BAUGE, C. | Search bioRxiv

bioRxiv2025

Systemic immune alterations in a murine experimental model of osteoarthritis

Osteoarthritis (OA) is accompanied by an inflamed synovium containing macrophages, dendritic cells, T and B lymphocytes. Macrophages predominate and drive cytokine-mediated cartilage catabolism, while T cells and B cells, though fewer, may shape chronic adaptive responses. However, systemic immune contributions, particularly within peripheral lymphoid organs such as the spleen, remain poorly characterized. Our study aims to profile systemic immune changes in experimental OA induced by injection of mono-iodoacetate (MIA) in mouse paw. At day 56 post-OA induction, analysis of splenocytes showed that macrophages and conventional dendritic cells (cDC1 and cDC2) displayed a significant downregulation of MHCII expression, suggesting a negative feedback mechanism that limits chronic T cell activation. OA is also associated with an increase in total DCs including mainly MHCII negative tolerogenic DCs. Notably, while the proportion of CD11b- tolerogenic DCs was reduced, CD11blow tolerogenic DCs markedly expanded in OA animals. Expression level of the CD11b integrin was upregulated on macrophages and cDC2 in MIA-induced OA mice potentially facilitating their adhesion and migration toward inflamed joint. OA mice showed a significant reduction in total splenic leukocytes, primarily due to a loss of B cells, while total T cell numbers remained stable. However, T cell composition shifted: CD4+ T cells including activated and regulatory subsets decreased, whereas activated CD8+ T cells increased. This indicates a systemic imbalance favoring cytotoxic over regulatory immune activity, possibly linked to chronic immune stress or redistribution of lymphocytes to inflamed joint. In conclusion, our data reveals that chronic OA induces a coordinated remodeling of systemic innate and adaptive immunity. These systemic immune dysregulations could reveal new biomarkers or therapeutic targets.

physiology↗

bioRxiv2024

Exploring Adenosine Analogues for Chondrosarcoma Therapy: In Vitro and In Vivo Insights

Chondrosarcoma (CS) is described as resistant to conventional chemotherapy and radiotherapy. The development of new therapeutic approaches is necessary. The aim of the present study is to validate the use of adenosine analogues as a new therapeutic strategy in the treatment of CS. Five adenosine analogues (aristeromycin, cladribine, clofarabine, formycin, and pentostatin) were evaluated in vitro on several chondrosarcoma cell lines using both 2D cultures and 3D alginate bead models. Cell viability was assessed using Acridine Orange and DAPI staining, or ATP assay. Apoptosis was measured via Annexin V and Propidium Iodide staining, while cell cycle progression was analyzed with DAPI staining. The most promising compounds were further tested in vivo using a xenograft chondrosarcoma model in nude mice. Results showed that four analogues (aristeromycin, formycin, cladribine, and clofarabine) significantly reduced cell viability in 2D cell cultures. Of these, cladribine and clofarabine demonstrated potent efficacy in both 2D and 3D models by inducing apoptosis. Cladribine was further found to induce cell cycle arrest, leading to apoptosis-mediated cell death. In vivo, both cladribine and clofarabine exhibited substantial antitumor effects in a xenograft model. In conclusion, cladribine and clofarabine, which are already approved for clinical use in leukemia and multiple sclerosis, show promise as potential candidates for chondrosarcoma treatment. Their efficacy in preclinical models suggests these molecules could be repurposed for Phase II clinical trials in CS patients.

cancer biology↗