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Combining single-cell RNA sequencing and population-based studies reveals hand osteoarthritis-associated chondrocyte subpopulations and pathways.

ABSTRACT: Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1 mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02-1.11) among participants (n = 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n = 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis.

SUBMITTER: Li H

PROVIDER: S-EPMC10620170 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Combining single-cell RNA sequencing and population-based studies reveals hand osteoarthritis-associated chondrocyte subpopulations and pathways.

Li Hui H Jiang Xiaofeng X Xiao Yongbing Y Zhang Yuqing Y Zhang Weiya W Doherty Michael M Nestor Jacquelyn J Li Changjun C Ye Jing J Sha Tingting T Lyu Houchen H Wei Jie J Zeng Chao C Lei Guanghua G

Bone research 20231102 1

Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a no ...[more]

PMID: 37914703

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Project description:BackgroundChondrocytes and synovial cells participate in the pathogenesis of osteoarthritis (OA). Nonetheless, the interactions and correlations between OA synovial cells and chondrocytes remain unclear. This study aims to elucidate the interactions and correlations between OA synovial cells and chondrocytes, so as to deepen understanding of OA pathogenesis.MethodsSingle-cell sequencing analysis was employed to analyze clusters of synovial and chondrocyte cells within the OA dataset. Through cell interaction analysis, the potential interactions between these two cell types were further explored. Differential gene expression analysis was used to examine the differences among synovial-related cell clusters.ResultsThe study identified specific characteristics of synovial fibroblasts through single-cell sequencing analysis. Subsequent cell interaction analysis revealed interactions and correlations between synovial fibroblast clusters and cell clusters in both damaged and non-damaged cartilages. CILP+ fibroblasts showed significant interactions with non-damaged chondrocytes, while POSTN+ fibroblasts exhibited significant interactions with damaged chondrocytes. Furthermore, differential gene expression analysis revealed that genes such as PRELP, CLU, COMP, TNFRSF12A, INHBA, CILP, and SERPINE2, were significantly upregulated in CILP+ fibroblasts. These genes are involved in promoting cell proliferation, inhibiting inflammatory pathways, and stabilizing cell structure, thereby exerting reparative and protective effects on chondrocytes. In contrast, COL6A3, COL6A1, COL1A2, COL1A1, COL3A1, TGF-β1, MMP2, AEBP1, SPARC, FNDC1, and POSTN were upregulated in POSTN+ fibroblasts. These genes may contribute to chondrocyte damage and further degeneration by promoting chondrocyte catabolism, driving inflammation, activating inflammatory pathways, and facilitating chondrocyte apoptosis and destruction.ConclusionOur study elucidated the interactions and correlations between OA synovial cells and chondrocytes. CILP+ synovial fibroblasts may exert reparative and protective effects on chondrocytes of patients with OA by promoting cell proliferation, inhibiting inflammation, and stabilizing cellular structures, thereby potentially mitigating the progression of cartilage lesions in affected patients. In contrast, POSTN+ synovial fibroblasts may exacerbate chondrocyte deterioration in patients with OA by enhancing degradation, inflammation, and apoptosis, thereby exacerbating cartilage lesions. Investigating the underlying molecular mechanisms between OA synovial cells and chondrocytes refines the understanding of OA pathogenesis and provides valuable insights for the clinical diagnosis and treatment of OA.

