No abstract

The aim of this paper was to investigate the protective effects of bromodomain containing 4 (BRD4) inhibition on the temporomandibular joint osteoarthritis (TMJ OA) induced by compressive mechanical stress and to explore the underlying mechanism. In vivo, a rat model of TMJ compressive loading device was used and BRD4 inhibitor was injected into the TMJ region. HE staining and micro-CT analysis were used for histological and radiographic assessment. Immunohistochemistry and qPCR were performed to detect inflammatory cytokines expressions. High-throughput ChIP-sequencing screening was performed to compare the BRD4 and H3K27ac binding patterns between condylar cartilage from control and mechanical force groups. In vitro, the mandibular condylar chondrocytes were treated with IL-1β. Small Interference RNA (siRNA) infection was used to silencing BRD4 or TREM1. qPCR was performed to detect inflammatory cytokines expressions. Our study showed that BRD4 inhibition can alleviate the thinning of condylar cartilage and subchondral bone resorption, as well as decrease the inflammatory factors expression both in vivo and in vitro. ChIP-seq analysis showed that BRD4 was more enriched in the promoter region of genes related to the stress and inflammatory pathways under mechanical stress in vivo. Trem1, a pro-inflammatory gene, was screened out from the overlapped BRD4 and H3K27ac increased binding sites, and Trem1 mRNA was found to be regulated by BRD4 inhibition both in vivo and in vitro. TREM1 inhibition reduced the expression of inflammatory factors induced by IL-1β in vitro. In summary, we concluded that BRD4 inhibition can protect TMJ OA-like pathological changes induced by mechanical stress and attenuate TREM1-mediated inflammatory response.

The aim of this study was to investigate the effect of high fat diet and excessive compressive mechanical force on temporomandibular joint. In vivo, a mouse model of temporomandibular joint compressive loading device was used. A high fat diet mouse model and a combined mouse model intraperitoneally treated with or without simvastatin were used in the study. The pathological changes of mandibular condylar cartilage were assessed by Safranin-O staining. The IL-1β, MMP-3, leptin expression changes in the cartilage were detected by immunohistochemistry. In vitro, the mandibular condylar chondrocytes were treated with or without L-1β and simvastatin. The mRNA expression level of matrix MMPs and leptin were assessed. Both excessive compressive mechanical force and high fat diet induced obesity caused TMJ osteoarthritis-like changes and increased expression of IL-1β, MMP-3, and leptin. These pathological changes were much more serious when the two interventions were exerted together, while simvastatin could obviously alleviate these changes. The mRNA expression of MMP-3, MMP-13, and leptin increased in the IL-1β treated chondrocytes treated with IL-1β, and decreased with simvastatin treatment. The development of temporomandibular joint pathological changes could be caused by the excessive compressive mechanical force and high fat diet induced obesity.

With the fifth and sixth census and road network data, and using a spatial interoperability evaluation model and a spatial lag model, the spatial coupling relationship between China's road transport superiority degree and urbanization rate at the county level was analyzed. The result shows that: (1) Regional difference of China's urbanization rate is significant at the county level. Urbanization rate is low in traditional agricultural areas, poor contiguous mountainous counties (districts), and the spatial mismatch between economic development and labor resources was widespread, with urbanization taking place in areas away from residents' place of origin in underdeveloped areas. (2) Regional difference of road transport superiority degree is clear between the eastern and western regions and between the transport hubs and peripheries, with a clear"pointaxis" spatial structure at the regional level. Road transport superiority degree showed a partial normal distribution at the county level. (3) The overall coverage of highways, national highways, provincial highways, and county and township roads affects road accessibility for production flow, information flow, and nonagricultural market entrance of rural production factors, which affect urbanization development at the county level. Urbanization was obviously facilitated by the presence of highway exits and railway stations. (4) The spatial interoperability grade of road transport superiority degree and urbanization rate shows a partial normal distribution, with significantly mutual influence between urbanization and road transport development levels.