ROR1/STAT3 positive feedback loop facilitates cartilage degeneration in Osteoarthritis through activation of NF-κB signaling pathway

  • Int Immunopharmacol. 2023 Jun 19;121:110433. doi: 10.1016/j.intimp.2023.110433.
Wei Huang  1 ,  Hao Tang  2 ,  Yang Liu  1 ,  WenWei Li  1 ,  Ajmeri Sultana Shimu  3 ,  BoFeng Li  4 ,  Chen Zhu  5
Affiliations
  • 1. Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 2. Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 3. Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 4. Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Electronic address: [email protected].
  • 5. Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Electronic address: [email protected].
PMID: 37343369 DOI: 10.1016/j.intimp.2023.110433
Abstract

Background: Osteoarthritis (OA) is a chronic joint disorder with a serious impact on society. The main pathological change in OA is articular cartilage degeneration, which is directly associated with imbalance of anabolic and catabolic activities in chondrocytes.

Objective: To evaluate the expression and biological effects of ROR1 in OA cartilage and determine whether knockdown of ROR1 attenuates cartilage degeneration.

Methods: ROR1 expression in OA clinical specimens was evaluated by western blotting and immunohistochemistry. The effects of ROR1 on anabolic and catabolic activities were evaluated in Wnt5a-treated human primary chondrocytes by western blotting, immunofluorescence, and luciferase assay. The effects of ROR1 knockdown on cartilage degeneration in a surgical OA mouse model were examined by X-ray imaging and Safranin O-Fast Green histological staining.

Results: ROR1 was considerably upregulated in cartilage tissues of OA patients. ROR1 knockdown alleviated the activation of the NF-κB signaling pathway and reversed the suppression of Collagen II and aggrecan by Wnt5a, as well as upregulation of ADAMTS-5 and MMP-13 in chondrocytes. In addition, ROR1 knockdown significantly reduced Wnt5a-induced STAT3 nuclear translocation. STAT3 binding to the ROR1 promoter indicated a positive feedback loop between ROR1 and STAT3. ROR1 knockdown was confirmed to dramatically alleviate cartilage degradation in the DMM induced-OA mouse model.

Conclusion: Increased expression of ROR1 in OA cartilage tissues leads to a positive feedback loop with STAT3, which activates the NF-κB signaling pathway, resulting in an imbalance between chondrocyte anabolism and catabolism. These results indicate a potential new therapeutic target for the treatment of OA.

Keywords
NF-κB; Osteoarthritis; ROR1; STAT3.
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