2. Academic Validation
  3. Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathway

Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathway

  • Cell Death Dis. 2021 Sep 28;12(10):886. doi: 10.1038/s41419-021-04170-0.
Tongzhou Liang  # 1,  Taiqiu Chen  # 1,  Jincheng Qiu  # 1,  Wenjie Gao  # 1,  Xianjian Qiu 1,  Yuanxin Zhu 1,  Xudong Wang 2,  Yanbo Chen 1,  Hang Zhou 1,  Zhihuai Deng 1,  Pengfei Li 1,  Caixia Xu 3,  Yan Peng 1,  Anjing Liang 1,  Peiqiang Su 2 4,  Bo Gao 5,  Dongsheng Huang 6
Affiliations

Affiliations

  • 1 Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Department of Orthopedics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Research Centre for Translational Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 5 Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. gaob5@mail.sysu.edu.cn.
  • 6 Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. hdongsh@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 34584074 DOI: 10.1038/s41419-021-04170-0
Abstract

Osteoarthritis (OA) is characterized by cartilage destruction, chronic inflammation, and local pain. Evidence showed that retinoic acid receptor-related orphan receptor-α (RORα) is crucial in cartilage development and OA pathogenesis. Here, we investigated the role and molecular mechanism of RORα, an important member of the nuclear receptor family, in regulating the development of OA pathologic features. Investigation into clinical cartilage specimens showed that RORα expression level is positively correlated with the severity of OA and cartilage damage. In an in vivo OA model induced by anterior crucial ligament transaction, intra-articular injection of si-Rora adenovirus reversed the cartilage damage. The expression of cartilage matrix components type II collagen and aggrecan were elevated upon RORα blockade. RNA-seq data suggested that the IL-6/STAT3 pathway is significantly downregulated, manifesting the reduced expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, including interaction with STAT3 and IL-6 promoter. Taken together, our findings indicated the pivotal role of the RORα/IL-6/STAT3 axis in OA progression and confirmed that RORα blockade improved the matrix catabolism in OA chondrocytes. These results may provide a potential treatment target in OA therapy.

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