparan Sulfate; D020782:Matrix Metalloproteinases; D000685:Serum Amyloid A Protein; D012835:Silver Nitrate; D000099175:Heparanase; C046748:amyloid enhancing factor