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

Marjan MC Steenvoorden¹^,2 , Tanja CA Tolboom¹ , Gabri van der Pluijm³ , Clemens Löwik³ , Cornelis PJ Visser⁴ , Jeroen DeGroot² , Adriana C Gittenberger-DeGroot⁵ , Marco C DeRuiter⁵ , Bert J Wisse⁵ , Tom WJ Huizinga¹ and René EM Toes¹

¹Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

²TNO Quality of Life, Business Unit Biomedical Research, Zernikedreef 9, 2333 CK Leiden, The Netherlands

³Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

⁴Department of Orthopaedics, Rijnland Hospital, Simon Smitweg 1, 2353 GA Leiderdorp, The Netherlands

⁵Department of Anatomy and Embryology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

author email corresponding author email

Arthritis Research & Therapy 2006, 8:R165doi:10.1186/ar2073


Published:	31 October 2006

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.