Abstract
The main causes of cartilage destruction during temporomandibular joint osteoarthritis (TMJOA) are extracellular matrix degradation and angiogenesis, accompanied by an increased level of matrix-degrading enzymes and proangiogenic factors. Interleukin 6 and extracellular signal–regulated kinase (ERK) signaling pathways may play a critical role in these two processes simultaneously, but researchers have not clearly determined the mechanism. We hypothesized that estrogen-related receptor γ (ERRγ) is involved in both cartilage degeneration and angiogenesis in TMJOA. The interactions between ERRγ and the Mmp9 and Vegfa promoter regions were investigated using a chromatin immunoprecipitation (ChIP) assay. A chick embryo chorioallantoic membrane (CAM) assay was performed to investigate the inhibitory effects of U0126 and GSK5182 on angiogenesis. Western blotting, reverse transcription–quantitative PCR (RT-qPCR), immunofluorescence staining, toluidine blue staining, and transfection with cDNAs or small interfering RNAs (siRNAs) were performed on primary mandibular condylar chondrocytes (MCCs). Unilateral anterior crossbite–induced TMJOA models were established in rats, and Western blotting, RT-qPCR, immunohistochemistry, and Safranin O-Fast Green staining were performed to evaluate changes in vivo. ERK1/2 activated matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor A (VEGFA), which are involved in cartilage destruction, through ERRγ. Based on the ChIP assay results, ERRγ directly activated the transcription of the Mmp9 and Vegfa genes. In chick embryo CAM models, U0126 and GSK5182 significantly inhibited angiogenesis. In conclusion, ERRγ is a downstream transcription factor of ERK1/2, and its upregulation leads to extracellular matrix degradation and angiogenesis in TMJOA. This study identified a common factor between inflammation and vascularization in OA as well as a new therapeutic target for OA: ERRγ.
Highlights
Osteoarthritis (OA) is a whole-joint disease characterized by cartilage matrix destruction, subchondral bone sclerosis, osteophyte formation, synovitis, and articular cartilage absorption (Li et al, 2018)
We explored the possible association of estrogen-related receptor γ (ERRγ) with temporomandibular joint osteoarthritis (TMJOA) pathogenesis and detected a significant increase in the expression of P-extracellular signal–regulated kinase (ERK), ERRγ, matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor A (VEGFA) in the rat TMJOA model using immunohistochemical staining (Figures 1A, B)
We detected the expression of interleukin 6 (IL-6), Phospho-ERK, total ERK, ERRγ, ERRα, HIF1α, matrix metalloproteinase 13 (MMP13), VEGFA, MMP9, COL2, and AGG using Western blotting to determine the expression patterns of the target proteins, as shown in Figures 2A, C
Summary
Osteoarthritis (OA) is a whole-joint disease characterized by cartilage matrix destruction, subchondral bone sclerosis, osteophyte formation, synovitis, and articular cartilage absorption (Li et al, 2018). Articular cartilage is an avascular tissue (Brucker et al, 2005), when OA occurs, increased angiogenesis in the synovium, articular disc, and resulting callus lead to osteophyte formation and deep ossification of the joint (Brown and Weiss, 1988; Franses et al, 2010). Matrix metalloproteinase 9 (MMP9) (Ahmad et al, 2018), and vascular endothelial growth factor A1 (VEGFA) (Shen et al, 2015) play crucial roles in cartilage destruction and synovial angiogenesis in subjects with temporomandibular joint osteoarthritis (TMJOA) because these proteins are expressed at high levels in MCCs
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