Biology subjects

Vinatier, C.

Publications and source records attributed to Vinatier, C..

4 recordsLinked to original sources

bioRxiv2026

Molecular and spatial profiling identifies immune endotypes for the stratification of OA patients

Osteoarthritis (OA) is a prevalent and heterogeneous joint disease in which synovial inflammation drives structural progression and pain. Despite the recognized heterogeneity of OA, the cellular and molecular organization of synovial tissue remains poorly characterized and defining distinct histological and immune endotypes could guide precision medicine and therapeutic targeting. We show that histologically defined synovial pathotypes are conserved across independent cohorts and correspond to distinct molecular immune endotypes. Integration of bulk and spatial transcriptomics with proteomics revealed niche-specific gene and protein signatures, reflecting the anatomical and functional diversity of OA synovium. The lympho-myeloid pathotype was characterized by mature ectopic lymphoid structures containing CD21+CD23+ follicular dendritic cells, spatially organized T and B cell zones, and clonally expanded T and B cells with shared immune cell receptor motifs, consistent with local adaptive immune activity correlating with radiological joint damage. These findings highlight how immune organization and cellular composition shape OA pathogenesis and provide a framework for endotype-guided stratification and therapeutic targeting.

immunology↗

bioRxiv2025

Transcriptomic and functional comparison of cells isolated from healthy and degenerated ovine intervertebral discs

Structured abstractO_ST_ABSBackgroundC_ST_ABSIntervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain and disability. Understanding the cellular and molecular mechanisms underlying disc degeneration is crucial for developing effective therapies. Sheep have emerged as a promising large-animal model for IVDD research due to their similarities with humans. They exhibit resembling spine anatomy and biomechanics, and they develop spontaneous age-associated degeneration of the disc. However, the specific cellular alterations occurring in annulus fibrosus (AF) and nucleus pulposus (NP) ovine cells during degeneration remain poorly characterized. In vitro, the benefits of using cells from aged sheep over young ones to mimic degenerative processes remain to be tested. MethodsAF and NP cells from young and aged sheep were analysed using bulk RNA sequencing, with a focus on two hallmarks of IVDD: cellular senescence and metabolic alterations. Functional assays completed this focus by assessing cells response under basal conditions and after pro-degenerative stimuli (IL-1{beta}, senescence induction). In addition, bulk transcriptomic data were deconvoluted using a reference single-cell RNA-seq dataset from healthy and degenerated human discs, and gene co-expression modules were compared across species. ResultsMRI and histological analyses revealed homogeneous mild degeneration across all lumbar discs in aged sheep, while lamb discs were uniformly healthy. Cells transcriptomic profiling identified robust age- and tissue-specific signatures, with aged NP and AF cells showing upregulation of inflammatory mediators, ECM-remodelling enzymes, and senescence-associated pathways. Cross-species analysis revealed shared transcriptional modules between aged sheep cells and human degenerated disc cells, supporting the translational relevance of the ovine model. Remarkably, young and aged cells shared a similar functional behaviour when exposed to stress-related stimuli. ConclusionsThis work confirms the compatibility of sheep cells with in vitro testing and their relevance to model human IVDD. Cross-validation with human single-cell data further highlights common pathogenic pathways, reinforcing the translational potential of the model. However, no added benefits were found in using older animals compared to younger ones as cell sources in functional assays. HighlightsO_LITranscriptomic profiling of AF and NP cells from young and aged sheep C_LIO_LIAged cells show inflammatory, ECM-remodelling and senescence signatures C_LIO_LIDeconvolution with human scRNA-seq links aged ovine and degenerated discs C_LIO_LISheep cells retain in vitro responsiveness to pro-degenerative stimuli C_LIO_LISupports the ovine model as a translational tool for IVDD research C_LI

cell biology↗

bioRxiv2025

Multimodal analysis of osteoarthritic chondrocytes reveals mitochondrial alterations and patient-specific OxPhos response to bezafibrate

