Invasiveness of fibroblast‐like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis

Abstract

Objective. Rheumatoid arthritis (RA) is characterized by inflammation and destruction of synovial joints. Fibroblast-like synoviocytes (FLS) harvested from synovial tissue of patients with RA can invade normal human cartilage in severe combined immunodeficient (SCID) mice and Matrigel basement membrane matrix in vitro. This study was undertaken to investigate the association of these in vitro characteristics with disease characteristics in patients with RA.Methods. Synovial tissue samples from 72 RA and 49 osteoarthritis (OA) patients were obtained. Samples of different joints were collected from 7 patients with RA. The FLS invasiveness in Matrigel was studied, and the intraindividual and interindividual differences were compared. From the patients with FLS who exhibited the most extreme differences in in vitro ingrowth (most and least invasive FLS), radiographs of the hands and feet were collected and scored according to the Sharp/ van der Heijde method to determine the relationship between in vitro invasion data and estimated yearly joint damage progression.Results. FLS from patients with RA were more invasive than FLS from patients with OA (P < 0.001). The mean intraindividual variation in FLS invasion was much less than the mean interindividual variation (mean ؎ SD 1,067 ؎ 926 and 3,845 ؎ 2,367 for intraindividual and interindividual variation, respectively; P ‫؍‬ 0.035), which shows that the level of FLS invasion is a patient characteristic. The mean ؎ SEM Sharp score on radiographs of the hands or feet divided by the disease duration was 4.4 ؎ 1.1 units per year of disease duration in patients with the least invasive FLS (n ‫؍‬ 9), which was much lower compared with the 21.8 ؎ 3.1 units per year of disease duration in patients with the most invasive FLS (n ‫؍‬ 9) (P < 0.001).Conclusion. The ex vivo invasive behavior of FLS from RA patients is associated with the rate of joint destruction and is a patient characteristic, given the much smaller intraindividual than interindividual FLS variation.

The Vitamin D Receptor Regulates Rheumatoid Arthritis Synovial Fibroblast Invasion and Morphology

“…The in vitro invasion of FLSs was assayed in a transwell system using Matrigel-coated inserts from BD (Franklin Lakes, NJ, USA) as previously described (20,21). Briefly, 70% to 80% confluent cells were harvested by trypsin-EDTA digestion and resuspended at 2.0 × 10 4 cells in 500 μL serum-free Dulbecco's modified Eagle's medium (DMEM).…”

“…We, and others, have shown that the in vitro invasive properties of FLSs through collagen-rich Matrigel correlate with radiographic erosive changes and with histological joint damage in patients with RA and in rats with pristane-induced arthritis (PIA) (20,21). Because vitamin D deficiency correlates with increased risk for erosive disease and treatment with VDR agonists reduce joint damage, we hypothesized that the increased VDR signature in rats with mild and nonerosive arthritis could identify a new inhibitory pathway of FLS invasion.…”

A Plant-Derived Ligand Favoring Monomeric Glucocorticoid Receptor Conformation with Impaired Transactivation Potential Attenuates Collagen-Induced Arthritis

“…This results in a significant loss of quality of life due to pain and reduced mobility. The prominent destruction of cartilage and bone is orchestrated by the hyperproliferative and invasive nature of fibroblast-like synoviocytes (FLS) and osteoclast activation (1,2). Activation of NF-B proteins plays a central role in inflammation through the transcription of genes encoding, among others, proinflammatory cytokines, adhesion molecules, and chemokines.…”

“…Second, the humoral response plays a significant role in the pathogenesis of both diseases (24) and third, proinflammatory cytokines, including TNF-␣ and IL-1␤, are expressed in the affected joints and show a disease-promoting role (25)(26)(27). Additionally, CpdA was studied ex vivo, by using RA FLS, a cell type implicated by various investigators in the joint inflammation and destruction occurring in RA pathophysiology (1,2).…”

Fractalkine mediates T cell–dependent proliferation of synovial fibroblasts in rheumatoid arthritis

“…FLS derived from patients with RA were shown to attach to and invade normal human cartilage in a SCID mouse model (4). It has been suggested that the invasive behavior of FLS from patients with RA correlates with the rate of joint destruction as the disease progresses (5). FLS have also been implicated in regulating the fate of tissue-invasive lymphocytes, placing them in a critical position in the rheumatoid disease process.…”