Distribution pattern of matrix metalloproteinases 1, 2, 3, and 9, tissue inhibitors of matrix metalloproteinases 1 and 2, and α2-macroglobulin in cases of generalized AA- and AL amyloidosis

Abstract

Matrix metalloproteinases (MMPs) degrade basement membranes and connective tissue and play an essential role in the homeostasis of the extracellular matrix which is disrupted by the deposition of amyloid. This immunohistochemical study investigated the distribution pattern of matrix metalloproteinases (MMP-1, -2, -3, and -9) and their inhibitors [alpha 2-macroglobulin (alpha 2-M), tissue inhibitors of MMPs (TIMP)-1, and TIMP-2] in human AA- and AL amyloid deposits. Specimens of liver, kidney, and spleen from 22 autopsy cases were investigated. Nine patients had suffered from generalized AA amyloidosis, eight from generalized AL amyloidosis, and five from rheumatoid arthritis or tuberculosis with no histological evidence of amyloid. In all amyloidotic and non-amyloidotic patients, each protease and protease inhibitor was detected in almost every organ investigated. In the amyloidotic cases, there was no indication that a specific protease or protease inhibitor was absent or expressed, but a difference was observed in their spatial distribution patterns. The most noticeable difference was found in immunostaining of amyloid. Only MMP-1, -2, and -3, and alpha 2-M were present in AA amyloid deposits, and only TIMP-1 and TIMP-2 were found in deposits of AL amyloid. This is the first study to show that MMP-1, -2, and -3 are present in AA amyloid deposits. They may be involved in tissue remodeling or in proteolysis of the precursor and fibril proteins.

Proteolysis of AA Amyloid Fibril Proteins by Matrix Metalloproteinases-1, -2, and -3

“…27 Thus, AA amyloidosis occurs under conditions that are known to generate significantly increased serum and tissue levels of MMPs, as compared with healthy control individuals, and it is tempting to speculate that these MMPs may influence the pathogenesis of AA amyloidosis. Previously we have shown that MMP-1, -2, and -3 are present within AA deposits, 12 and we hypothesize that MMPs may be involved in the processing of the precursor (SAA) or fibril proteins (AFP). In the present study we believe that we are the first to show that human SAA and AFP are indeed susceptible to proteolytic cleavage by MMPs.…”

“…However, if redundancy is present for the degradation of SAA and AFP, then why does AA occur or persist? It is possible that the degrading system becomes imbalanced during the course of AA deposition or that the presence of protease inhibitors such as ␣2-macroglobulin, which have been detected in AA deposits, 12 may prevent sufficient degradation. To the best of our knowledge, AFP ending at position 51, 56, 57, or 58 (as generated here by degradation with MMPs) have not been described, which would have indicated in vivo activity of MMPs.…”

“…8 -11 In a recent immunohistochemical investigation we showed that MMP-1, -2, and -3 were present in AA amyloid (AA) deposits and that all three were localized within the deposits independent of the organs involved (liver, kidney, or spleen). 12 These findings suggest that MMPs may participate in amyloidogenesis by either processing the precursor protein SAA, by degrading the amyloid deposits, or by remodeling the interstitial matrix after amyloid deposition. 1 We did not find any MMPs within immunoglobulin-associated AL amyloid deposits, therefore it seems unlikely that the presence of MMPs within the deposits is an essential prerequisite for tissue remodeling during amyloid deposition.…”

Susceptibility to AA amyloidosis in rheumatic diseases: A critical overview

“…The pathogenetic role of metalloendoprotease cleavage in amyloidogenesis has been previously established in another type of systemic amyloidosis, i.e., hereditary gelsolin amyloidosis, in which amyloidogenic low molecular weight fragments of this protein ultimately are specifically released by membrane type 1-MMP (35). Rocken et al were the first investigators to show that MMP-1, MMP-2, and MMP-3 are found in association with AA amyloid deposits but are not observed in light chain amyloidosis (36). Subsequently, in vitro studies confirmed that human SAAs and AA amyloid fibrils are susceptible to proteolytic cleavage by MMPs, generating fragments of different sizes (37).…”

Advanced Glycation End Products and Receptor for Advanced Glycation End Products in AA Amyloidosis

“…These patients have been described previously when histological examination demonstrated the presence of generalized amyloidosis, either AA, AL, or ATTR amyloidosis. 20,21 Age, sex distribution, and underlying diseases are summarized in Table 1. The classification of amyloid was based on immunohistochemistry and clinical history as described elsewhere.…”