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

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.

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Maltol inhibits the progression of osteoarthritis via the nuclear factor-erythroid 2-related factor-2/heme oxygenase-1 signal pathway in vitro and in vivo

Food & Function ◽

10.1039/d0fo02325f ◽

2021 ◽

Author(s):

Ding-Chao Zhu ◽

Yi-Han Wang ◽

Jia-Hao Lin ◽

Zhi-Min Miao ◽

Jia-Jing Xu ◽

...

Keyword(s):

Cartilage Degeneration ◽

Degenerative Joint Disease ◽

Signal Pathway ◽

Joint Disease ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Nuclear Factor ◽

Articular Cartilage Degeneration

Osteoarthritis (OA) is a common degenerative joint disease characterized by articular cartilage degeneration and inflammation. Currently, there is hardly any effective treatment for OA due to its complicated pathology and...

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Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study

Frontiers in Pharmacology ◽

10.3389/fphar.2021.687033 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiyuan Yan ◽

Yingchi Zhang ◽

Gaohong Sheng ◽

Bowei Ni ◽

Yifan Xiao ◽

...

Keyword(s):

Therapeutic Potential ◽

Cartilage Damage ◽

Cartilage Degradation ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Therapeutic Effects ◽

Exact Role

Osteoarthritis (OA) is a prevalent degenerative joint disease. Its development is highly associated with inflammatory response and apoptosis in chondrocytes. Selonsertib (Ser), the inhibitor of Apoptosis Signal-regulated kinase-1 (ASK1), has exhibited multiple therapeutic effects in several diseases. However, the exact role of Ser in OA remains unclear. Herein, we investigated the anti-arthritic effects as well as the potential mechanism of Ser on rat OA. Our results showed that Ser could markedly prevent the IL-1β-induced inflammatory reaction, cartilage degradation and cell apoptosis in rat chondrocytes. Meanwhile, the ASK1/P38/JNK and NFκB pathways were involved in the protective roles of Ser. Furthermore, intra-articular injection of Ser could significantly alleviate the surgery induced cartilage damage in rat OA model. In conclusion, our work provided insights into the therapeutic potential of Ser in OA, indicating that Ser might serve as a new avenue in OA treatment.

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Bax Targeted by miR-29a Regulates Chondrocyte Apoptosis in Osteoarthritis

BioMed Research International ◽

10.1155/2019/1434538 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Guiqiang Miao ◽

Xuehui Zang ◽

Huige Hou ◽

Hui Sun ◽

Lihui Wang ◽

...

Keyword(s):

Cartilage Degeneration ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Luciferase Reporter ◽

Chondrocyte Apoptosis ◽

Reporter Assay ◽

Proapoptotic Protein ◽

Regulation Mechanisms ◽

Direct Target

Osteoarthritis (OA) is a chronic degenerative joint disease, where chondrocyte apoptosis is responsible for cartilage degeneration. Bax is a well-known proapoptotic protein of the Bcl-2 family, involved in a large number of physiological and pathological processes. However, the regulation mechanisms of Bax underlying chondrocyte apoptosis in OA remain unknown. In the present study, we determined the role of Bax in human OA and chondrocyte apoptosis. The results showed that Bax was upregulated in chondrocytes from the articular cartilage of OA patients and in cultured chondrocyte-like ATDC5 cells treated by IL-1β. Bax was identified to be the direct target of miR-29a by luciferase reporter assay and by western blotting. Inhibition of miR-29a by the mimics protested and overexpression by miR-29a inhibitors aggravated ATDC5 apoptosis induced by IL-1β. These data reveal that miR-29a/Bax axis plays an important role in regulating chondrocyte apoptosis and suggest that targeting the proapoptotic protein Bax and increasing expression levels of miR-29a emerge as potential approach for protection against the development of OA.

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The Role of Fibrosis in Osteoarthritis Progression

Life ◽

10.3390/life11010003 ◽

2020 ◽

Vol 11 (1) ◽

pp. 3

Author(s):

Yeri Alice Rim ◽

Ji Hyeon Ju

Keyword(s):

Knee Joint ◽

Total Joint Replacement ◽

Cartilage Degeneration ◽

Critical Issue ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Joint Movement ◽

Synovial Membrane Inflammation ◽

Osteoarthritis Progression

Osteoarthritis (OA) is a chronic degenerative joint disease where the main characteristics include cartilage degeneration and synovial membrane inflammation. These changes in the knee joint eventually dampen the function of the joint and restrict joint movement, which eventually leads to a stage where total joint replacement is the only treatment option. While much is still unknown about the pathogenesis and progression mechanism of OA, joint fibrosis can be a critical issue for better understanding this disease. Synovial fibrosis and the generation of fibrocartilage are the two main fibrosis-related characteristics that can be found in OA. However, these two processes remain mostly misunderstood. In this review, we focus on the fibrosis process in OA, especially in the cartilage and the synovium tissue, which are the main tissues involved in OA.

