2. Academic Validation
  3. ADAM8 silencing suppresses the migration and invasion of fibroblast-like synoviocytes via FSCN1/MAPK cascade in osteoarthritis

ADAM8 silencing suppresses the migration and invasion of fibroblast-like synoviocytes via FSCN1/MAPK cascade in osteoarthritis

  • Arthritis Res Ther. 2024 Jan 13;26(1):20. doi: 10.1186/s13075-023-03238-w.
Kai Chen # 1 2,  Huaqiang Tao # 1,  Pengfei Zhu # 1,  Miao Chu # 1 3,  Xueyan Li 4,  Yi Shi 4,  Liyuan Zhang 4,  Yaozeng Xu 1,  Shujun Lv 5,  Lixin Huang 6,  Wei Huang 7,  Dechun Geng 8
Affiliations

Affiliations

  • 1 Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China.
  • 2 Department of Orthopedics, Hai'an People's Hospital, Zhongba Road 17, Hai'an, Jiangsu, China.
  • 3 Department of Orthopedics, Yixing Peoples's Hospital, Xincheng Road 1588, Yixing, Jiangsu, China.
  • 4 Anesthesiology department, Suzhou Municipal Hospital (North District), Nanjing Medical University Affiliated Suzhou Hospital, Guangjj Road 242, Suzhou, Jiangsu, China.
  • 5 Department of Orthopedics, Hai'an People's Hospital, Zhongba Road 17, Hai'an, Jiangsu, China. shujunlv@163.com.
  • 6 Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China. szhuanglx@yeah.net.
  • 7 Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road 17, Hefei, An'hui, China. zgkdhwei@ustc.edu.cn.
  • 8 Department of Orthopedics, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, Jiangsu, China. szgengdc@suda.edu.cn.
  • # Contributed equally.
PMID: 38218854 DOI: 10.1186/s13075-023-03238-w
Abstract

Objective: Osteoarthritis (OA) is a degenerative joint disease that affects elderly populations worldwide, causing pain and disability. Alteration of the fibroblast-like synoviocytes (FLSs) phenotype leads to an imbalance in the synovial inflammatory microenvironment, which accelerates the progression of OA. Despite this knowledge, the specific molecular mechanisms of the synovium that affect OA are still unclear.

Methods: Both in vitro and in vivo experiments were undertaken to explore the role of ADAM8 playing in the synovial inflammatory of OA. A small interfering RNA (siRNA) was targeting ADAM8 to intervene. High-throughput Sequencing was also used.

Results: Our Sequencing analysis revealed significant upregulation of the MAPK signaling cascade and ADAM8 gene expression in IL-1β-induced FLSs. The in vitro results demonstrated that ADAM8 blockade inhibited the invasion and migration of IL-1β-induced FLSs, while also suppressing the expression of related matrix metallomatrix proteinases (MMPs). Furthermore, our study revealed that inhibiting ADAM8 weakened the inflammatory protein secretion and MAPK signaling networks in FLSs. Mechanically, it revealed that inhibiting ADAM8 had a significant effect on the expression of migration-related signaling proteins, specifically FSCN1. When siADAM8 was combined with BDP-13176, a FSCN1 inhibitor, the migration and invasion of FLSs was further inhibited. These results suggest that FSCN1 is a crucial downstream factor of ADAM8 in regulating the biological phenotypes of FLSs. The in vivo experiments demonstrated that ADAM8 inhibition effectively reduced synoviocytes inflammation and alleviated the progression of OA in rats.

Conclusions: ADAM8 could be a promising therapeutic target for treating OA by targeting synovial inflammation.

Keywords

ADAM8; Fibroblast-like synoviocytes; Inflammation; MAPK; Osteoarthritis.

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