Inhibition of Ihh Reverses Temporomandibular Joint Osteoarthritis via a PTH1R Signaling Dependent Mechanism.

Hongxu Yang,Hongyun Zhang,Mian Zhang,Meiqing Wang,Mianjiao Xie,Lei Lu,Di Chen,Qian Liu,Jing Zhang

doi:10.3390/ijms20153797

Abstract

The temporomandibular joint (TMJ), which is biomechanically related to dental occlusion, is often insulted by osteoarthritis (OA). This study was conducted to clarify the relationship between Indian hedgehog (Ihh) and parathyroid hormone receptor 1 (PTH1R) signaling in modulating the enhanced chondrocyte terminal differentiation in dental stimulated TMJ osteoarthritic cartilage. A gain- and loss-of-function strategy was used in an in vitro model in which fluid flow shear stress (FFSS) was applied, and in an in vivo model in which the unilateral anterior cross-bite (UAC) stimulation was adopted. Ihh and PTH1R signaling was modulated through treating the isolated chondrocytes with inhibitor/activator and via deleting Smoothened (Smo) and/or Pth1r genes in mice with the promoter gene of type 2 collagen (Col2-CreER) in the tamoxifen-inducible pattern. We found that both FFSS and UAC stimulation promoted the deep zone chondrocytes to undergo terminal differentiation, while cells in the superficial zone were robust. We demonstrated that the terminal differentiation process in deep zone chondrocytes promoted by FFSS and UAC was mediated by the enhanced Ihh signaling and declined PTH1R expression. The FFSS-promoted terminal differentiation was suppressed by administration of the Ihh inhibitor or PTH1R activator. The UAC-promoted chondrocytes terminal differentiation and OA-like lesions were rescued in Smo knockout, but were enhanced in Pth1r knockout mice. Importantly, the relieving effect of Smo knockout mice was attenuated when Pth1r knockout was also applied. Our data suggest a chondrocyte protective effect of suppressing Ihh signaling in TMJ OA cartilage which is dependent on PTH1R signaling.

Highlights

Osteoarthritis (OA) is a type of joint problem, which is often caused by biomechanical factors, and cartilage is the most frequently involved site [1]
Consistent with our previous results, OA-like lesions in temporomandibular joint (TMJ) cartilage were induced by unilateral anterior cross-bite (UAC), displayed as a decreased thickness of the deep zone, and included predominantly prehypertrophic and hypertrophic layers, and a reduction of the cartilage matrix from two to eight weeks (Figure 1b,c)
The present data confirm our previous findings that deep zone chondrocytes respond to UAC, as well as fluid flow shear stress (FFSS), by terminal differentiation in addition to death [26]

Summary

Introduction

Osteoarthritis (OA) is a type of joint problem, which is often caused by biomechanical factors, and cartilage is the most frequently involved site [1]. Cells located in articular cartilage are differentiated from early to late stage [2]. The superficial zone cells are proliferative, and the deep zone chondrocytes are hypertrophic, from which stage the cells undergo terminal differentiation [3]. One of the main characteristics of OA is accelerated cellular differentiation [4]. In OA cartilage, chondrocytes recapitulate a course that resembles the process of chondrocyte terminal differentiation in terms of phenotypic and gene expression changes in the growth plate [5]. Cellular differentiation in the growth plate has been extensively reported [6]. Little is known about the molecular mechanisms of the biomechanically accelerated chondrocyte differentiation in osteoarthritic degenerative cartilage

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