Dataset Information

The Therapeutic Effects of Treadmill Exercise on Osteoarthritis in Rats by Inhibiting the HDAC3/NF-KappaB Pathway in vivo and in vitro.

ABSTRACT: Osteoarthritis (OA) is a disease characterized by non-bacterial inflammation. Histone deacetylase 3 (HDAC3) is a crucial positive regulator in the inflammation that leads to the development of non-OA inflammatory disease. However, the precise involvement of HDAC3 in OA is still unknown, and the underlying mechanism of exercise therapy in OA requires more research. We investigated the involvement of HDAC3 in exercise therapy-treated OA. Expression levels of HDAC3, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), matrix metalloproteinase-13 (MMP-13), HDAC3 and nuclear factor-kappaB (NF-kappaB) were measured by western blotting, reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Cartilage damage and OA evaluation were measured by hematoxylin and eosin staining and Toluidine blue O staining according to the Mankin score and OARSI score, respectively. We found that moderate-intensity treadmill exercise could relieve OA. Meanwhile, the expression of HDAC3, MMP-13, ADAMTS-5 and NF-kappaB decreased, and collagen II increased in the OA + moderate-intensity treadmill exercise group (OAM) compared with the OA group (OAG) or OA + high- or low-intensity treadmill exercise groups (OAH or OAL). Furthermore, we found the selective HDAC3 inhibitor RGFP966 could also alleviate inflammation in OA rat model through inhibition of nuclear translocation of NF-kappaB. To further explore the relationship between HDAC3 and NF-kappaB, we investigated the change of NF-kappaB relocation in IL-1?-treated chondrocytes under the stimulation of RGFP966. We found that RGFP966 could inhibit the expression of inflammatory markers of OA via regulation of HDAC3/NF-kappaB pathway. These investigations revealed that RGFP966 is therefore a promising new drug for treating OA.

SUBMITTER: Zhang H

PROVIDER: S-EPMC6710443 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Therapeutic Effects of Treadmill Exercise on Osteoarthritis in Rats by Inhibiting the HDAC3/NF-KappaB Pathway <i>in vivo</i> and <i>in vitro</i>.

Zhang He H Ji Lu L Yang Yue Y Wei Yingliang Y Zhang Xiaoning X Gang Yi Y Lu Jinghan J Bai Lunhao L

Frontiers in physiology 20190820

Osteoarthritis (OA) is a disease characterized by non-bacterial inflammation. Histone deacetylase 3 (HDAC3) is a crucial positive regulator in the inflammation that leads to the development of non-OA inflammatory disease. However, the precise involvement of HDAC3 in OA is still unknown, and the underlying mechanism of exercise therapy in OA requires more research. We investigated the involvement of HDAC3 in exercise therapy-treated OA. Expression levels of HDAC3, a disintegrin and metalloprotein ...[more]

PMID: 31481898

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Project description:BackgroundIn the past decade, mesenchymal stem cells (MSCs) have been widely used for the treatment of osteoarthritis (OA), and noncoding RNAs in exosomes may play a major role.AimThe present study is aimed at exploring the effect and mechanism of miR-326 in exosomes secreted by bone marrow mesenchymal stem cells (BMSCs) on pyroptosis of cartilage and OA improvement.MethodsExosomes from BMSCs (BMSC-Exos) were isolated and identified to incubate with OA chondrocytes. Proliferation, migration, specific gene and miR-326 expression, and pyroptosis of chondrocytes were detected. BMSCs or chondrocytes were transfected with miR-326 mimics or inhibitors to investigate the effect of miR-326 in BMSC-Exos on pyroptosis of chondrocytes and the potential mechanism. Finally, a rat OA model was established to verify the effect and mechanism of miR-326 in BMSC-Exos on cartilage of pyroptosis.ResultsIncubation with BMSC-Exos could significantly improve the survival rate, migration ability, and chondrocyte-specific genes (COL2A1, SOX9, Agg, and Prg4) and miR-326 expression of OA chondrocytes and significantly inhibit pyroptosis of chondrocytes by downregulation of the levels of inflammatory cytokines, Caspase-1 activity, and pyroptosis-related proteins such as GSDMD, NLRP3, ASC, IL-1β, and IL-18 (P < 0.01). PKH26 labeling confirmed the uptake of BMSC-Exos by chondrocytes. Incubation with exosomes extracted from BMSCs overexpressing miR-326 can significantly repress the pyroptosis of chondrocytes, while knockdown of miR-326 had the opposite effect (P < 0.01). The same result was also demonstrated by direct interference with the expression level of miR-326 in chondrocytes (P < 0.01). In addition, we found that the overexpression of miR-326 significantly inhibited the expression of HDAC3 and NF-κB p65 and significantly promoted the expression of STAT1, acetylated STAT1, and acetylated NF-κB p65 in chondrocytes (P < 0.01). The targeted relationship between miR-326 and HDAC3 was verified by dual-luciferase reporter assay. Animal experiments confirmed the mechanism by which miR-326 delivered by BMSC-Exos inhibits pyroptosis of cartilage by targeting HDAC3 and STAT1/NF-κB p65 signaling pathway.ConclusionBMSC-Exos can deliver miR-326 to chondrocytes and cartilage and improve OA by targeting HDAC3 and STAT1//NF-κB p65 to inhibit pyroptosis of chondrocytes and cartilage. Our findings provide a new mechanism for BMSC-Exos to treat OA.

Dataset Information

The Therapeutic Effects of Treadmill Exercise on Osteoarthritis in Rats by Inhibiting the HDAC3/NF-KappaB Pathway in vivo and in vitro.

Publications

The Therapeutic Effects of Treadmill Exercise on Osteoarthritis in Rats by Inhibiting the HDAC3/NF-KappaB Pathway <i>in vivo</i> and <i>in vitro</i>.

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