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A green-lipped mussel reduces pain behavior and chondrocyte inflammation and attenuated experimental osteoarthritis progression

PLoS ONE ◽

10.1371/journal.pone.0259130 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0259130

Author(s):

JooYeon Jhun ◽

Hyun Sik Na ◽

Keun-Hyung Cho ◽

Jiyoung Kim ◽

Young-Mee Moon ◽

...

Keyword(s):

Cartilage Damage ◽

Cartilage Degeneration ◽

Kinase Domain ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Omega 3 ◽

Expression Levels ◽

Oa Chondrocytes ◽

And Cartilage

The green-lipped mussel (GLM) contains novel omega-3 polyunsaturated fatty acids, which exhibit anti-inflammatory and joint-protecting properties. Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive loss of cartilage; oxidative stress plays a role in the pathogenesis of OA. The objectives of this study were to investigate the in vivo effects of the GLM on pain severity and cartilage degeneration using an experimental rat OA model, and to explore the mode of action of GLM. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) into the knee. Oral GLM was initiated on the day after 3dyas of MIA injection. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Samples were analyzed both macroscopically and histologically. Immunohistochemistry was used to investigate the expression of interleukin-1β (IL-1β), IL-6, nitrotyrosine, and inducible nitric oxide synthase (iNOS) in knee joints. Also, the GLM was applied to OA chondrocyte, and the expression on catabolic marker and necroptosis factor were evaluated by real-time polymerase chain reaction. Administration of the GLM improved pain levels by preventing cartilage damage and inflammation. GLM significantly attenuated the expression levels of mRNAs encoding matrix metalloproteinase-3 (MMP-3), MMP-13, and ADAMTS5 in IL-1β-stimulated human OA chondrocytes. GLM decreased the expression levels of the necroptosis mediators RIPK1, RIPK3, and the mixed lineage kinase domain-like protein (MLKL) in IL-1β-stimulated human OA chondrocytes. Thus, GLM reduced pain and cartilage degeneration in rats with experimentally induced OA. The chondroprotective properties of GLM included suppression of oxidative damage and inhibition of catabolic factors implicated in the pathogenesis of OA cartilage damage. We suggest that GLM may usefully treat human OA.

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Anticoagulant Properties of Three Mucopolysaccharides Used in Rheumatology

Thrombosis and Haemostasis ◽

10.1055/s-0038-1665279 ◽

1983 ◽

Vol 50 (03) ◽

pp. 652-655 ◽

Cited By ~ 1

Author(s):

F Bauer ◽

P Schulz ◽

G Reber ◽

C A Bouvier

Keyword(s):

Factor Xa ◽

Degenerative Joint Disease ◽

Joint Disease ◽

Thrombin Time ◽

Coagulation Tests ◽

Amplification System ◽

Relative Potencies ◽

In Vivo Administration

SummaryThree mucopolysaccharides (MPS) used in the treatment of degenerative joint disease were compared to heparin to establish their relative potencies on 3 coagulation tests, the aPTT, the antifactor X a activity and the dilute thrombin time. One of the compounds, Arteparon®, was one fourth as potent as heparin on the aPTT, but had little or no influence on the 2 other tests. Further in vitro studies suggested that Arteparon® acted at a higher level than factor Xa generation in the intrinsic amplification system and that its effect was independent of antithrombin III. In vivo administration of Arteparon® confirmed its anticoagulant properties, which raises the question of the clinical use of this MPS.

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Involvement of HECTD1 in LPS-induced astrocyte activation via σ-1R-JNK/p38-FOXJ2 axis

Cell & Bioscience ◽

10.1186/s13578-021-00572-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ying Tang ◽

Mengchun Zhou ◽

Rongrong Huang ◽

Ling Shen ◽

Li Yang ◽

...

