Identification of TGFβ signatures in six murine models mimicking different osteoarthritis clinical phenotypes

Maumus, Marie; Noël, Danièle; Korng, Hang; Moulin, David; Ruiz, Maxime; Haÿ, Eric; Houard, Xavier; Cleret, Damien; Cohen‐Solal, Martine; Jacques, Claire; Jouzeau, Jean‐Yves; Lafage‐Proust, Marie‐Hélène; Reboul, Pascal; Sellam, Jérémie; Vinatier, Claire; Rannou, François; Guicheux, Jérôme; Bérenbaum, Francis

doi:10.1016/j.joca.2020.06.008

Cited by 7 publications

(4 citation statements)

References 38 publications

(41 reference statements)

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“…A precision medicine approach to treat musculoskeletal disorders requires a deeper understanding of the relationship between genetics and disease, as well as stratification of patients based on the underlying biology (39). In OA, there is increasing evidence for different molecular pathways underlying disease subtypes, ultimately presenting with the same endotype but requiring distinct therapeutic approaches (40,41). The identification of OA risk genes, such as COLGALT2, provides scope for novel pharmacologic interventions within patient subgroups.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Interplay Within a COLGALT2 Enhancer Associated With Osteoarthritis

Kehayova

Watson

Wilkinson

et al. 2021

Arthritis & Rheumatology

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Objective The osteoarthritis (OA)–associated single‐nucleotide polymorphism (SNP) rs11583641 is located in COLGALT2, encoding a posttranslational modifier of collagen. In cartilage, the SNP genotype correlates with DNA methylation in a putative enhancer. This study was undertaken to characterize the mechanistic relationship between rs11583641, the putative enhancer, and COLGALT2 expression using cartilage samples from human patients and a chondrocyte cell model. Methods Nucleic acids were extracted from articular cartilage samples obtained from patients with OA (n = 137). Samples were genotyped, and DNA methylation was quantified at 12 CpGs using pyrosequencing. The putative enhancer was deleted in Tc28a2 chondrocytes using clustered regularly interspaced short palindromic repeat/Cas9, and the impact on nearby gene expression was determined using real‐time quantitative polymerase chain reaction. Targeted modulation of the epigenome using catalytically dead Cas9 (dCas9) constructs fused to DNA methyltransferase 3a or ten–eleven translocase 1 allowed for the investigation of a causal relationship between DNA methylation and enhancer activity. Results The genotype at rs11583641 correlated with DNA methylation at 3 CpGs, and the presence of the OA risk allele, C, corresponded to reduced levels of methylation. Deletion of the enhancer resulted in a 2.7‐fold reduction in COLGALT2 expression. Targeted methylation and demethylation of the CpGs had antagonistic effects on COLGALT2 expression. An allelic imbalance in the expression of COLGALT2 was identified in the cartilage from patients with OA, with relative overexpression of the OA risk allele. Allelic expression ratios correlated with DNA methylation at 4 CpGs. Conclusion COLGALT2 is a target of OA genetic risk at this locus. The genotype at rs11583641 impacts DNA methylation in a gene enhancer, which, in turn, modulates COLGALT2 expression. COLGALT2 encodes an enzyme that initiates posttranslational glycosylation of collagens and is therefore a compelling OA susceptibility target.

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Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Interplay Within a COLGALT2 Enhancer Associated With Osteoarthritis

Kehayova

Watson

Wilkinson

et al. 2021

Arthritis & Rheumatology

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“…Osteoarthritis (OA) represents the most frequent age-associated chronic degenerative joint disease ( Maumus et al, 2020 ). Aging is the key driving force in OA ( Deng et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Profiles of Age-Related Osteoarthritis Uncover Underlying Heterogeneity Associated With Disease Progression

Liu

Chen

Zeng

et al. 2022

Front. Mol. Biosci.

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Objective: Osteoarthritis (OA) is the most common chronic degenerative joint disease, which represents the leading cause of age-related disability. Here, this study aimed to depict the intercellular heterogeneity of OA synovial tissues.Methods: Single-cell RNA sequencing (scRNA-seq) data were preprocessed and quality controlled by the Seurat package. Cell cluster was presented and cell types were annotated based on the mRNA expression of corresponding marker genes by the SingleR package. Cell-cell communication was assessed among different cell types. After integrating the GSE55235 and GSE55457 datasets, differentially expressed genes were identified between OA and normal synovial tissues. Then, differentially expressed marker genes were overlapped and their biological functions were analyzed.Results: Totally, five immune cell subpopulations were annotated in OA synovial tissues including macrophages, dendritic cells, T cells, monocytes and B cells. Pseudo-time analysis revealed the underlying evolution process in the inflammatory microenvironment of OA synovial tissue. There was close crosstalk between five cell types according to the ligand-receptor network. The genetic heterogeneity was investigated between OA and normal synovial tissues. Furthermore, functional annotation analysis showed the intercellular heterogeneity across immune cells in OA synovial tissues.Conclusion: This study offered insights into the heterogeneity of OA, which provided in-depth understanding of the transcriptomic diversities within synovial tissue. This transcriptional heterogeneity may improve our understanding on OA pathogenesis and provide potential molecular therapeutic targets for OA.

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“…OA was induced in mice by DMM of the right knee as previously described ( 44 ); a sham operation was performed on the contralateral knee by incision of the cutaneous and muscular planes at baseline. Mice underwent two types of induction of DNA recombination.…”

Section: Methodsmentioning

confidence: 99%

Lin28a induces SOX9 and chondrocyte reprogramming via HMGA2 and blunts cartilage loss in mice

et al. 2022

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Articular cartilage has low regenerative capacity despite permanent stress. Irreversible cartilage lesions characterize osteoarthritis (OA); this is not followed by tissue repair. Lin28a, an RNA binding protein, is detected in damaged cartilage in humans and mice. We investigated the role of LIN28a in cartilage physiology and in osteoarthritis. Lin28a-inducible conditional cartilage deletion up-regulated Mmp13 in intact mice and exacerbated the cartilage destruction in OA mice. Lin28a-specific cartilage overexpression protected mice against cartilage breakdown, stimulated chondrocyte proliferation and the expression of Prg4 and Sox9, and down-regulated Mmp13 . Lin28a overexpression inhibited Let-7b and Let-7c miRNA levels while RNA-sequencing analysis revealed five genes of transcriptional factors regulated by Let-7. Moreover, Lin28a overexpression up-regulated HMGA2 and activated SOX9 transcription, a factor required for chondrocyte reprogramming. HMGA2 siRNA knockdown inhibited the cartilage protective effect of Lin28a overexpression. This study provides insights into a new pathway including the Lin28a-Let7 axis, thus promoting chondrocyte anabolism in injured cartilage in mice.

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Identification of TGFβ signatures in six murine models mimicking different osteoarthritis clinical phenotypes

Cited by 7 publications

References 38 publications

Genetic and Epigenetic Interplay Within a COLGALT2 Enhancer Associated With Osteoarthritis

Genetic and Epigenetic Interplay Within a COLGALT2 Enhancer Associated With Osteoarthritis

Single-Cell Profiles of Age-Related Osteoarthritis Uncover Underlying Heterogeneity Associated With Disease Progression

Lin28a induces SOX9 and chondrocyte reprogramming via HMGA2 and blunts cartilage loss in mice

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