BackgroundOsteoarthritis (OA) is the most common joint disease and is characterized by bone remodeling, cartilage degradation and synovial inflammation. To date, no effective treatment is available for this debilitating condition. Recent evidence suggests that mitochondrial dysfunction, including oxidative phosphorylation (OxPhos) failure, accumulates within OA chondrocytes and may contribute to pathogenesis. In this context, mitochondrial dysfunction may be associated with observable changes in mitochondrial number, size and shape. However, a comprehensive characterization of mitochondria-related features during OA, from tissue-to-cell level, is still lacking. Addressing these gaps could inform therapeutic strategies, such as the partial restoration of OxPhos, which has been proposed as a therapeutic approach. MethodsHere, we employed a multimodal approach that included Fourier-transform infrared spectroscopy (FTIR), scanning transmission electron microscopy (STEM) and real-time cellular metabolic assays (Seahorse technology) to better characterize mitochondrial parameters in cartilage during OA. Two types of experimental models were used using human cartilage: (1) undamaged versus damaged OA zones, and (2) non-OA versus OA samples. In addition, we investigated the potential of repurposing bezafibrate, an approved peroxisome proliferator-activated receptor (PPAR) agonist, as a mitochondria-based therapy to restore OxPhos in OA chondrocytes. ResultsWe identified that OA chondrocytes exhibit a decrease in glycogen deposits surface, and an increased number of mitochondria alongside an OxPhos dysfunction compared to non-OA chondrocytes. A similar trend toward glycogen storage deficiency and increased mitochondria number was observed in OA chondrocytes from damaged cartilage areas. Furthermore, multivariate analyses revealed that the clinical profiles of OA patients allowed OA chondrocytes to be separated into responders and non-responders to bezafibrate. ConclusionWe provide evidence that OA chondrocytes display decreased glycogen deposits surface, increased mitochondrial number and OxPhos dysfunction. Additionally, we identified that bezafibrate, a PPAR agonist, improved OxPhos function in a subgroup of OA chondrocytes derived from patients.

pathology↗

bioRxiv2025

Inhibiting EZH2 Alleviates Osteoarthritis and Pain in an Experimental Murine Model Through Modulating Synovial and Macrophage Inflammation, Axon Guidance, and Osteoclastogenesis

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for H3K27 trimethylation, has emerged as a potential therapeutic target in osteoarthritis (OA). However, its contribution to the multicellular mechanisms driving joint degeneration and pain remains poorly understood. Here, we investigated the effects of pharmacological EZH2 inhibition in a pain-relevant murine OA model and explored its cellular and molecular consequences across OA-associated cell populations. OA was induced in mice by intra-articular monosodium iodoacetate (MIA) injection followed by local administration of the EZH2 inhibitor EPZ-6438. Joint pathology and pain-related behaviors were assessed by histological and functional analyses. Mechanistic studies were performed in primary human OA fibroblast-like synoviocytes and bone marrow-derived cells using targeted gene expression analyses, proteomics and ChIP-seq approaches. EZH2 inhibition reduced cartilage damage, synovial inflammation and pain-related behavioral alterations in vivo. In OA synoviocytes, EPZ-6438 decreased the expression of inflammatory, catabolic and pain-associated mediators while promoting autophagy-related responses. Proteomic and ChIP-seq analyses revealed EZH2-dependent regulation of inflammatory pathways, cellular homeostasis and neuronal-associated processes, including axon guidance-related pathways. ChIP-seq further identified inflammation-dependent EZH2 recruitment to promoters of neurodevelopmental regulators, including PAX6, suggesting a potential contribution of EZH2 to neuronal-associated mechanisms in OA. In addition, EZH2 inhibition reduced macrophage inflammatory activation and osteoclast differentiation. Together, these findings identify EZH2 as a candidate epigenetic regulator linking inflammatory, neuroimmune and osteoimmune pathways across the osteoarthritic joint. Targeting EZH2 may represent a therapeutic strategy to simultaneously modulate joint inflammation, remodeling and pain-associated pathways.

physiology↗