Keyword(s):

Inflammatory Responses ◽

Astrocyte Activation ◽

Hect Domain ◽

P38 Inhibitor ◽

Ubiquitin Protein Ligase ◽

Primary Mouse ◽

Lps Treatment

Abstract Background Astrocytes participate in innate inflammatory responses within the mammalian central nervous system (CNS). HECT domain E3 ubiquitin protein ligase 1 (HECTD1) functions during microglial activation, suggesting a connection with neuroinflammation. However, the potential role of HECTD1 in astrocytes remains largely unknown. Results Here, we demonstrated that HECTD1 was upregulated in primary mouse astrocytes after 100 ng/ml lipopolysaccharide (LPS) treatment. Genetic knockdown of HECTD1 in vitro or astrocyte-specific knockdown of HECTD1 in vivo suppressed LPS-induced astrocyte activation, whereas overexpression of HECTD1 in vitro facilitated LPS-induced astrocyte activation. Mechanistically, we established that LPS activated σ-1R-JNK/p38 pathway, and σ-1R antagonist BD1047, JNK inhibitor SP600125, or p38 inhibitor SB203580 reversed LPS-induced expression of HECTD1, thus restored LPS-induced astrocyte activation. In addition, FOXJ2 functioned as a transcription factor of HECTD1, and pretreatment of primary mouse astrocytes with BD1047, SB203580, and SP600125 significantly inhibited LPS-mediated translocation of FOXJ2 into the nucleus. Conclusions Overall, our present findings suggest that HECTD1 participates in LPS-induced astrocyte activation by activation of σ-1R-JNK/p38-FOXJ2 pathway and provide a potential therapeutic strategy for neuroinflammation induced by LPS or any other neuroinflammatory disorders.

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Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock

Scientific Reports ◽

10.1038/s41598-020-79607-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shinjini Chakraborty ◽

Veronika Eva Winkelmann ◽

Sonja Braumüller ◽

Annette Palmer ◽

Anke Schultze ◽

...

Keyword(s):

Hemorrhagic Shock ◽

Inflammatory Responses ◽

Experimental Models ◽

Lung Damage ◽

C5a Receptor ◽

Cytokine Levels ◽

Vitro Model

AbstractSingular blockade of C5a in experimental models of sepsis is known to confer protection by rescuing lethality and decreasing pro-inflammatory responses. However, the role of inhibiting C5a has not been evaluated in the context of sterile systemic inflammatory responses, like polytrauma and hemorrhagic shock (PT + HS). In our presented study, a novel and highly specific C5a L-aptamer, NoxD21, was used to block C5a activity in an experimental murine model of PT + HS. The aim of the study was to assess early modulation of inflammatory responses and lung damage 4 h after PT + HS induction. NoxD21-treated PT + HS mice displayed greater polymorphonuclear cell recruitment in the lung, increased pro-inflammatory cytokine levels in the bronchoalveolar lavage fluids (BALF) and reduced myeloperoxidase levels within the lung tissue. An in vitro model of the alveolar-capillary barrier was established to confirm these in vivo observations. Treatment with a polytrauma cocktail induced barrier damage only after 16 h, and NoxD21 treatment in vitro did not rescue this effect. Furthermore, to test the exact role of both the cognate receptors of C5a (C5aR1 and C5aR2), experimental PT + HS was induced in C5aR1 knockout (C5aR1 KO) and C5aR2 KO mice. Following 4 h of PT + HS, C5aR2 KO mice had significantly reduced IL-6 and IL-17 levels in the BALF without significant lung damage, and both, C5aR1 KO and C5aR2 KO PT + HS animals displayed reduced MPO levels within the lungs. In conclusion, the C5aR2 could be a putative driver of early local inflammatory responses in the lung after PT + HS.

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Selective STAT3 Inhibitor Alantolactone Ameliorates Osteoarthritis via Regulating Chondrocyte Autophagy and Cartilage Homeostasis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.730312 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wenbin Pei ◽

Xiaojian Huang ◽

Bowei Ni ◽

Rui Zhang ◽

Guangyi Niu ◽

...

