Dataset Information

Osteoarthritis-Induced Metabolic Alterations of Human Hip Chondrocytes.

ABSTRACT: Osteoarthritis (OA) alters chondrocyte metabolism and mitochondrial biology. We explored whether OA and non-OA chondrocytes show persistent differences in metabolism and mitochondrial function and different responsiveness to cytokines and cAMP modulators. Hip chondrocytes from patients with OA or femoral neck fracture (non-OA) were stimulated with IL-1β, TNF, forskolin and opioid peptides. Mediators released from chondrocytes were measured, and mitochondrial functions and glycolysis were determined (Seahorse Analyzer). Unstimulated OA chondrocytes exhibited significantly higher release of IL-6, PGE₂ and MMP1 and lower production of glycosaminoglycan than non-OA chondrocytes. Oxygen consumption rates (OCR) and mitochondrial ATP production were comparable in unstimulated non-OA and OA chondrocytes, although the non-mitochondrial OCR was higher in OA chondrocytes. Compared to OA chondrocytes, non-OA chondrocytes showed stronger responses to IL-1β/TNF stimulation, consisting of a larger decrease in mitochondrial ATP production and larger increases in non-mitochondrial OCR and NO production. Enhancement of cAMP by forskolin prevented IL-1β-induced mitochondrial dysfunction in OA chondrocytes but not in non-OA chondrocytes. Endogenous opioids, present in OA joints, influenced neither cytokine-induced mitochondrial dysfunction nor NO upregulation. Glycolysis was not different in non-OA and OA chondrocytes, independent of stimulation. OA induces persistent metabolic alterations, but the results suggest upregulation of cellular mechanisms protecting mitochondrial function in OA.

SUBMITTER: Eitner A

PROVIDER: S-EPMC9220245 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Osteoarthritis-Induced Metabolic Alterations of Human Hip Chondrocytes.

Eitner Annett A Sparing Simon S Kohler Felix C FC Müller Sylvia S Hofmann Gunther O GO Kamradt Thomas T Schaible Hans-Georg HG Aurich Matthias M

Biomedicines 20220608 6

Osteoarthritis (OA) alters chondrocyte metabolism and mitochondrial biology. We explored whether OA and non-OA chondrocytes show persistent differences in metabolism and mitochondrial function and different responsiveness to cytokines and cAMP modulators. Hip chondrocytes from patients with OA or femoral neck fracture (non-OA) were stimulated with IL-1β, TNF, forskolin and opioid peptides. Mediators released from chondrocytes were measured, and mitochondrial functions and glycolysis were determi ...[more]

PMID: 35740371

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Project description:Objective: Osteoarthritis (OA) is a common joint disorder characterized by degenerative articular cartilage, subchondral bone remodeling, and inflammation. Increasing evidence suggests that the substantial crosstalk between cartilage and synovium is closely related to Osteoarthritis development, but the events that cause this degeneration remain unknown. This study aimed to explore the alterations in intercellular communication involved in the pathogenesis of Osteoarthritis using bioinformatics analysis. Methods: Single-cell transcriptome sequencing (scRNA-seq) profiles derived from articular cartilage tissue of patients with Osteoarthritis were downloaded from a public database. Chondrocyte heterogeneity was assessed using computational analysis, and cell type identification and clustering analysis were performed using the "FindClusters" function in the Seurat package. Intercellular communication networks, including major signaling inputs and outputs for cells, were predicted, and analyzed using CellChat. Results: Seven molecularly defined chondrocytes clusters (homeostatic chondrocytes, hypertrophic chondrocyte (HTC), pre-HTC, regulatory chondrocytes, fibro-chondrocytes (FC), pre-FC, and reparative chondrocyte) with different compositions were identified in the damaged cartilage. Compared to those in the intact cartilage, the overall cell-cell communication frequency and communication strength were remarkably increased in the damaged cartilage. The cellular communication among chondrocyte subtypes mediated by signaling pathways, such as PTN, VISFATIN, SPP1, and TGF-β, was selectively altered in Osteoarthritis. Moreover, we verified that SPP1 pathway enrichment scores increased, but VISFATIN pathway enrichment scores decreased based on the bulk rna-seq datasets in Osteoarthritis. Conclusion: Our results revealed alterations in cell-cell communication among OA-related chondrocyte subtypes that were mediated by specific signaling pathways, which might be a crucial underlying mechanism associated with Osteoarthritis progression.

Project description:There is growing evidence in support of the involvement of inflammatory response in the pathogenesis of osteoarthritis (OA). Harpagoside, one of the bioactive components of Harpagophytum procumbens (Hp), has been shown to possess anti-inflammatory properties. Here we used an in vitro model of inflammation in OA to investigate the potential of harpagoside to suppress the production of inflammatory cytokines/chemokines such as IL-6 and matrix degrading proteases. We further investigated the likely targets of harpagoside in primary human OA chondrocytes. OA chondrocytes were pre-treated with harpagoside before stimulation with IL-1β. mRNA expression profile of 92 cytokines/chemokines was determined using TaqMan Human Chemokine PCR Array. Expression levels of selected mRNAs were confirmed using TaqMan assays. Protein levels of IL-6 and MMP-13 were assayed by ELISA and immunoblotting. Total protein levels and phosphorylation of signaling proteins were determined by immunoblotting. Cellular localization of IL-6 and c-Fos was performed by immunofluorescence and confocal microscopy. DNA binding activity of c-FOS/AP-1 was determined by ELISA. Harpagoside significantly altered the global chemokine expression profile in IL-1β-stimulated OA chondrocytes. Expression of IL-6 was highly induced by IL-1β, which was significantly inhibited by pre-treatment of OA chondrocytes with harpagoside. Harpagoside did not inhibit the IL-1β-induced activation of NF-κB and C/EBPβ transcription factors but suppressed the IL-1β-triggered induction, phosphorylation, and DNA binding activity of c-FOS, one of the main components of AP-1 transcription factors. Further, harpagoside significantly inhibited the expression of MMP-13 in OA chondrocytes under pathological conditions. siRNA-mediated knockdown of IL-6 resulted in suppressed expression and secretion of MMP-13 directly linking the role of IL-6 with MMP-13 expression. Taken together, the present study suggests that harpagoside exerts a significant anti-inflammatory effect by inhibiting the inflammatory stimuli mediated by suppressing c-FOS/AP-1 activity in OA chondrocytes under pathological conditions. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:311-320, 2017.

Dataset Information

Osteoarthritis-Induced Metabolic Alterations of Human Hip Chondrocytes.

Publications

Osteoarthritis-Induced Metabolic Alterations of Human Hip Chondrocytes.

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