Dual Inhibition of TNF-α and OX40L on Synovial Inflammation and Osteoclastogenesis in Rheumatoid Arthritis

Hee Sung Kwon¹, Mi Hyeon Kim², Jeoung Yeon Kim², Seon Uk Kim², Hae Rim Kang¹, Seo Yoon Ban³, Gyong Sik Ha⁴, Chung Min Lee⁴, Jeong Seok Lee⁵ and Eun Young Lee², ¹Interdisciplinary Program in Cancer Biology, Integrated Major in Innovative Medical Science, Seoul National University, Seoul, South Korea, ²Seoul National University College of Medicine, Seoul, South Korea, ³Department of Cancer biology, Graduate School of College of Medicine, Seoul National University, Seoul, South Korea, ⁴Research institute, IMBiologics Corp, Suwon, South Korea, ⁵Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Seoul, South Korea

Meeting: ACR Convergence 2023

Keywords: Fibroblasts, Synovial, Gene Expression, osteoclastogenesis, rheumatoid arthritis

Session Information

Date: Tuesday, November 14, 2023

Title: (1734–1775) RA – Etiology and Pathogenesis Poster

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Rheumatoid arthritis (RA) is a chronic, inflammatory disease that leads to progressive cartilage and bone destruction. TNF superfamily member OX40 ligand (OX40L; CD252) is expressed specifically to synovial tissue and OX40/OX40L interaction is contributed to the development of T-cell mediated immunity in RA. In collagen-induced arthritis mouse model, it was demonstrated that blockade of TNF-α or OX40L significantly ameliorated disease activity. We present targeting both TNF-α and OX40L is superior to single treatment in fibroblast-like synoviocytes (FLS) invasiveness and osteoclast activation which are crucial RA pathology.

Methods: RA FLS were used from passage 4-6. FLS were stimulated with TNF-α (10ng/ml) for 2h and then treated with single TNF-α inhibitor (50nM), OX40L inhibitor (50nM) or IMB-101, a TNF-α/OX40L bispecific antibody (50nM) for 24hrs. Differential expression of RA FLS genes were analyzed by RT-PCR. For osteoclast differentiation assay, FLS were stimulated with TNF-α (10ng/ml) for 3 days, after which CD14+ monocytes were co-cultured with the IMB-101 (50nM) in the presence of M-CSF (20ng/ml) for 3 weeks. Osteoclasts were evaluated by tartrate-resistant acid phosphatase (TRAP) staining.

Results: OX40L was increased in TNF- α induced RA FLS compared to unstimulated RA FLS (p< 0.05) (n=7). RT-PCR analysis revealed significant reduction of IL-6, IL-1β, CCL2, CX3CL1, MMP-1, MMP-3, ICAM-1, RANKL, VEGF and HIF1-α in TNF-α stimulated RA FLS after IMB-101 or anti TNF treatment (n=4). Among these genes, MMP-3, RANKL and VEGF were significantly reduced in dual inhibition of TNF-α and OX40L than single target therapies. In co-culture system of RA FLS and CD14+ monocytes for osteoclast formation, IMB-101 decrease the number of TRAP-positive multinucleated cells over TNF-α inhibitor.

Conclusion: These results indicated that dual inhibition of TNF-α and OX40L axis simultaneously are associated with reduction of invasiveness in synovial fibroblast and joint destruction in RA.

Disclosures: H. Kwon: None; M. Kim: None; J. Kim: None; S. Kim: None; H. Kang: None; S. Ban: None; G. Ha: None; C. Lee: None; J. Lee: None; E. Lee: None.

To cite this abstract in AMA style:

Kwon H, Kim M, Kim J, Kim S, Kang H, Ban S, Ha G, Lee C, Lee J, Lee E. Dual Inhibition of TNF-α and OX40L on Synovial Inflammation and Osteoclastogenesis in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/dual-inhibition-of-tnf-%ce%b1-and-ox40l-on-synovial-inflammation-and-osteoclastogenesis-in-rheumatoid-arthritis/. Accessed .

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