Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics

Abstract

The healthy synovial lining layer consists of a single cell layer that regulates the transport between the joint cavity and the surrounding tissue. It has been suggested that abnormalities such as somatic mutations in the p53 tumor-suppressor gene contribute to synovial hyperplasia and invasion in rheumatoid arthritis (RA). In this study, expression of epithelial markers on healthy and diseased synovial lining tissue was examined. In addition, we investigated whether a regulated process, resembling epithelial to mesenchymal transition (EMT)/fibrosis, could be responsible for the altered phenotype of the synovial lining layer in RA. Synovial tissue from healthy subjects and RA patients was obtained during arthroscopy. To detect signs of EMT, expression of E-cadherin (epithelial marker), collagen type IV (indicator of the presence of a basement membrane) and α-smooth muscle actin (α-sma; a myofibroblast marker) was investigated on frozen tissue sections using immunohistochemistry. Fibroblast-like synoviocytes (FLSs) from healthy subjects were isolated and subjected to stimulation with synovial fluid (SF) from two RA patients and to transforming growth factor (TGF)-β. To detect whether EMT/fibrotic markers were increased, expression of collagen type I, α-sma and telopeptide lysylhydroxylase (TLH) was measured by real time PCR. Expression of E-cadherin and collagen type IV was found in healthy and arthritic synovial tissue. Expression of α-sma was only found in the synovial lining layer of RA patients. Stimulation of healthy FLSs with SF resulted in an upregulation of α-sma and TLH mRNA. Collagen type I and TLH mRNA were upregulated after stimulation with TGF-β. Addition of bone morphogenetic protein (BMP)-7 to healthy FLS stimulated with SF inhibited the expression of α-sma mRNA. The finding that E-cadherin and collagen type IV are expressed in the lining layer of healthy and arthritic synovium indicates that these lining cells display an epithelial-like phenotype. In addition, the presence of α-sma in the synovial lining layer of RA patients and induction of fibrotic markers in healthy FLSs by SF from RA patients indicate that a regulated process comparable to EMT might cause the alteration in phenotype of RA FLSs. Therefore, BMP-7 may represent a promising agent to counteract the transition imposed on synoviocytes in the RA joint.

Systemic Wound Healing Associated with local sub-Cutaneous Mechanical Stimulation

“…3b and Supplementary Data S8) of the 3 serological settings (MS+, MS−, FBS) refer to c ell cycle activation with emphasis on the mitotic phase, indicating positive survival signals received by the cells towards an active division and duplication. This translates equally likely in RASFLs as a message of proliferation, proxy for tissue invasion (synovial hyperplasia, cell over-proliferation in an inflammatory milieu), or tissue regeneration (homeostasis and repair, cell proliferation in a physiologic microenvironment), corresponding to a transition towards a mesenchymal or epidermal phenotype, respectively32. To disambiguate the epithelial versus mesenchymal conformation, three distinctive key molecules, Fos, Wnt5b and Gjb2 , were validated by qRT-PCR.…”

IL-22 Promotes Fibroblast-Mediated Wound Repair in the Skin

“…The results presented here could help explain some aspects of IL-22’s pathogenicity, since IL-22 may act on fibroblast-like chondrocytes in the joints and fibroblasts in the skin to induce excessive collagen production in patients with rheumatoid arthritis or psoriasis, respectively (Koivukangas et al , 1995; Steenvoorden et al , 2006). In fact, IL-22 was recently shown to worsen synovitis by inducing the production of RANKL from synovial fibroblasts and therefore indirectly promoting osteoclastogenesis (Kim et al , 2011).…”

Stromal cell markers are differentially expressed in the synovial tissue of patients with early arthritis

“…RA FLS show a gene expression profile reminiscent of myofibroblasts, and cells of the intimal lining layer in RA have been found to express α-smooth muscle actin (α-SMA) and type IV collagen [ 47 , 48 ]. It has therefore been suggested that RA FLS can undergo a process resembling epithelial-mesenchymal transition (EMT), whereby static epithelial cells lose cell-cell contacts, acquire mesenchymal features and manifest a migratory phenotype.…”