Identification Of SOX5 and SOX6 As Potent Regulators Of RANKL Expression Contributing To Bone Erosion In Rheumatoid Arthritis and Experimental Arthritis Model

Wenfeng Tan¹, Xiaoke Feng², Lingxiao Xu³, Ke Gan⁴, Fang Wang³, Miaojia Zhang⁵, Hui Wu⁶ and Betty P. Tsao⁷, ¹Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China, ²Rheumatology, the First Affiliated Hospital of Nanjing Medical University, China, Nanjing, China, ³Department of Rheumatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, CHINA., Nanjing, China, ⁴Rheumatology Department, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China, ⁵Department of Rheumatology, Jiangsu Provincial People's Hospital, Nanjing, China, ⁶Rheumatology, David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, ⁷Medicine/Rheumatology, UCLA School of Medicine, Los Angeles, CA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Bone, RANK/RANKL pathway, rheumatoid arthritis (RA) and transcription factor

Session Information

Title: Cytokines, Mediators, Cell-cell Adhesion, Cell Trafficking and Angiogenesis II

Session Type: Abstract Submissions (ACR)

Background/Purpose:

We previously reported a RANKLpromoter SNP confers an elevated promoter activity after stimulation via binding to a SOX family transcription factor SOX5 and is associated with younger age at onset of rheumatoid arthritis (RA). Here, we examine the expression of SOX family in RA patients and to elucidate their potential role in RA pathogenesis.

Methods:

SOX expression levels in PBMC, plasma, and synovium were tested using RT-PCR, ELISA and immunohistochemistry. RNA interference and immunoprecipitation were used to determine the role of SOX5 and 6 on cytokine mediated RANKLexpression. Effect of SOX5 and 6 on bone erosion was analyzed using collagen-induced arthritis (CIA) model.

Results:

Among the 9 SOX family genes, expression of SOX5 and SOX6 were robust in 42 RA PBMC and 20 RA synovium smples. Compared to 40 osteoarthritis (OA) and 40 healthy controls (HC) samples, increased expression of SOX5 and 6 were observed consistently in PBMC (p<0.05, respectively), plasma (p=0.0002,p=0.0378, respectively) and synovium (p=0.0205,p<0.0001, respectively) from RA patients. Both SOX5 and 6 could be co-immunoprecipitated with Mab specific to RANKL upon TNFα and IL6 stimulation of rheumatoid fibroblast-like synoviocytes MH7A. An increase in RANKL expression was observed in MH7A after TNFα and IL6 treatment. Transfectiom with SOX5 and/or SOX6-shRNA significantly downregulated cytokine-mediated RANKL upregulation in MH7A. Intra-articular injection of lentivirus expressing shRNA for SOX5 and/or 6 gene silenced RANKL expression, suppressed arthritic development, and markedly ameliorated bone erosion inDAB/1mice of a CIA model.

Conclusion:

These findings identify SOX5 and 6 as potential targets for inhibition RANKL expression and preventing bone erosion in RA.

Disclosure:

W. Tan,
None;

X. Feng,
None;

L. Xu,
None;

K. Gan,
None;

F. Wang,
None;

M. Zhang,
None;

H. Wu,
None;

B. P. Tsao,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-sox5-and-sox6-as-potent-regulators-of-rankl-expression-contributing-to-bone-erosion-in-rheumatoid-arthritis-and-experimental-arthritis-model/