Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis.
OBJECTIVE
Genetic polymorphisms in serum amyloid A (SAA) have been shown to substantially influence the risk of developing type AA amyloidosis. Recently, a role for MMP-1 has been suggested in the pathogenesis of AA amyloidosis. Therefore, we investigated if the SAA1 isotypes are differentially degraded by MMP-1.


METHODS
Degradation of different SAA isotypes by MMP-1 was assessed by immunoblotting. MALDI-TOF mass spectrometry was used to identify degradation fragments.


RESULTS
We found that SAA1.5 is more resistant to degradation by MMP-1 than SAA1.1. This difference is caused by the capacity of MMP-1 to cleave at the site of the polymorphism at position 57.


CONCLUSIONS
These results may explain the higher risk of amyloidosis in patients with a SAA1.1/1.1 genotype vs SAA1.5/1.5 or SAA1.1/1.5 genotype. In addition, the impaired degradation of SAA1.5 by MMP-1 could also explain the higher serum SAA concentrations in persons with a SAA1.5 genotype.
van der Hilst
J C H
JC
Department of General Internal Medicine (463), Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands. j.vanderhilst@aig.umcn.nl
Yamada
T
T
Op den Camp
H J M
HJ
van der Meer
J W M
JW
Drenth
J P H
JP
Simon
A
A
D000686:Amyloidosis / Q000209:etiology* / Q000235:genetics; D015153:Blotting, Western / Q000379:methods; D004198:Disease Susceptibility; D004591:Electrophoresis, Polyacrylamide Gel; D005838:Genotype; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012306:Risk; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D010446:Peptide Fragments; D020033:Protein Isoforms; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; D020781:Matrix Metalloproteinase 1