한빛사논문
- 조회596
Jimin Jeon 1, Hyemi Lee 1, Min-Seung Jeon 2, Seok-Jung Kim 3, Cham Choi 4, Ki Woo Kim 5, Dong Joo Yang 5, Sangho Lee 1, Yong-Soo Bae 1, Won Il Choi 6, Juyeon Jung 7, Seong-il Eyun 2*, Siyoung Yang 1*
1Department of Biological Sciences Sungkyunkwan University Suwon 16419, Republic of Korea
2Department of Life Science Chung-Ang UniversitySeoul 06974, Republic of Korea
3Department of Orthopaedic SurgeryUijeongbu St. Mary’s HospitalThe Catholic University of Korea College of MedicineUijeongbu 11765, Republic of Korea
4MicroCT Applications 3rd floor, 11, Sumyeong-ro 1-gil, Gangseo-gu, Seoul 07644, Republic of Korea
5Department of Oral Biology Yonsei University College of DentistrySeoul 03722, Republic of Korea
6Center for Bio-Healthcare MaterialsBio-Convergence Materials R&D DivisionKorea Institute of Ceramic Engineering and Technology Cheongju, Chungbuk 28160, Republic of Korea
7Bionanotechnology Research CenterKorea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon 34141, Republic of Korea
*Corresponding authors: Correspondence to Seong-il Eyun or Siyoung Yang
Abstract
Although activin receptor IIB (ACVR2B) is emerging as a novel pathogenic receptor, its ligand and assembled components (or assembly) are totally unknown in the context of osteoarthritis (OA) pathogenesis. The present results suggest that upregulation of ACVR2B and its assembly could affect osteoarthritic cartilage destruction. It is shown that the ACVR2B ligand, activin A, regulates catabolic factor expression through ACVR2B in OA development. Activin A Tg mice (Col2a1-Inhba) exhibit enhanced cartilage destruction, whereas heterozygous activin A KO mice (Inhba+/−) show protection from cartilage destruction. In silico analysis suggests that the Activin A-ACVR2B axis is involved in Nox4-dependent ROS production. Activin A Tg:Nox4 KO (Col2a1-Inhba:Nox4−/−) mice show inhibition of experimental OA pathogenesis. NOX4 directly binds to the C-terminal binding site on ACVR2B-ACVR1B and amplifies the pathogenic signal for cartilage destruction through SMAD2/3 signaling. Together, the findings reveal that the ACVR2B assembly, which comprises Activin A, ACVR2B, ACVR1B, Nox4, and AP-1-induced HIF-2α, accelerates OA development. Furthermore, it is shown that shRNA-mediated ACVR2B knockdown or trapping ligands of ACVR2B abrogate OA development by competitively disrupting the ACVR2B-Activin A interaction. These results suggest that the ACVR2B assembly is required to amplify osteoarthritic cartilage destruction and could be a potential therapeutic target in efforts to treat OA.
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-05-24)
- 국내 연구진
- 의약학 > 면역의학
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