title: Modulation of IL-6 induced RANKL expression in arthritic synovium by a transcription factor SOX5.
abstract: Receptor activator of nuclear factor κB ligand (RANKL) is critically involved in bone erosion of rheumatoid arthritis (RA). We previously reported association between younger age at onset of RA and a RANKL promoter SNP that conferred an elevated promoter activity via binding to a transcription factor SOX5. Here we study the regulation of SOX5 levels in relation to RANKL expression in RA synovial fibroblasts (SF) and the development of bone erosion in the collagen-induced arthritis (CIA) mouse. Our data indicated SOX5 levels were higher in synovium and synovial fluid from RA compared to osteoarthritis patients. Pro-inflammatory cytokines upregulated SOX5 and RANKL expression in both primary RA SF and the rheumatoid synovial fibroblast cell line, MH7A. Overexpression of SOX5 resulted in significantly increased RANKL levels, while knockdown of SOX5 resulted in diminished IL-6 mediated RANKL upregulation in MH7A cells. Chromatin immunoprecipitation (ChIP) showed approximately 3-fold enrichment of RANKL-specific DNA in anti-SOX5 immunoprecipitate in IL-6 treated MH7A cells as compared to untreated cells. Locally silencing SOX5 gene significantly diminished RANKL positive cells and bone erosion in CIA mice. These findings suggest SOX5 is an important regulator of IL-6-induced RANKL expression in RA SF.
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, China.|Department of Traditional Chinese Medicine, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Yumeng
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Traditional Chinese Medicine, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Qiuyue
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Division of Rheumatology, UCLA School of Medicine, USA.
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Miaojia
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Tan
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism*; D002460:Cell Line; D003094:Collagen / Q000009:adverse effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D010003:Osteoarthritis / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D053245:RANK Ligand / Q000235:genetics*; D055755:SOXD Transcription Factors / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D053245:RANK Ligand; C490301:SOX5 protein, human; D055755:SOXD Transcription Factors; C505688:TNFSF11 protein, human; D003094:Collagen