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Repurposing of a known antipsychotic drug to target arthritogenic synovial fibroblasts

ABSTRACT: We applied quantitative mass spectrometry (MS)-based proteomics to investigate the phosphoproteome of hTNF-stimulated and Amisulpride-treated synovial fibroblasts (SFs), as part of a study aiming to find new potent orally-administered therapeutics to reverse the pathogenic expression signature of arthritogenic SFs. Phosphoproteomics analysis were done by DIA-based phosphoproteomic profiling of synovial fibroblasts. Samples consisted of hTNF-induced WT SFs. Three different time points (5’, 15’, 30’) of hTNF induction were used and compared to cells pretreated with Amisulpride for 1h before being stimulated at similar time points with hTNF (5’, 15’, 30’).

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Anna-Kathrine Pedersen

LAB HEAD: Jesper Velgaard Olsen

PROVIDER: PXD035230 | Pride | 2023-04-11

REPOSITORIES: Pride

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			Action	DRS
	20191129_QE7_EVO4_AKP_EPIC_XS_Kollias_Greece_WT1_GLK1h_Phos500ug_22.raw	Raw
	20191129_QE7_EVO4_AKP_EPIC_XS_Kollias_Greece_WT1_Phos500ug_01.raw	Raw
	20191129_QE7_EVO4_AKP_EPIC_XS_Kollias_Greece_WT1_TNF15_GLK1h_Phos500ug_16.raw	Raw
	20191129_QE7_EVO4_AKP_EPIC_XS_Kollias_Greece_WT1_TNF15_Phos500ug_07.raw	Raw
	20191129_QE7_EVO4_AKP_EPIC_XS_Kollias_Greece_WT1_TNF30_GLK1h_Phos500ug_19.raw	Raw

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Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis.

Project description:Synovial Fibroblasts (SFs) are key pathogenic drivers in arthritis and their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models. TNF blockade has been efficacious for a large percentage of Rheumatoid Arthritis (RA) patients, although characterized by a plethora of side effects. Novel therapeutic discoveries remain however challenging, especially in optimizing drug safety, side effects, longer-term responses, costs and administration routes. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, in order to identify compounds that could potentially reverse the pathogenic expression signature of arthritogenic SFs, derived from the human TNF transgenic mouse model (hTNFtg). We identified a neuroleptic drug, namely Amisulpride, which was validated to reduce SFs’ inflammatory potential while decreasing the clinical score of hTNFtg polyarthritis. Notably, we found that Amisulpride did not exert its biological activities through its known targets Dopamine receptors 2 and 3 and Serotonin Receptor 7, nor through TNFTNFRI binding inhibition. By applying a click chemistry approach, novel potential targets of Amisulpride were identified, which were further validated to repress hTNFtg SFs’ inflammatory potential in vitro (Ascc3 and Sec62), while phosphoproteomics analysis revealed important fibroblast activation pathways, such as adhesion, to be altered upon treatment. Our data support that Amisulpride could provide an additive beneficial effect to patients suffering from RA and comorbid dysthymia, as it may reduce SFs pathogenicity in parallel with its antidepressive activity. Importantly, Amisulpride may also serve as a “lead” compound for the development of novel, more potent therapeutics against chronic inflammatory diseases

2023-04-06 | PXD036283 | Pride

Identification of microRNAs association with Rheumatoid Arthritis Synovial Fibroblasts using the Human TNF Transgenic Mouse Model

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DNA methylation analysis of synovial fibroblasts from mice undergoing collagen-induced arthritis (CIA) treated, or not, with the the helminth-derived immunomodulator, ES-62

Project description:Aim: Synovial fibroblasts (SFs) undergo a rewiring of their DNA methylation landscape that is associated with their development of an aggressive pathogenic phenotype during Rheumatoid Arthritis (RA), both in humans and in CIA, a mouse model of this chronic inflammatory disease. The helminth-derived immunomodulator, ES-62 acts to prevent joint destruction in CIA by suppressing pathogenic SF responses. We therefore investigated whether ES-62 suppressed the changes in DNA methylation observed in SFs from CIA, relative to those from healthy, mice. Methods: The DNA methylation status of SFs from naïve (no induction of CIA), CIA and ES-62-treated mice undergoing CIA (CIA_ES-62) was compared by Reduced Representation Bilsulphite Sequencing (RRBS) analysis performed by the Active Motif service. Results: Synovial fibroblasts from naive, CIA and CIA_ES-62 mice exhibit differential genomic methylation profiles. Conclusion: ES-62 protection against joint protection in CIA is not associated with prevention of the changes in DNA methylation occurring during rewiring of naive SFs to aggressively pathogenic CIA SFs but rather, reflects generation of a distinct ES-62 phenotype of SF genomic methylation.

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miR-221/222 drive synovial fibroblast expansion and pathogenesis of TNF-mediated arthritis

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