2. Academic Validation
  3. TGFβ attenuates cartilage extracellular matrix degradation via enhancing FBXO6-mediated MMP14 ubiquitination

TGFβ attenuates cartilage extracellular matrix degradation via enhancing FBXO6-mediated MMP14 ubiquitination

  • Ann Rheum Dis. 2020 Aug;79(8):1111-1120. doi: 10.1136/annrheumdis-2019-216911.
Gangliang Wang  # 1 2,  Shuai Chen  # 1 2,  Ziang Xie  # 1 2,  Shuying Shen  # 1 2,  Wenbin Xu 1 2,  Wenxiang Chen 1 2,  Xiang Li 1 2,  Yizheng Wu 1 2,  Liangping Li 1 2,  Bin Liu 3,  Xianjun Ding 1 2,  An Qin 4,  Shunwu Fan 5 2
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 2 Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 3 Key Laboratory of Protein Modification and Tumor, Hubei Polytechnic University School of Medicine, Huangshi, Hubei, China.
  • 4 Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China shunwu_fan@zju.edu.cn dr_qinan@163.com.
  • 5 Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China shunwu_fan@zju.edu.cn dr_qinan@163.com.
  • # Contributed equally.
PMID: 32409323 DOI: 10.1136/annrheumdis-2019-216911
Abstract

Objectives: FBXO6, a component of the ubiquitin E3 Ligases, has been shown to bind high mannose N-linked glycoproteins and act as ubiquitin Ligase subunits. Most proteins in the secretory pathway, such as Matrix Metalloproteinases, are modified with N-glycans and play important roles in the development of osteoarthritis (OA). However, whether FBXO6 exerts regulatory effects on the pathogenesis of OA remains undefined.

Methods: The expression of FBXO6 was examined in the cartilage of human and multiple mouse OA models. The role of FBXO6 in cartilage degeneration was analysed with global FBXO6-/- mice, transgenic Col2a1-CreERT2;FBXO6f/f mice. The FBXO6 interacting partner MMP14 and its regulatory transcriptional factor SMAD2/3 were identified and validated in different pathological models as well as SMAD2-/- mice.

Results: The expression of FBXO6 decreased in the cartilage from human OA samples, anterior cruciate ligament transaction (ACLT) -induced OA samples, spontaneous OA STR/ort samples and aged mice samples. Global knockout or conditional knockout of FBXO6 in cartilage promoted experimental OA process. The molecular mechanism study revealed that FBXO6 decreased MMP14 by ubiquitination and degradation, leading to inhibited proteolytic activation of MMP13. Interestingly, FBXO6 expression is regulated by transforming growth factor β (TGFβ)-SMAD2/3 signalling pathway. Therefore, the overexpression of FBXO6 protected mice from post-injury OA development.

Conclusions: TGFβ-SMAD2/3 signalling pathway suppressed MMP13 activation by upregulating of FBXO6 transcription and consequently promoting MMP14 proteasomal degradation. Inducement of FBXO6 expression in OA cartilage might provide a promising OA therapeutic strategy.

Keywords

chondrocytes; cytokines; osteoarthritis.

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