Abstract
Temporomandibular disorders are a common cause of chronic pain in the orofacial region and have a complex and multi-factorial pathophysiology. Mechanical loading or inflammatory conditions have been shown to decrease oxygen tension within the joint cartilage and activate the hypoxia-inducible factor (HIF) pathway, which in turn aggravates the pathological processes underlying temporomandibular joint (TMJ) disorders. We previously showed that low-intensity pulsed ultrasound (LIPUS) treatment effectively repairs TMJ injury induced by chronic sleep deprivation (CSD). Here, we explored the effects of LIPUS treatment on hypoxia-induced chondrocyte injury. We found that it effectively restored the proliferation capacity of mandibular chondrocytes under hypoxic conditions and lowered their rate of apoptosis. Chondrogenic capacity, as assessed by type II collagen levels, and mucin-positive areas were also significantly increased after LIPUS treatment. Levels of matrix metalloprotein-3 and interleukin-6 decreased in mandibular chondrocytes following this treatment, whereas the expression of tissue inhibitor of metalloproteinase-1 increased. We also found that HIF-1α expression was upregulated in mandibular chondrocytes under hypoxic conditions and was further enhanced by LIPUS treatment. Similarly, HIF-2α levels increased in mandibular chondrocytes under hypoxic conditions but decreased following LIPUS treatment. Subsequently, we established a CSD-induced TMJ injury model and found that LIPUS increased mucin-positive areas as well as HIF-1α expression and decreased HIF-2 level in the chondrocyte layer. Together, our results indicate that the protective effect of LIPUS on chondrocyte is partly associated with the HIF pathway.
Highlights
Temporomandibular disorders (TMDs) affect approximately 6– 12% of the population (Lipton et al, 1993; Brett et al, 2018) and manifest as pain in the mastication muscles and temporomandibular joint (TMJ), with associated joint noise when opening or closing the mouth (Scrivani et al, 2008; Wadhwa and Kapila, 2008)
We showed that the proliferative capacity of mandibular chondrocytes was significantly suppressed under hypoxic conditions and that low-intensity pulsed ultrasound (LIPUS) application partially restored cell growth (Figure 1A)
The apoptotic rate of mandibular chondrocytes significantly increased under hypoxic conditions compared to that in controls; hypoxia-induced apoptosis was ameliorated upon treatment with LIPUS (14.58% of cells were apoptotic in the hypoxia group at day 3 vs. 11.09% in the LIPUS-treated group and 11.28% in the control group; Figures 1B, C)
Summary
Temporomandibular disorders (TMDs) affect approximately 6– 12% of the population (Lipton et al, 1993; Brett et al, 2018) and manifest as pain in the mastication muscles and temporomandibular joint (TMJ), with associated joint noise when opening or closing the mouth (Scrivani et al, 2008; Wadhwa and Kapila, 2008). These disorders can occur due to muscle hyperfunction or parafunction, trauma, or hormonal and/or articular changes (Scrivani et al, 2008; Liu and Steinkeler, 2013).
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