Differential expression of gelatinase B (MMP-9) and stromelysin-1 (MMP-3) by rheumatoid synovial cells in vitro and in vivo

Abstract

Primary cultures of adherent rheumatoid synovial cells (ASC) are comprised of variable proportions of fibroblasts, macrophages and stellate cells (activated fibroblasts). These cultures were shown to produce the metalloproteinases stromelysin-1 (MMP-3), gelatinase A (MMP-2) and gelatinase B (MMP-9) by Western blotting and zymography techniques. Immunolocalisation studies showed that MMP-3 was mainly produced by the fibroblastic cells whereas MMP-9 was restricted to macrophages (CD68 positive). Subcultured synovial fibroblasts, devoid of macrophages, did not produce MMP-9 as judged by zymography and immunolocalisation; but when stimulated with phorbol myristate acetate and interleukin-1 alpha both MMP-9 and MMP-3 were co-expressed. These 'activated' fibroblasts assumed a dendritic or stellate morphology, which in localisation studies was usually associated with enhanced enzyme production. Immunolocalisation studies of rheumatoid synovial tissue showed that relatively few cells were positive for MMP-3 and MMP-9. Localisation of MMP-9 corresponded to a proportion of macrophages positive for the CD68 marker throughout the synovial tissue. MMP-3 localisation was not associated with the macrophage marker, but was observed in both the synovial lining layer and deeper stromal locations. Widespread distribution of both enzymes was not observed in fresh tissues, but this increased in tissues subjected to short-term explant cultures. Thus, both in vitro and in vivo studies indicated that synovial fibroblasts or B-cells are effective producers of MMP-3 whereas macrophages elaborate MMP-9, observations that demonstrated different metalloproteinase phenotypes under similar environmental conditions.

Prothymosin α Lacking the Nuclear Localization Signal as an Effective Gene Therapeutic Strategy in Collagen-Induced Arthritis

“…This finding is in accordance with earlier work showing that rheumatoid synovial cells, which consist of variable proportions of fibroblasts, macrophages, and stellate cells, produce MMP-2, MMP-3, and MMP-9, and among which only MMP-9 production is mainly restricted to macrophages (52). Thus, down-regulation of the MMP-9 expression in the arthritic joints by AdProT⌬NLS treatment may have been attributable to the reduced numbers of infiltrating macrophages in the ankle joints of rats with CIA.…”

Regulation of fibronectin and metalloproteinase expression by Wnt signaling in rheumatoid arthritis synoviocytes

“…Although RA FLS do not have a high growth fraction, several lines of evidence suggest that they have enhanced survival (1)(2)(3). RA FLS also secrete matrix metalloproteinases (MMPs) such as proMMP-3 (stromelysin 1), which in its mature form, enhances both cartilage degradation and invasion of FLS into cartilage (11)(12)(13). Consequently, FLS gradually accumulate to form part of an invasive pannus, which contributes to joint destruction.…”

“…It has been reported that Wnt-1 can increase the activity of the activator protein 1 (AP-1) transcription factor (38). Since the proMMP-3 (precursor form of MMP-3) gene promoter has an AP-1 binding site (39), and since increased levels of MMP-3 in the joint fluid is a clear indicator of disease progression and joint destruction in RA (12,13,40), it was of interest to determine whether Wnt-1 signaling regulates proMMP-3 synthesis in RA FLS.…”

BorreliaSpirochetes Upregulate Release and Activation of Matrix Metalloproteinase Gelatinase B (MMP-9) and Collagenase 1 (MMP-1) in Human Cells

“…In rheumatoid arthritis (RA), MMPs play a similar destructive role (5,28,30,53). Monocyte/macrophage-derived MMP-1 and MMP-9 along with MMPs released from synoviocytes and neutrophils are thought to be responsible for collagen degradation and joint destruction in RA (11,48,51,56). Thus, MMPs may be associated with many of the pathological processes and clinical manifestations that are part of Lyme disease and relapsing fever.…”