Sonic hedgehog signaling drives proliferation of synoviocytes in rheumatoid arthritis: a possible novel therapeutic target.

Mingxia Wang,Xiaoxue Feng,Zhuofeng Lin,Zhaoxia Li,Weixiang Peng,Jianlin Huang,Minqi Luo,Qiuxia Li,Shangling Zhu

doi:10.1155/2014/401903

Abstract

Sonic hedgehog (Shh) signaling controls many aspects of human development, regulates cell growth and differentiation in adult tissues, and is activated in a number of malignancies. Rheumatoid arthritis (RA) is characterized by chronic synovitis and pannus formation associated with activation of fibroblast-like synoviocytes (FLS). We investigated whether Shh signaling plays a role in the proliferation of FLS in RA. Expression of Shh signaling related components (Shh, Ptch1, Smo, and Gli1) in RA synovial tissues was examined by immunohistochemistry (IHC) and in FLS by IHC, immunofluorescence (IF), quantitative RT-PCR, and western blotting. Expression of Shh, Smo, and Gli1 in RA synovial tissue was higher than that in control tissue (P < 0.05). Cyclopamine (a specific inhibitor of Shh signaling) decreased mRNA expression of Shh, Ptch1, Smo, and Gli1 in cultured RA FLS, Shh, and Smo protein expression, and significantly decreased FLS proliferation. Flow cytometry analysis suggested that cyclopamine treatment resulted in cell cycle arrest of FLS in G1 phase. Our data show that Shh signaling is activated in synovium of RA patients in vivo and in cultured FLS form RA patients in vitro, suggesting a role in the proliferation of FLS in RA. It may therefore be a novel therapeutic target in RA.

Highlights

Rheumatoid arthritis (RA) is characterized by persistent synovitis, systemic inflammation, and autoantibodies [1]
Ptch1, Smo, and Gli1 Protein Were Highly Expressed in Synovium from Patients with RA
Our results show that Sonic hedgehog (Shh), Ptch1, Smo, and Gli1 proteins were highly expressed in synovial tissue of patients with RA, especially in Fibroblast-like synoviocytes (FLS), while expression in synovial tissue of patients with knee trauma was much lower

Summary

Introduction

Rheumatoid arthritis (RA) is characterized by persistent synovitis, systemic inflammation, and autoantibodies ( rheumatoid factor and anticitrullinated peptide) [1]. FLS contribute significantly to the perpetuation of disease and perhaps play a role in the initiation phase These FLS from RA patients constitute a quite unique cell type and they distinguish RA from other inflammatory conditions of the joints. A number of studies have demonstrated that FLS from RA patients showed alterations in morphology and behaviour, including molecular changes in signaling cascades, in apoptosis, expression of adhesion molecules, and matrix-degrading enzymes. These changes appear to reflect a stable activation of FLS in RA, which occurs independently through continuous exogenous stimulation. FLS are no longer considered passive bystanders in RA but active players in the complex intercellular network of RA [4]

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Conclusion