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Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathway.

ABSTRACT: Osteoarthritis (OA) is characterized by cartilage destruction, chronic inflammation, and local pain. Evidence showed that retinoic acid receptor-related orphan receptor-α (RORα) is crucial in cartilage development and OA pathogenesis. Here, we investigated the role and molecular mechanism of RORα, an important member of the nuclear receptor family, in regulating the development of OA pathologic features. Investigation into clinical cartilage specimens showed that RORα expression level is positively correlated with the severity of OA and cartilage damage. In an in vivo OA model induced by anterior crucial ligament transaction, intra-articular injection of si-Rora adenovirus reversed the cartilage damage. The expression of cartilage matrix components type II collagen and aggrecan were elevated upon RORα blockade. RNA-seq data suggested that the IL-6/STAT3 pathway is significantly downregulated, manifesting the reduced expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, including interaction with STAT3 and IL-6 promoter. Taken together, our findings indicated the pivotal role of the RORα/IL-6/STAT3 axis in OA progression and confirmed that RORα blockade improved the matrix catabolism in OA chondrocytes. These results may provide a potential treatment target in OA therapy.

SUBMITTER: Liang T

PROVIDER: S-EPMC8478978 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathwa

Project description:Osteoarthritis is characterized by cartilage destruction, chronic inflammation, and subchondral sclerosis. Evidence showed that nuclear receptor family is closely associated with cartilage damage in an unclear molecular mechanism. Here, we investigated the role and molecular mechanism of the retinoic acid receptor-related orphan receptor-α (RORα), an important member of nuclear receptor, in regulating cartilage degradation and osteoarthritis pathogenesis. Investigation to osteoarthritis clinical specimen showed that the degree of RORα elevation is positively correlated with the severity of osteoarthritis and cartilage damage. In an in vivo osteoarthritis models induced by anterior crucial ligament transaction, intraarticularly injection of siRora adenovirus reversed the cartilage damage. RORα knock-down increased the protein expression level of anabolic factor such as type II collagen, Aggrecan, and decreased the expression of catabolic factor. RNA-seq data suggested IL-6/STAT3 pathway is significantly down-regulated. Mechanistically, RORα knock-down decreased the expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, which includes interaction with STAT3 and IL6 promoter. Taken together, our findings indicated the pivotal role of RORα/IL-6/STAT3 axis in osteoarthritis progression and confirmed RORα knock-down exerted therapeutic effect in human chondrocyte thus providing a potential drug target in osteoarthritis therapy.

2021-04-20 | GSE172291 | GEO

Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathwa

Project description:Inhibition of nuclear receptor RORα attenuates cartilage damage in osteoarthritis by modulating IL-6/STAT3 pathwa

| PRJNA722842 | ENA

Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation.

Project description:Pathologic ocular angiogenesis is a leading cause of blindness, influenced by both dysregulated lipid metabolism and inflammation. Retinoic-acid-receptor-related orphan receptor alpha (RORα) is a lipid-sensing nuclear receptor with diverse biologic function including regulation of lipid metabolism and inflammation; however, its role in pathologic retinal angiogenesis remains poorly understood. Using a mouse model of oxygen-induced proliferative retinopathy, we showed that RORα expression was significantly increased and genetic deficiency of RORα substantially suppressed pathologic retinal neovascularization. Loss of RORα led to decreased levels of proinflammatory cytokines and increased levels of antiinflammatory cytokines in retinopathy. RORα directly suppressed the gene transcription of suppressors of cytokine signaling 3 (SOCS3), a critical negative regulator of inflammation. Inhibition of SOCS3 abolished the antiinflammatory and vasoprotective effects of RORα deficiency in vitro and in vivo. Moreover, treatment with a RORα inverse agonist SR1001 effectively protected against pathologic neovascularization in both oxygen-induced retinopathy and another angiogenic model of very-low-density lipoprotein receptor (Vldlr)-deficient (Vldlr (-/-) ) mice with spontaneous subretinal neovascularization, whereas a RORα agonist worsened oxygen-induced retinopathy. Our data demonstrate that RORα is a novel regulator of pathologic retinal neovascularization, and RORα inhibition may represent a new way to treat ocular neovascularization.

| S-EPMC4547221 | biostudies-literature

Danshen attenuates cartilage injuries in osteoarthritis in vivo and in vitro by activating JAK2/STAT3 and AKT pathways.