Keyword(s):

Western Blot ◽

Inflammatory Responses ◽

Cartilage Degeneration ◽

Cartilage Destruction ◽

Signaling Molecules ◽

Inflammatory Factors ◽

Signal Pathways ◽

Autophagic Flux ◽

Safranin O

Osteoarthritis (OA), which is identified by chronic pain, impacts the quality of life. Cartilage degradation and inflammation are the most relevant aspects involved in its development. Signal transducer and activator of transcription 3(STAT3), a member of the STATs protein family, is associated with inflammation. Alantolactone (ALT), a sesquiterpene lactone compound, can selectively suppress the phosphorylation of STAT3. However, the pharmacological effect of ALT on OA is still imprecise. In this study, IL-1β (10 ng/ml) was applied to cartilage chondrocytes, which were treated with different concentrations of Alantolactone for 24 h. The expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2(COX2), matrix metalloproteinases (MMPs) and thrombospondin motifs-5 (ADAMTS5) were detected by western blot. Protein expression of Collagen Ⅱ was observed by western blot, safranin O staining and immunofluorescence. Manifestation of autophagy related proteins such as autophagy-related gene-5 (ATG5), P62, LC3Ⅱ/Ⅰ and PI3K/AKT/mTOR-related signaling molecules were measured by western blot and autophagic flux monitored by confocal microscopy. Expression of STAT3 and NF-κB-related signaling molecules were evaluated by western blot and immunofluorescence. In vivo, 2 mg/kg ALT or equal bulk of vehicle was engaged in the destabilization of medial meniscus (DMM) mouse models by intra-articular injection, the degree of cartilage destruction was classified by Safranin O/Fast green staining. Our findings reported that the enhance of inflammatory factors containing iNOS, COX2, MMPs and ADAMTS5 induced by IL-1β could be ameliorated by ALT. Additionally, the diminish of Collagen Ⅱ and autophagy which was stimulated by IL-1β could be alleviated by ALT. Mechanistically, STAT3, NF-κB and PI3K/AKT/mTOR signal pathways might be involved in the effect of ALT on IL-1β-induced mouse chondrocytes. In vivo, ALT protected cartilage in the DMM mouse model. Overall, this study illustrated that ALT attenuated IL-1β-induced inflammatory responses, relieved cartilage degeneration and promoted impaired autophagy via restraining of STAT3 and NF-κB signal pathways, implying its auspicious therapeutical effect for OA.

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USP7 Inhibition Alleviates H2O2-Induced Injury in Chondrocytes via Inhibiting NOX4/NLRP3 Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.617270 ◽

2021 ◽

Vol 11 ◽

Author(s):

Gang Liu ◽

Qingbai Liu ◽

Bin Yan ◽

Ziqiang Zhu ◽

Yaozeng Xu

Keyword(s):

Treatment Options ◽

Current Treatment ◽

Pathological Process ◽

Joint Disease ◽

Matrix Remodeling ◽

Ros Production ◽

Caspase 1 ◽

Enhanced Production

Osteoarthritis (OA), the most common form of arthritis, is a very common joint disease that often affects middle-aged to elderly people. However, current treatment options for OA are predominantly palliative. Thus, understanding its pathological process and exploring its potential therapeutic approaches are of great importance. Rat chondrocytes were isolated and exposed to hydrogen peroxide (H2O2) to mimic OA. The effects of H2O2 on ubiquitin-specific protease 7 (USP7) expression, reactive oxygen species (ROS) levels, proliferation, inflammatory cytokine release, and pyroptosis were measured. USP7 was knocked down (KD) or overexpressed to investigate the role of USP7 in OA. Co-immunoprecipitation (Co-IP) was used to study the interaction between USP7 and NAD(P)H oxidases (NOX)4 as well as NOX4 ubiquitination. NOX4 inhibitor was applied to study the involvement of NOX4 in USP7-mediated OA development. USP7 inhibitor was given to OA animals to further investigate the role of USP7 in OA in vivo. Moreover, H2O2 treatment significantly increased USP7 expression, enhanced ROS levels, and inhibited proliferation in rat chondrocytes. The overexpression of USP7 enhanced pyroptosis, ROS production, interleukin (IL)-1β and IL-18 levels, and the expression level of NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, matrix metalloproteinases (MMP) 1, and MMP13, which was abolished by ROS inhibition. The USP7 KD protected rat chondrocytes against H2O2-induced injury. Co-IP results showed that USP7 interacted with NOX4, and USP7 KD enhanced NOX4 ubiquitinylation. The inhibition of NOX4 blocked the pro-OA effect of USP7. Moreover, the USP7 inhibitor given to OA animals suppressed OA in vivo. USP7 inhibited NOX4 ubiquitination for degradation which leads to elevated ROS production. ROS subsequently activates NLPR3 inflammasome, leading to enhanced production of IL-1β and IL-18, GSDMD-N-dependent pyroptosis, and extracellular matrix remodeling. Thus, UPS7 contributes to the progression of OA via NOX4/ROS/NLPR3 axis.

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