Expression of the Collagenolytic and Ras-Induced Cysteine Proteinase Cathepsin L and Proliferation-Associated Oncogenes in Synovial Cells of MRL/I Mice and Patients with Rheumatoid Arthritis

Self Cite

Objective. To compare the expression of cathepsin L, cathepsin D, and collagenase messenger RNA (mRNA) in synovial specimens from patients with rheumatoid arthritis (RA) and osteoarthritis (OA).Methods. The expression of cathepsins L and D as well as collagenase mRNA in synovial tissues from 8 patients with RA, 6 patients with OA, and 2 patients with noninflamed joints was evaluated using in situ hybridization with digoxigenin-labeled RNA probes.Results. Both RA and OA synovial tissue expressed cathepsins L and D as well as collagenase mRNA. The expression of the cathepsins was markedly higher in interstitial regions and, to some extent, in perivascular infiltrates of RA synovial tissue compared with OA specimens. Conclusion. Cathepsins L and D mRNA are expressed differently in RA and OA synovial tissues, supporting the concept that these enzymes may contribute to the influx of mononuclear cells into RA synovium. Moreover, the data reveal that the expression of collagenase and cathepsins in RA and OA synovial lining is otherwise largely similar, and suggest that the adhesion

Section: Discussionsupporting

confidence: 91%

Comparative analysis of cathepsin l, cathepsin d, and collagenase messenger rna expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis, by in situ hybridization

Keyszer

Heer²,

Kriegsmann³

et al. 1995

Self Cite

“…In RASFs, c-Myc has been demonstrated to be upregulated (39), especially at sites of destruction in RA joints (40). Recently, it was shown that the delivery of c-myc antisense oligodeoxynucleotides significantly reduces the proliferation of RASFs and may induce apoptosis through caspase signaling (41).…”

Section: Discussionmentioning

confidence: 99%

Cooperation of Ras‐ and c‐Myc–dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis

Pap

Nawrath

Heinrich

et al. 2004

Self Cite

Conclusion. The data demonstrate that Ras-and c-Myc-dependent signaling events cooperate to regulate the growth and invasiveness of RASFs. Targeting of both c-Raf-1 and c-Myc may constitute an interesting therapeutic approach in RA.Growing evidence suggests that activated synovial fibroblasts (SFs) play a pivotal role in the pathogenesis of rheumatoid arthritis (RA), a systemic disabling disease that primarily affects the joints and results in their progressive destruction (1). Such activated fibroblasts are found predominantly in the synovial lining and appear largely responsible for the progressive destruction of articular cartilage. Apart from an altered morphology (2), changes in the expression of protooncogenes (3) and tumor suppressor genes (4,5) have been demonstrated in RASFs. Among the signaling molecules Supported by grants from the Swiss National Science Foundation (SNSF 32-64142.00) and the Deutsche Forschungsgemeinschaft (DFG Pa 698/1-1, Pa 698/2-1, and Mu 1383/3-3).

“…FLS express MMPs 1, 3, 9, and 10, and the expression of FLS from patients with RA express several oncogenes at higher levels than do FLS from normal controls. Oncogenes that are up-regulated in RA are c-myc (11), ras (5), and p53 (6,7). These data have led to the suggestion that aspects of behavior of FLS in RA resemble those of malignant tissue.…”

mentioning

confidence: 99%

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

Tolboom¹,

Mil²,

Nelissen³

et al. 2005

130

102

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.