Research article

Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis

Seung-Jun Hwang^†, Bongkun Choi^†, Soon-Suk Kang, Jae-Ho Chang, Yong-Gil Kim, Yeon-Ho Chung, Dong H Sohn, Min W So, Chang-Keun Lee, William H Robinson and Eun-Ju Chang^*

• * Corresponding author: Eun-Ju Chang ejchang@amc.seoul.kr

• † Equal contributors

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Arthritis Research & Therapy 2012, 14:R14 doi:10.1186/ar3693

Published: 20 January 2012

Abstract (provisional)

Introduction

Interleukin-34 (IL-34) is a recently defined cytokine, showing a functional overlap with macrophage colony stimulating factor (M-CSF). This study was undertaken to address the expression of IL-34 in rheumatoid arthritis (RA) patients and to investigate its regulation and pathogenic role in RA.

Methods

IL-34 levels were determined in the RA synovium, synovial fluid (SF) and fibroblast-like synovial cells (FLS) by immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay and immunoblotting. RA activity was assessed using Disease Activity Score 28 (DAS28) activity in the plasma collected at baseline and 1-yr after treatment. Conditioned media (CM) was prepared from RA FLS culture with tumor necrosis factor alpha (TNFa) for 24 h and used for functional assay.

Results

IL-34 was expressed in the synovium, SF, and FLS from RA patients. The production of IL-34 in FLS was up-regulated by TNFa in RA samples compared with osteoarthritis (OA) patients. Importantly, the preferential induction of IL-34 rather than M-CSF by TNFa in RA-FLS was mediated by the transcription factor nuclear factor kappa B (NF-kappaB) and activation of c-Jun N-terminal kinase (JNK). IL-34 elevation in plasma from RA patients was decreased after disease-modifying anti-rheumatic drugs (DMARDs) administration in accordance with a decrease in DAS28. CM from RA-FLS cultured with TNFa promoted chemotactic migration of human peripheral blood mononuclear cells (PBMCs) and subsequent osteoclast (OC) formation, effects that were attenuated by an anti-IL-34 antibody.

Conclusions

These data provide novel information about the production of IL-34 in RA FLS and indicate that IL-34 is an additional osteoclastogenic factor regulated by TNFa in RA, suggesting a discrete role of IL-34 in inflammatory RA diseases.