An insight into osteoarthritis susceptibility: Integration of immunological and genetic background

Štefik, Debora; Vranic, Vladimir; Ivkovic, Nemanja; Abazović, Džihan; Marić, D; Vojvodić, Danilo; Šupić, Gordana

doi:10.17305/bjbms.2020.4735

Cited by 6 publications

(4 citation statements)

References 76 publications

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“…COX2 and iNOS, the major pro-inflammatory cytokines in the development of OA, are abnormal raising ( Stefik et al, 2021 ). In this study, chondrocytes were stimulated by ALT in the presence or absence of IL-1β (10 ng/ml) for 24 h. As shown in Figure 2 , iNOS and COX2 were enhanced remarkably in IL-1β-induced chondrocytes.…”

Section: Resultsmentioning

confidence: 99%

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

Pei

Huang

et al. 2021

Front. Pharmacol.

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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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Section: Resultsmentioning

confidence: 99%

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

Pei

Huang

et al. 2021

Front. Pharmacol.

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“…Chronic inflammation is usually a debilitating condition, as in disorders such as osteoarthritis [ 54 , 55 ], multiple sclerosis [ 56 , 57 ], rheumatoid arthritis [ 58 ], and atherosclerosis [ 59 , 60 ]. Routine anti-inflammatory therapy includes the use of steroids, immunosuppressant drugs, and non-steroidal anti-inflammatory drugs (NSAID) [ 61 ], which, however, also have pronounced adverse effects [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening for CEBPD-Modulating Compounds in THP-1-Derived Reporter Macrophages Identifies Anti-Inflammatory HDAC and BET Inhibitors

Ullmann

Luckhardt

Wolf

et al. 2021

IJMS

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This study aimed to identify alternative anti-inflammatory compounds that modulate the activity of a relevant transcription factor, CCAAT/enhancer binding protein delta (C/EBPδ). C/EBPδ is a master regulator of inflammatory responses in macrophages (Mϕ) and is mainly regulated at the level of CEBPD gene transcription initiation. To screen for CEBPD-modulating compounds, we generated a THP-1-derived reporter cell line stably expressing secreted alkaline phosphatase (SEAP) under control of the defined CEBPD promoter (CEBPD::SEAP). A high-throughput screening of LOPAC®1280 and ENZO®774 libraries on LPS- and IFN-γ-activated THP-1 reporter Mϕ identified four epigenetically active hits: two bromodomain and extraterminal domain (BET) inhibitors, I-BET151 and Ro 11-1464, as well as two histone deacetylase (HDAC) inhibitors, SAHA and TSA. All four hits markedly and reproducibly upregulated SEAP secretion and CEBPD::SEAP mRNA expression, confirming screening assay reliability. Whereas BET inhibitors also upregulated the mRNA expression of the endogenous CEBPD, HDAC inhibitors completely abolished it. All hits displayed anti-inflammatory activity through the suppression of IL-6 and CCL2 gene expression. However, I-BET151 and HDAC inhibitors simultaneously upregulated the mRNA expression of pro-inflammatory IL-1ß. The modulation of CEBPD gene expression shown in this study contributes to our understanding of inflammatory responses in Mϕ and may offer an approach to therapy for inflammation-driven disorders.

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“…According to recent studies, resident macrophages and non-resident dendritic cells, but not chondrocytes, express interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and TNF-α, all of which are mostly expressed in synovial membranes [ 33 ]. ADAMTS-5 expression is mainly activated by IL-1β, TNF-α, and TGF-β [ 210 ]. Notably, MMP-13, the main collagen type II cleaving enzyme, is expressed not only by chondrocytes but also by FLSs and osteocytes, thus pointing to a relationship between joint cells and their increased impact on cartilage [ 7 ].…”

Section: Pathological Changes In Oa-affected Joint Tissuesmentioning

confidence: 99%

Healthy and Osteoarthritis-Affected Joints Facing the Cellular Crosstalk

Semenistaja

Skuja

Kadisa

et al. 2023

IJMS

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Osteoarthritis (OA) is a chronic, progressive, severely debilitating, and multifactorial joint disease that is recognized as the most common type of arthritis. During the last decade, it shows an incremental global rise in prevalence and incidence. The interaction between etiologic factors that mediate joint degradation has been explored in numerous studies. However, the underlying processes that induce OA remain obscure, largely due to the variety and complexity of these mechanisms. During synovial joint dysfunction, the osteochondral unit undergoes cellular phenotypic and functional alterations. At the cellular level, the synovial membrane is influenced by cartilage and subchondral bone cleavage fragments and extracellular matrix (ECM) degradation products from apoptotic and necrotic cells. These “foreign bodies” serve as danger-associated molecular patterns (DAMPs) that trigger innate immunity, eliciting and sustaining low-grade inflammation in the synovium. In this review, we explore the cellular and molecular communication networks established between the major joint compartments—the synovial membrane, cartilage, and subchondral bone of normal and OA-affected joints.

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An insight into osteoarthritis susceptibility: Integration of immunological and genetic background

Cited by 6 publications

References 76 publications

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

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

High-Throughput Screening for CEBPD-Modulating Compounds in THP-1-Derived Reporter Macrophages Identifies Anti-Inflammatory HDAC and BET Inhibitors

Healthy and Osteoarthritis-Affected Joints Facing the Cellular Crosstalk

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