Project description:Articular cartilage degradation is a main feature of osteoarthritis (OA). The effects of Danshen, a traditional Chinese herb, in mitigating cartilage damage have been reported before. This study was conducted to investigate the effects of Danshen on cartilage injuries in OA. Rabbit OA models were established by surgical destabilization of the medial meniscus and the anterior and posterior cruciate ligaments in the left knee joint. Injection of Danshen into the articular cavity attenuated OA cartilage destruction in vivo. The levels of phosphorylated Janus kinase 2 (JAK2) and phosphorylated signal transducer and activator of transcription 3 (STAT3) were decreased in osteoarthritic cartilage, while they were rescued upon Danshen treatment. Furthermore, chondrocytes isolated from normal rabbit cartilage were exposed to 2 mM sodium nitroprusside (SNP) to establish an OA model in vitro. We found that the oxidative stress and chondrocyte apoptosis induced by SNP were suppressed by Danshen. The phosphorylation levels of JAK2 and STAT3 were decreased in response to SNP treatment, whereas they were rescued by Danshen. Additionally, AG490, a specific JAK2 inhibitor, counteracted the anti-apoptotic effect of Danshen. The phosphorylation level of protein kinase B (AKT) was also altered in response to SNP and reversed by Danshen. The anti-apoptotic effect of Danshen was counteracted by AKT pathway inhibitor LY194002. Taken together, Danshen attenuates OA cartilage destruction by regulating the JAK2/STAT3 and AKT signaling pathways.

| S-EPMC5955744 | biostudies-literature

The Xiaogu San Attenuates Pain and Cartilage Damage in Rats with Monosodium Iodoacetate Induced Osteoarthritis

Project description:Methods: A total of 24 Sprague Dawley rats were evenly and randomly divided into three separate groups including the normal control (NC), OA and XGS groups. MIA (50 μL, 10 mg/mL) was injected into the left knee joints of the rats to induce OA. After 7 days, The rats of XGS group were given XGS (0.45 g) that was externally applied to the left knee joint, were fixed with gauze and continuously administered XGS for 28 days. Morphological changes in tissues and organs were examined using H&E staining. Biochemical indicators were measured using an automatic biochemical analyzer. Inflammatory cytokines were detected using ELISA kits and immunohistochemistry. RNA-based high-throughput sequencing (RNA-seq) was performed to detect differential expression of mRNAs in normal and MIA–induced OA rats.

2021-09-02 | GSE183109 | GEO

Wnt7a Inhibits IL-1β Induced Catabolic Gene Expression and Prevents Articular Cartilage Damage in Experimental Osteoarthritis.

Project description:Wnt7a is a protein that plays a critical role in skeletal development. However, its effect on cartilage homeostasis under pathological conditions is not known. In this study, we found a unique inverse correlation between Wnt7a gene expression and that of MMP and IL-1β in individual human OA cartilage specimens. Upon ectopic expression in primary human articular chondrocytes, Wnt7a inhibited IL-1β-induced MMP and iNOS gene expression. Western blot analysis indicated that Wnt7a induced both canonical Wnt signaling and NFAT and Akt non-canonical signaling. Interestingly, inhibiting the canonical and Akt pathway did not affect Wnt7a activity. However, inhibiting the NFAT pathway impaired Wnt7a's ability to inhibit MMP expression, suggesting that Wnt7a requires NFAT signaling to exert this function. In vivo, intraarticular injection of lentiviral Wnt7a strongly attenuated articular cartilage damage induced by destabilization of the medial meniscus (DMM) OA-inducing surgery in mice. Consistently, Wnt7a also inhibited the progressive increase of joint MMP activity in DMM animals. These results indicate that Wnt7a signaling inhibits inflammatory stimuli-induced catabolic gene expression in human articular chondrocytes and is sufficient to attenuate MMP activities and promote joint cartilage integrity in mouse experimental OA, demonstrating a novel effect of Wnt7a on regulating OA pathogenesis.

| S-EPMC5292965 | biostudies-literature

Blockade of IL-33 signalling attenuates osteoarthritis.