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:BackgroundOsteoarthritis (OA) is the most common degenerative joint disease primarily characterized by cartilage destruction. The aim of this study was to investigate the role, molecular characteristics and potential therapeutic target of chondrocyte ferroptosis in the pathogenesis of OA.MethodsThe expression of ferroptotic hallmarks (iron and lipid peroxidation accumulation, glutathione deletion) were analyzed in paired intact and damaged cartilages from OA patients. Single cell RNA sequencing (scRNA-seq) analysis was performed on 17,638 chondrocytes to verify the presence, investigate the molecular signatures and unveil the potential therapeutic target of ferroptotic chondrocyte cluster in human OA cartilages. Destabilization of medial meniscus (DMM)-induced OA model and tert-butyl hydroperoxide (TBHP)-treated primary mouse chondrocytes and human cartilage explants were used to evaluate the protective effect of pharmacologically activated transient receptor potential vanilloid 1 (TRPV1). The downstream molecular mechanisms of TRPV1 was further investigated in glutathione peroxidase 4 (Gpx4) heterozygous genetic deletion mice (Gpx4+/-).FindingsThe concentrations of iron and lipid peroxidation and the expression of ferroptotic drivers in the damaged areas of human OA cartilages were significantly higher than those in the intact cartilage. scRNA-seq analysis revealed a chondrocyte cluster characterized by preferentially expressed ferroptotic hallmarks and genes, namely ferroptotic chondrocyte cluster. Comprehensive gene set variation analysis revealed TRPV1 as an anti-ferroptotic target in human OA cartilage. Pharmacological activation of TRPV1 significantly abrogated cartilage degeneration by protecting chondrocytes from ferroptosis. Mechanistically, TRPV1 promoted the expression of GPX4, and its anti-ferroptotic role was largely mitigated in the OA model of Gpx4+/- mice.InterpretationTRPV1 activation protects chondrocytes from ferroptosis and ameliorates OA progression by upregulating GPX4.FundingNational Key R&D Program of China (2018YFC1105904), Key Program of NSFC (81730067), National Science Foundation of China (81772335, 81941009, 81802196), Natural Science Foundation of Jiangsu Province, China (BK20180127), Jiangsu Provincial Key Medical Talent Foundation, Six Talent Peaks Project of Jiangsu Province (WSW-079).

Project description:BackgroundOne of the main causes of low back pain is intervertebral disc degeneration (IDD). Annulus fibrosus (AF) is important for the integrity and functions of the intervertebral disc (IVD). However, the resident functional cell components such as progenitors and vascularization-associated cells in AF are yet to be fully identified.PurposeIdentification of functional AF cell subpopulations including resident progenitors and vascularization-associated cells.MethodsIn this study, the single-cell RNA sequencing data of rat IVDs from a public database were analyzed using Seurat for cell clustering, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional analysis, StemID for stem cell identification, Monocle and RNA velocity for pseudotime differentiation trajectory validation, single-cell regulatory network inference and clustering (SCENIC) for gene regulatory network (GRN) analysis, and CellChat for cell-cell interaction analysis. Immunostaining on normal and degenerated rat IVDs, as well as human AF, was used for validations.ResultsFrom the data analysis, seven AF cell clusters were identified, including two newly discovered functional clusters, the Grem1 + subpopulation and the Lum + subpopulation. The Grem1 + subpopulation had progenitor characteristics, while the Lum + subpopulation was associated with vascularization during IDD. The GRN analysis showed that Sox9 and Id1 were among the key regulators in the Grem1 + subpopulation, and Nr2f2 and Creb5 could be responsible for the vascularization function in the Lum + subpopulation. Cell-cell interaction analysis revealed highly regulated cellular communications between these cells, and multiple signaling networks including PDGF and MIF signaling pathways were involved in the interactions.ConclusionsOur results revealed two new functional AF cell subpopulations, with stemness and vascularization induction potential, respectively.The translational potential of this articleThese findings complement our knowledge about IVDs, especially the AF, and in return provide potential cell source and regulation targets for IDD treatment and tissue repair. The existence of the cell subpopulations was also validated in human AF, which strengthen the clinical relevance of the findings.

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Combining single-cell RNA sequencing and population-based studies reveals hand osteoarthritis-associated chondrocyte subpopulations and pathways.

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Combining single-cell RNA sequencing and population-based studies reveals hand osteoarthritis-associated chondrocyte subpopulations and pathways.

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