Monocytes and Macrophages in Synovitis: Villains or Victims?
© Current Science Ltd 2000
Published: 15 November 1999
Rheumatoid arthritis (RA) is characterized by cartilage and bone destruction via pannus formation. It is also a systemic disease, where monocytes are known to play an important role in the inflammatory processes. To further investigate mechanisms of monocyte activation, differential gene analysis appears to be a powerful tool. Thus, we have differentially analyzed gene expression in activated monocytes from first (activated) and third (nonactivated) leukapheresis preparations from an RA patient. Typical genes identified were IL-1α, IL-1β, IL-6, and TNF-α. Furthermore, GRO-α/melanoma growth-stimulatory activity, MIP-2/GRO-β, ferritin, α-1 antitrypsin, lysozyme, transaldolase, EBER-1/EBER-2 associated protein, thrombospondin-1, an angiotensin receptor-II C-terminal homologue, RNA polymerase-III elongation factor (elongin), three unknown (BSK-66, -80, -89), and homologues of functionally undefined genes (BSK-67, -83) were differentially expressed. Overexpression was confirmed for selected genes by semiquantitative PCR analysis in monocytes from RA patients versus healthy donors, including IL-1β, the ATR-11 homologue, BSK 66, -67 and -89. To investigate the importance of monocytes in the synovial tissue and to take other cells in the synovial pannus into account, especially fibroblasts, which may modulate the destructive process essentially, a representational difference analysis has been performed in whole synovial tissue between RA and osteoarthritis (OA). Furthermore, a modified technique of semiquantitative PCR was used to verify these data and to analyze a group of genes possibly involved in the tissue homeostasis of cartilage. A preliminary analysis of 151 clones revealed that genes other than regulatory cytokines dominate the difference. Especially genes of effector functions like immunoglobulin and collagen type 1 are over-represented. Furthermore, receptors with immunoregulatory function like HLA-DR, natural killer cell receptor p58, and a homologue to the cytokine receptor EB13 as well as genes involved in global cell activity are upregulated in RA. Many clones with unknown sequences need further investigation. Using semiquantitative PCR, a group of genes not yet considered for RA, the bone morphogenetic proteins (BMP), were differentially studied between RA, OA, traumatic joint diseases, and normal tissue. Specific members of this huge family of genes are selectively down-regulated in synovial inflammation and possibly differentially regulated depending on the type or stage of inflammation.
In summary, monocytes are certainly global players in the inflammatory process in RA. However, in the synovial tissue, modulating factors from fibroblasts, natural killer cells, or T- and B-cells play an essential role. Especially in chronic cartilage degradation, the decrease of differentiation factors most likely derived from cartilage nursing synovial fibroblasts may contribute to joint destruction.
- Hahn G, Stuhlmüller B, Hain N, Kalden JR, Pfizenmaier K, Burmester GR: Modulation of monocyte activation in patients with rheumatoid arthritis by leukapheresis therapy. J Clin Invest 1993, 91:862–870.View ArticlePubMed
- Burmester GR, Stuhlmuller B, Keyszer G, Kinne RW: Mononuclear phagocytes and rheumatoid synovitis. Mastermind or workhorse in arthritis? Arthritis Rheum 1997, 40:5–18.View ArticlePubMed
- Dörffel Y, Lätsch C, Stuhlmüller B, et al.: Pre-activated peripheral blood monocytes in patients with essential hypertension. Hypertension 1999, in press.
- Stuhlmüller B, Ungethüm U, Scholze S, Backhaus M, Kinne RW, Burmester GR: Differential gene expression of activated and non-activated monocytes from patients with rheumatoid arthritis. 1999, in press.
- Seki T, Selby J, Häupl T, Winchester R: Use of differential subtraction method to identify genes that characterize the phenotype of cultured rheumatoid arthritis synoviocytes. Arthritis Rheum 1998, 41:1356–1364.View ArticlePubMed
- Häupl T, Ungethüm U, Bramlage C, et al.: Bone morphogenetic proteins in synovial tissue from RA, OA and normal joints: implications for protective mechanisms. Arthritis Rheum 1998, 41(suppl):S195.
- Keyszer G, Redlich A, Häupl T, et al.: Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: a parallel investigation by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. Arthritis Rheum 1998, 41:1378–1387.View ArticlePubMed
- Ungethüm U, Häupl T, Burmester G-R: Gene products identified by RDA subtraction in rheumatoid arthritis. J Autoimmunity 1999., (suppl):