Wnt16 attenuates osteoarthritis progression through a PCP/JNK-mTORC1-PTHrP cascade

Author:

Tong WenxueORCID,Zeng Yelin,Chow Dick Ho Kiu,Yeung Wai,Xu Jiankun,Deng Yujie,Chen Shihui,Zhao Hui,Zhang Xiaoling,Ho Kevin Kiwai,Qin Ling,Mak Kingston King-lun

Abstract

ObjectivesWnt16 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.MethodsThe 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.ResultsWnt16 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.ConclusionsOur 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.

Funder

Direct grant for research from Research Grant Council, Hong Kong

the Seed Fund of the School of Biomedical Sciences, The Chinese University of Hong Kong

Hong Kong Theme-based Research Scheme from General Research Fund

Publisher

BMJ

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology

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