Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-beta and retinoids.

Abstract

Exuberant tumor-like synovial cell proliferation with invasion of periarticular bone is a feature of rheumatoid arthritis in humans and of streptococcal cell wall (SCW)-induced arthritis in rats. These histologic observations prompted us to examine synoviocytes from arthritic joints for phenotypic characteristics of transformed cells. The capacity to grow in vitro under anchorage-independent conditions is a characteristic that correlates closely with potential in vivo tumorigenicity. In medium supplemented with 20% serum or in basal media supplemented with platelet-derived growth factor (PDGF), early passage synoviocytes from both SCW-induced and rheumatoid arthritic joints formed colonies in soft agarose. Epidermal growth factor (EGF), interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta) did not support growth, although EGF enhanced PDGF-dependent growth. On the other hand, TGF-beta, as well as all-trans-retinoic acid, inhibited colony growth. Early passage normal rat and human synoviocytes also grew under the same conditions, but lung, skin, and late-gestation embryonic fibroblast-like cells did not. Considered in the context of other published data, our findings provide cogent evidence that synoviocytes, but not other types of fibroblast-like cells, readily acquire phenotypic characteristics commonly associated with transformed cells. Expression of the transformed phenotype in the inflammatory site is likely regulated by paracrine growth factors, such as PDGF and TGF-beta.

MicroRNA‐124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast‐like synoviocytes from patients with rheumatoid arthritis

“…Recent reports have shown that in human cancers, the expression of specific miRNA closely related to the regulation of cell growth and apoptosis differs from that in normal tissues (25,26). RA is characterized by pronounced synovial hyperplasia and by synovial fibroblasts that appear to be transformed (27,28). In animal models of RA, this transformed appearance of RA synoviocytes could be mitigated by transferring the CDK inhibitor genes p16 INK4a and p21 Cip1 into inflamed joints (29,30).…”

Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis

“…Both PDGF and FGF may be produced by macrophages, and they can stimulate DNA synthesis and proliferation of human synovial fibroblasts, without inducing PGE, production (68). Also, PDGF enhances anchorage-independent growth of rheumatoid synovial cells in soft agarose cultures (69). PDGF and IL-1 exhibit complex interactions on cultured rheumatoid synovial cells.…”

Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis: A potential marker of erosive joint destruction

“…The origins of the cells of the pannus are not clear, but they express inflammation mediators, including neutral proteases (13) and free radicals, leading to DNA damage (2). As a result, fibroblast-like synoviocytes express p53 (14,15), lose contact inhibition (16), and express oncogenes typical of neoplastic cellular growth (17). These cellular phenotypic and protein expression changes may contribute to progressive joint erosion, independent of inflammation (18).…”