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Wnt16 attenuates osteoarthritis progression through a PCP/JNK-mTORC1-PTHrP cascade
  1. Wenxue Tong1,
  2. Yelin Zeng2,
  3. Dick Ho Kiu Chow1,
  4. Wai Yeung2,
  5. Jiankun Xu1,
  6. Yujie Deng2,
  7. Shihui Chen1,
  8. Hui Zhao2,
  9. Xiaoling Zhang3,
  10. Kevin Kiwai Ho1,
  11. Ling Qin1,
  12. Kingston King-lun Mak2,4
  1. 1 Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
  2. 2 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
  3. 3 Department of Orthopedic Surgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China
  4. 4 The Joint Center for Musculoskeletal Research, Guangzhou Regenerative Medicine and Health-Guangdong Laboratory, Guangzhou, China
  1. Correspondence to Professor Ling Qin, Prince of Wales Hospital, Hong Kong, China; lingqin{at}cuhk.edu.hk; Professor Kingston King-lun Mak, Joint Center for Musculoskeletal Research, Guangzhou Regenerative Medicine and Health-Guangdong Laboratory, Guangzhou, China; kingston_mak{at}grmh-gdl.cn

Abstract

Objectives Wnt16 is implicated in bone fracture and bone mass accrual both in animals and humans. However, its functional roles and molecular mechanism in chondrocyte differentiation and osteoarthritis (OA) pathophysiology remain largely undefined. In this study, we analysed its mechanistic association and functional relationship in OA progression in chondrocyte lineage.

Methods The role of Wnt16 during skeletal development was examined by Col2a1-Wnt16 transgenic mice and Wnt16fl/fl;Col2a1-Cre (Wnt16-cKO) mice. OA progression was assessed by micro-CT analysis and Osteoarthritis Research Society International score after anterior cruciate ligament transection (ACLT) surgery with Wnt16 manipulation by adenovirus intra-articular injection. The molecular mechanism was investigated in vitro using 3D chondrocyte pellet culture and biochemical analyses. Histological analysis was performed in mouse joints and human cartilage specimens.

Results Wnt16 overexpression in chondrocytes in mice significantly inhibited chondrocyte hypertrophy during skeletal development. Wnt16 deficiency exaggerated OA progression, whereas intra-articular injection of Ad-Wnt16 markedly attenuated ACLT-induced OA. Cellular and molecular analyses showed that, instead of β-catenin and calcium pathways, Wnt16 activated the planar cell polarity (PCP) and JNK pathway by interacting mainly with AP2b1, and to a lesser extend Ror2 and CD146, and subsequently induced PTHrP expression through phosphor-Raptor mTORC1 pathway.

Conclusions Our findings indicate that Wnt16 activates PCP/JNK and crosstalks with mTORC1-PTHrP pathway to inhibit chondrocyte hypertrophy. Our preclinical study suggests that Wnt16 may be a potential therapeutic target for OA treatment.

  • osteoarthritis
  • Wnt16
  • PCP
  • mTORC1
  • PTHrP

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Footnotes

  • WT and YZ contributed equally.

  • Handling editor Josef S Smolen

  • Contributors WT and YZ performed most of the experiments and analysed the data. DHKC partly designed the experiments and helped perform the animal surgery. WY partly performed the in vitro experiments. JX, YD and SC contributed to the adenovirus infection analyses. KKH collected the clinical specimens. WT, YZ, DHKC, HZ and XZ were involved in manuscript preparation. LQ and KKM provided the conceptual framework, designed the study, supervised the project and wrote the manuscript.

  • Funding This work was partially supported by the Seed Fund of the Guangzhou Regenerative Medicine of Health-Guangdong Laboratory, the Hong Kong Theme-based Research Scheme from General Research Fund (No T13-402/17-N), the Seed Fund of the School of Biomedical Sciences, The Chinese University of Hong Kong (4620504) and direct grant for research from Research Grant Council, Hong Kong (2013.2.040).

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval All animal experiments were approved by the Chinese University of Hong Kong, Animal Experimentation Ethics Committee (AEEC). The tissue bank for the study of degenerative joint disease was approved by the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CUHK-NTEC CREC).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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