Project description:ObjectivesOsteoarthritis (OA) is the most common form of arthritis characterised by cartilage degradation, synovitis and pain. Disease modifying treatments for OA are not available. The critical unmet need is to find therapeutic targets to reduce both disease progression and pain. The cytokine IL-33 and its receptor ST2 have been shown to play a role in immune and inflammatory diseases, but their role in osteoarthritis is unknown.MethodsNon-OA and OA human chondrocytes samples were examined for IL-33 and ST2 expression. Novel inducible cartilage specific knockout mice (IL-33Acan CreERT2) and inducible fibroblast-like synoviocyte knockout mice (IL-33Col1a2 CreERT2) were generated and subjected to an experimental OA model. In addition, wild-type mice were intra-articularly administered with either IL-33- or ST2-neutralising antibodies during experimental OA studies.ResultsIL-33 and its receptor ST2 have increased expression in OA patients and a murine disease model. Administering recombinant IL-33 increased OA and pain in vivo. Synovial fibroblast-specific deletion of IL-33 decreased synovitis but did not impact disease outcomes, whilst cartilage-specific deletion of IL-33 improved disease outcomes in vivo. Blocking IL-33 signalling also reduced the release of cartilage-degrading enzymes in human and mouse chondrocytes. Most importantly, we show the use of monoclonal antibodies against IL-33 and ST2 attenuates both OA and pain in vivo.ConclusionOverall, our data reveal blockade of IL-33 signalling as a viable therapeutic target for OA.

| S-EPMC7587452 | biostudies-literature

Tirbanibulin Attenuates Pulmonary Fibrosis by Modulating Src/STAT3 Signaling.

Project description:Tirbanibulin (KX-01) is the first clinical Src inhibitor of the novel peptidomimetic class that targets the peptide substrate site of Src providing more specificity toward the Src kinase. This study assessed the impact of KX-01 on cobalt chloride (CoCl2)-treated L929 cells and bleomycin (BLM)-induced pulmonary fibrosis in rats to evaluate the efficacy of this compound in vitro and in vivo, respectively. In CoCl2-treated L929 cells, KX-01 significantly reduced the expression of smooth muscle actin (α-SMA), collagen I, collagen III, hypoxia inducing factor (HIF-1α), signal transducers and transcriptional activators (p-STAT3), and p-Src. In BLM-induced pulmonary fibrosis rats, KX-01 reduced pathological scores, collagen deposition, α-SMA, collagen I, collagen III, p-Src, HIF-1α, and p-STAT3. Overall, these findings revealed that KX-01 can alleviate experimental pulmonary fibrosis via suppressing the p-SRC/p-STAT3 signaling pathways.

| S-EPMC8326405 | biostudies-literature

Noggin Inhibits IL-1β and BMP-2 Expression, and Attenuates Cartilage Degeneration and Subchondral Bone Destruction in Experimental Osteoarthritis.

Project description:Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1β) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1β increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1β, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1β increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1β promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1β and BMP-2, which prevents cartilage degeneration and OA development.

| S-EPMC7226847 | biostudies-literature

MicroRNA-10a-3p Improves Cartilage Degeneration by Regulating CH25H-CYP7B1-RORα Mediated Cholesterol Metabolism in Knee Osteoarthritis Rats.

Project description:Osteoarthritis (OA) is a worldwide degenerative joint disease that seriously impaired the quality of life of patients. OA has been established as a disease with metabolic disorder. Cholesterol 25-hydroxylase (CH25H) was proved to play a key role in cartilage cholesterol metabolism. However, the biological function and mechanism of CH25H in OA remains further investigation. Growing researches have proved the vital roles of miRNAs in OA progression. In this study, we screened out miR-10a-3p through high-throughput miRNA sequencing which may bind to CH25H. Molecular mechanism investigation indicated that miR-10a-3p is an upstream target of CH25H. Functional exploration revealed miR-10a-3p suppressed the inflammatory responses, cholesterol metabolism and extracellular matrix (ECM) degradation in primary chondrocytes. Moreover, rescue assays implied that miR-10a-3p reversed CH25H plasmids induced inflammatory cytokine production and ECM degradation. Furthermore, the OA rat model was established to explore the function of miR-10a-3p in vivo. The results showed that miR-10a-3p can recover the OA features through targeting CH25H/CYP7B1/RORα axis. In conclusion, these findings implied a crucial role of miR-10a-3p/CH25H/CYP7B1/RORα axis in OA, which may provide a promising therapeutic strategy for OA.

| S-EPMC8209416 | biostudies-literature

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