Conditional Deletion of Fgfr3 in Chondrocytes leads to Osteoarthritis-like Defects in Temporomandibular Joint of Adult Mice.

Siru Zhou,Yangli Xie,Xianding Sun,Wei Xu,Qiaoyan Tan,Xiaolan Du,Nan Su,Shuo Huang,Junzhou Tang,Wei Li,Hangang Chen,Junlan Huang,Zuqiang Wang,Tingting Wu,Meng Xu,Jun Wang,Fei Luo ,Ya Shen

doi:10.1038/srep24039

Siru Zhou, Yangli Xie + Show 16 more

Open Access

https://doi.org/10.1038/srep24039

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Journal: Scientific Reports	Publication Date: Apr 4, 2016
Citations: 44	License type: CC BY 4.0

Affiliation: Army Medical University, Sichuan University

Abstract

Osteoarthritis (OA) in the temporomandibular joint (TMJ) is a common degenerative disease in adult, which is characterized by progressive destruction of the articular cartilage. To investigate the role of FGFR3 in the homeostasis of TMJ cartilage during adult stage, we generated Fgfr3f/f; Col2a1-CreERT2 (Fgfr3 cKO) mice, in which Fgfr3 was deleted in chondrocytes at 2 months of age. OA-like defects were observed in Fgfr3 cKO TMJ cartilage. Immunohistochemical staining and quantitative real-time PCR analyses revealed a significant increase in expressions of COL10, MMP13 and AMAMTS5. In addition, there was a sharp increase in chondrocyte apoptosis at the Fgfr3 cKO articular surface, which was accompanied by a down-regulation of lubricin expression. Importantly, the expressions of RUNX2 and Indian hedgehog (IHH) were up-regulated in Fgfr3 cKO TMJ. Primary Fgfr3 cKO chondrocytes were treated with IHH signaling inhibitor, which significantly reduced expressions of Runx2, Col10, Mmp13 and Adamts5. Furthermore, the IHH signaling inhibitor partially alleviated OA-like defects in the TMJ of Fgfr3 cKO mice, including restoration of lubricin expression and improvement of the integrity of the articular surface. In conclusion, our study proposes that FGFR3/IHH signaling pathway plays a critical role in maintaining the homeostasis of TMJ articular cartilage during adult stage.

Highlights

As a load-bearing and shock-absorbing joint during jaw movement, the temporomandibular joint (TMJ) is frequently used during daily activities in human[1]
Due to the abnormal craniofacial morphology resulting from the gain-of-function mutation of Fibroblast growth factor receptor 3 (FGFR3) during skeletal development, the precise role of FGFR3 signaling in the homeostasis of TMJ articular cartilage during adult stage remains elusive
Previous studies have shown that FGFR3 expression is significantly down-regulated in articular cartilage from OA patients compared to that from human without OA, implying that FGFR3 signaling in articular cartilage is involved in the OA process during adult stage[38]

Summary

Introduction

As a load-bearing and shock-absorbing joint during jaw movement, the temporomandibular joint (TMJ) is frequently used during daily activities in human[1]. Given that the biomechanical properties of TMJ were already altered during early craniofacial development prior to the postnatal degenerative changes of condylar articular cartilage in Fgfr3P244R mutant mice, the functional roles and mechanisms of FGFR3 signaling in maintaining articular cartilage of adult TMJ has not been adequately investigated. To determine whether and how FGFR3 signaling affects the maintenance of TMJ articular cartilage homeostasis, we conditionally deleted Fgfr[3] in chondrocytes of mice during adult stage to avoid the involvement of abnormal craniofacial development in the maintenance of TMJ cartilage These Fgfr3-deficient mice exhibit progressive TMJOA-like changes, indicating that FGFR3 signaling is critically involved in the maintenance of the structure integrity and function of TMJ articular cartilage during adult stage

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