Rheumatoid arthritis synovial fibroblast and U937 macrophage/monocyte cell line interaction in cartilage degradation

Abstract

Objective. To examine the interaction between synovial fibroblasts and macrophages in the context of cartilage degradation.Methods. An in vitro model of human cartilage degradation was used, in which purified populations of fibroblasts and macrophages were added to a radiolabeled cartilage disc. Cartilage destruction was measured by the percentage of radiolabel release.Results. Fibroblasts, obtained from either rheumatoid arthritis (RA) or osteoarthritis synovial tissue, could mediate cartilage degradation if cocultured with the U937 macrophage cell line. Skin and RA bone marrow fibroblasts had no degradative effect on cartilage. Fibroblast-macrophage contact was not required for cartilage degradation. Cartilage degradation by synovial fibroblasts was inhibited by antibodies to tumor necrosis factor a (TNFa), interleukin-lp (IL-lp), and IL-6. Cartilage degradation was almost completely abrogated by a combination of antibodies to TNFa and IL-1p. Contact between fibroblasts and cartilage was shown to be essential. Antibodies to CD44, but not to intercellular adhesion molecule 1, markedly inhibited cartilage degradation.Conclusion. TNFar, IL-lp, and IL-6 were involved in the activation of synovial fibroblasts to cause cartilage degradation. Cartilage degradation occurred only when fibroblasts were in contact with cartilage. CD44 was demonstrated to be involved in the fibroblastcartilage interaction. Rheumatoid arthritis (RA) is a disease in which immune system mediators evoke an inflammatory response within the joint resulting in cartilage and bone destruction. Evidence has been accumulated to indicate that the cartilage and bone destruction is mediated by synovial macrophages and fibroblasts as a consequence of metallaproteinase release (1-4). It has been suggested that fibroblasts and macrophages within the synovium orchestrate the destructive processes via a self-perpetuating autocrine/paracrine network (5). In support of this concept, fibroblasts and macrophages have an activated phenotype and secrete cytokines capable of paracrine interactions (i.e., interleukin-la [ILla], tumor necrosis factor a [TNFa], IL-6, and granulocyte-macrophage colony-stimulating factor) (6-10). In addition, it has been recently demonstrated that anti-TNFa therapy is effective in the treatment of RA To study the pathobiologic process within the RA joint, we reduced the inflammatory response to the level of its constitutive cellular elements. Using purified populations of cells, we were able to determine, in vitro, the cellular interactions that lead to joint destruction. We demonstrated a key, contact-dependent role for the synovial fibroblast in the destruction of cartilage, in synergy with 1 or more macrophage-generated cytokines. We also demonstrated that cartilage degradation in our assay system could be inhibited with antibodies directed to macrophage-or fibroblast-generated cytokines (i.e., anti-TNFa, anti-IL-la, and anti-IL-6) and with antibodies to adhesion molecule CD44. An additional inhibitory effect was demonstrated by usi...

The Increase of Parathyroid Hormone-Related Peptide and Cytokine Levels in Synovial Fluid of Elderly Rheumatoid Arthritis and Osteoarthritis.

“…PTHrP seems to be locally working in an autocrine or paracrine factor mediated through cytokines in synovitis of elderly RA or OA patients. The importance of IL-1,I, TNF-a and IL-6 has already been discussed in connection with inflammatory synovitis [14]. TNF-a, IL-2 and IL-6 concentrations in RA synovial fluids were significantly higher than that in SF of OA.…”

“…Although the role of PTHrP in synovitis is unknown, the action of cytokines in synovitis has already been reported [14] . Contact between fibroblasts and cartilage is necessary for cartilage destruction.…”

“…Cytokines are released from either macrophages [14] or fibroblasts [10] and possibly stimulate the release of PTHrP from synovium subsequently, since IL-la, IL-i /I and IL-6 induced PTHrP production into the cultured medium of synovial fibroblasts [10]. PTHrP induced by TNF-a, IL-1f or IL-6, in turn, might be involved in the cell proliferation of synovium, since PTHrP is important for cell growth and differntiation [2].…”

Macrophages Promote the Invasion of Breast Carcinoma Cells via a Colony-Stimulating Factor-1/Epidermal Growth Factor Paracrine Loop

“…We propose that macrophages promote invasive tumor cell behavior at these sites and this ultimately leads to increased metastasis. The ability of macrophages to promote the invasive behavior of other cell types is not restricted to tumors; macrophages can also promote fibroblast invasion into cartilage in rheumatoid arthritis (23).…”

Induction of cartilage damage by overexpression of T cell interleukin‐17A in experimental arthritis in mice deficient in interleukin‐1

“…The importance of IL-1 in cartilage damage in RA has been shown in many studies (39)(40)(41), and IL-1 has recently become a therapeutic target through the introduction of anakinra, a recombinant IL-1Ra. Anti-IL-1 treatment in various murine models of experimental arthritis showed protection against cartilage damage and PG synthesis inhibition (18,42).…”