Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis.

Abstract

OBJECTIVE:

To study the expression of messenger RNA (mRNA) for different membrane-type matrix metalloproteinases (MT-MMPs) and compare their expression pattern in rheumatoid arthritis (RA) and normal synovium.

METHODS:

Polymerase chain reaction (PCR) with specific primers was performed to analyze the presence of MT1-, MT2-, MT3-, and MT4-MMP in synovial tissue and synovial fibroblasts from 10 patients with RA and 4 subjects without arthritis. In addition, in situ hybridization with digoxigenin-labeled RNA probes was used to investigate the expression pattern of MT-MMPs in the synovium of these subjects. MT-MMP-expressing cells were characterized by immunohistochemical double labeling with anti-CD68 monoclonal antibodies.

RESULTS:

Reverse transcription-PCR revealed the expression of MT1-, MT2-, MT3-, and MT4-MMP mRNA in all tissues and cell cultures examined. However, in situ hybridization showed considerable differences in the expression pattern of the different MT-MMPs in RA synovium. MT1- and MT3-MMP mRNA were highly expressed in both the lining and the sublining layer, with more intense staining in the lining. Immunohistochemical double labeling demonstrated the presence of mRNA for MT1-MMP in fibroblasts and macrophages, as well as in osteoclast-like cells at sites of bone resorption. Expression of MT3-MMP mRNA was seen in fibroblasts and some macrophages. Expression of MT2- and MT4-MMP was characterized by staining of only a few CD68-negative fibroblasts, and no differences could be found between the lining and sublining. Normal synovial samples showed only limited staining for all MT-MMPs.

CONCLUSION:

Our results indicate a role for MT1-MMP not only in the matrix degradation by fibroblasts, but also in osteoclast-mediated bone resorption in RA. Given the ability of MT1-MMP to activate MMP-2 and MMP-13, the findings also point to a cooperation between fibroblasts and macrophages in degrading cartilage and bone. While MT3-MMP is also intensely expressed in RA synovium, MT2- and MT4-MMP appear not to be involved in rheumatoid joint destruction.

• Authors: T Pap, Y Shigeyama, S Kuchen, J K Fernihough, B Simmen, R E Gay, M Billingham, S Gay
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 43 Issue 6 Pg. 1226-32 (Jun 2000) ISSN: 0004-3591 [Print] United States
• PMID: 10857781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Isoforms
• RNA, Messenger
• Matrix Metalloproteinases

Topics

• Arthritis, Rheumatoid (enzymology, metabolism)
• Humans
• Immunohistochemistry
• In Situ Hybridization
• Matrix Metalloproteinases (genetics, metabolism)
• Protein Isoforms (genetics, metabolism)
• RNA, Messenger (metabolism)
• Reference Values
• Reverse Transcriptase Polymerase Chain Reaction
• Synovial Membrane (metabolism)