The Protective Effects of Salubrinal on the Cartilage and Subchondral Bone of the Temporomandibular Joint under Various Compressive Mechanical Stimulations.

Juan Wen,Sheng Chen,Caixia Zhang,Yuanyuan Jiang,Huang Li,Jie Zheng

doi:10.1371/journal.pone.0155514

Abstract

Excessive mechanical loads on the temporomandibular joint (TMJ) can cause mandibular cartilage degradation and subchondral bone erosion, but the treatment of these conditions remains challenging. Salubrinal, which target eukaryotic translation initiation factor 2 alpha, has been shown to have multiple beneficial effects on skeletal tissue. Here, we examined the effect of a Salubrinal injection on the mandibular cartilage and subchondral bone of the TMJ under various compressive stresses. We conducted in vivo analyses in rat models using various compressive stresses (40 g and 80 g), and we observed time-related degeneration and pathological changes in the cartilage and subchondral bone of the TMJ at days 1, 3 and 7 through histological measurements, subcellular observation, and changes in proliferation and apoptosis. After the Salubrinal injection, the thickness of the cartilage recovered, and the pathological change was alleviated. In the Salubrinal/light (Sal/light) compressive stress group, the drug altered the proliferation and apoptosis of chondrocytes most significantly at day 1. In the Salubrinal/heavy (Sal/heavy) compressive stress group, the drug increased the proliferation of chondrocytes most significantly at day 1 and reduced the apoptosis of chondrocytes most significantly at day 7. Salubrinal also increased the area of the bone trabeculae and suppressed inflammatory responses and pathological change in the subchondral bone of the TMJ. Together, these results indicate that the administration of Salubrinal reduces apoptosis and strengthens the proliferation of chondrocyte to varying degrees at days 1, 3 and 7 under various compressive mechanical stresses, both of which contribute to the recovery of cartilage thickness and the alleviation of pathological change. Salubrinal also suppresses inflammatory responses and pathological change in the subchondral bone of the TMJ.

Highlights

IntroductionAppropriate mechanical loads on the temporomandibular joint (TMJ) are vital for the maintenance and remodeling of mandibular condylar cartilage
The temporomandibular joint (TMJ) is a diarthrodial joint in the human body
To explore the effect of eIF-2alpha inhibitor Salubrinal on the mandibular cartilage under compressive mechanical stress, we used hematoxylin and eosin (H&E) staining to observe the thickness of the mandibular cartilage (Fig 1A)

Summary

Introduction

Appropriate mechanical loads on the TMJ are vital for the maintenance and remodeling of mandibular condylar cartilage. Excessive mechanical stress, which can be generated by parafunction, has been recognized as a major factor in the development of osteochondral damage or diseases of the TMJ [1]. Previous studies have reported increased apoptosis of chondrocytes in cartilage and reduced proliferation of mandibular chondrocytes in vivo and vitro in response to excessive mechanical stress [2,3,4]. The treatment of osteochondral damage and TMJ diseases still remains a major challenge. We have proven that endoplasmic reticulum stress (ERS) regulates mechanical stressinduced cartilage thinning [3]. Salubrinal, which is an inhibitor of ERS, can elevate the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) [5]. Salubrinal suppresses osteoclastogenesis, followed by bone resorption and protection [8,9]

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Results

Discussion

Conclusion