Increased HIF-1<i>α</i> in Knee Osteoarthritis Aggravate Synovial Fibrosis via Fibroblast-Like Synoviocyte Pyroptosis

Zhang, Li; Huang, Zhengquan; Xing, Runlin; Li, Xiaochen; Yin, Songjiang; Mao, Jun J.; Zhang, Nongshan; Mei, Wei; Ding, Liang; Wang, Peimin

doi:10.1155/2019/6326517

Cited by 73 publications

(87 citation statements)

References 29 publications

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“…Gasdermin E is a member of a family of proteins that facilitate necrotic programmed cell death (pyroptosis) following cleavage by caspase-3 56 . Pyroptosis has recently been shown to promote knee osteoarthritis 57,58 , and upregulation of Gsdme in high-grade osteoarthritis cartilage ( Figure 5), supports a role for gasdermin E in disease progression. Ccdc6 -/mice had increased articular cartilage surface damage affecting the medial compartment ( Supplementary Tables 3, 4 and 6).…”

Section: And 6)mentioning

confidence: 63%

Accelerating functional gene discovery in osteoarthritis

Butterfield

Curry

Steinberg

et al. 2019

Preprint

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Osteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by Crispr/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.

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Section: And 6)mentioning

confidence: 63%

Accelerating functional gene discovery in osteoarthritis

Butterfield

Curry

Steinberg

et al. 2019

Preprint

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“…In our last studies, the correlation between the NLRP inflammasomes and synovial fibroblast pyroptosis was investigated in vivo and in vitro [13]. We also revealed that increased hypoxia-inducible factor-1 α in KOA aggravates synovial fibrosis via synovial fibroblast pyroptosis [14].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Synovial Macrophage Pyroptosis Alleviates Synovitis and Fibrosis in Knee Osteoarthritis

Zhang

Xing

Huang

et al. 2019

Mediators of Inflammation

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Increasing evidence has shown that macrophage pyroptosis in different tissues participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last studies also revealed the vital role of synovial fibroblast pyroptosis in the onset and development of knee osteoarthritis (KOA). In this study, we aimed to investigate whether synovial macrophage pyroptosis did occur and whether this form of cell death should be related to synovitis and fibrosis of KOA. In the synovial tissue of KOA model rats, we observed a decrease of caspase1, NLRP3, ASC, and GSDMD caused by macrophage depletion in both the mRNA and protein expressions. Besides, rats treated with the specific caspase1 inhibitor Ac-YVAD-CMK showed less inflammatory reaction and fibrosis, not only in the expression of proinflammatory factors IL-1β, IL-18, and HMGB1 and fibrosis markers TGF-β, PLOD2, COL1A1, and TIMP1 but also in the observation of HE staining, Sirius Red staining, and the transverse diameters of the right knees. Subsequently, we established an LPS+ATP-induced model in macrophages mimicking the inflammatory environment of KOA and inducing macrophage pyroptosis. Macrophages transfected with caspase1 siRNA showed reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins were also downregulated. In addition, the level of fibrotic markers in synovial fibroblasts were significantly decreased after coculture with siRNA GSDMD-transfected macrophages. To conclude, synovial macrophage pyroptosis may occur in the pathological processes of KOA and inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in KOA model rats.

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“…In the first 14 days, ten rats in the normal group were injected with 50 ul sterilized physiologic saline, and the KOA model was constructed by MIA as previously mentioned, using both knees. 22 From the 14th day, Chrysin (oscillated dissolved in 0.5% sodium carboxymethylcellulose (CMC) overnight) was administered by intragastric administration. The normal group and the MIA group were administered 0.5% CMC as the control, and each rat in the MIA+Chrysin group was treated with a dose of 10 mg/kg Chrysin.…”

Section: In Vivo Animal Experimental Designmentioning

confidence: 99%

<p>Chrysin Attenuates the NLRP3 Inflammasome Cascade to Reduce Synovitis and Pain in KOA Rats</p>

Liao

Ding

et al. 2020

DDDT

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Our recent reports have revealed that inhibiting NLRP3 activation reduces synovial inflammation and fibrosis in knee osteoarthritis (KOA). Synovial inflammation is involved the entire process of KOA and promotes the progression of KOA. Natural flavonoid Chrysin from Scutellariae Radix, a traditional Chinese medicine, exhibits multifarious biological activities and potentially has protective activity against osteoarthritis. However, the mechanism of Chrysin in the treatment of synovial inflammation remains elusive. The purpose of our research was to explore the anti-inflammatory effects of Chrysin on KOA, which was induced by monoiodoacetic acid (MIA) in rats by targeting the NLRP3 inflammasome in the hopes of identifying an effective drug to treat KOA. Methods: The MIA-induced KOA model was used to evaluate the cold pain threshold and paw withdrawal threshold (PWT) of joints after MIA (40 mg/mL) injection into the knee joints. Microscopically, we used LPS (5 ug/mL) and ATP (4 mmol/L) to stimulate fibroblast-like synovial cells (FLSs) to explore the underlying mechanisms and effects of Chrysin. Two staining methods, H&E and Sirius Red, were applied to assess histopathological changes in synovial membranes. Cellular signal transduction was determined by qRT-PCR and WB. Cytokine expression (inflammatory cytokines and pain-related cytokines) was detected by ELISA. The degree of chronic inflammatory pain was evaluated by c-Fos immunofluorescence. Results: The results showed that Chrysin not only attenuated synovial inflammation but also reduced the secretion of pain-related factors and increased the PWT and cold pain threshold in rats. Chrysin also inhibited NLRP3 inflammasome activation and increased IL-1β levels to alleviate the synovitis. Conclusion: Chrysin can relieve knee synovial inflammation and improve pain behavior in KOA rats, which may be related to the ability of Chrysin to inhibit NLRP3 inflammasome activation. Therefore, Chrysin may be developed as a new drug for the treatment of KOA.

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Increased HIF-1α in Knee Osteoarthritis Aggravate Synovial Fibrosis via Fibroblast-Like Synoviocyte Pyroptosis

Cited by 73 publications

References 29 publications

Accelerating functional gene discovery in osteoarthritis

Accelerating functional gene discovery in osteoarthritis

Inhibition of Synovial Macrophage Pyroptosis Alleviates Synovitis and Fibrosis in Knee Osteoarthritis

<p>Chrysin Attenuates the NLRP3 Inflammasome Cascade to Reduce Synovitis and Pain in KOA Rats</p>

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