Biology subjects

Edalat, S. G.

Publications and source records attributed to Edalat, S. G..

4 recordsLinked to original sources

bioRxiv2026

Synovitis in systemic sclerosis is an interferon-driven stromal condition distinct from rheumatoid arthritis

Joint involvement is a major driver of disability in systemic sclerosis (SSc), yet its pathophysiology remains poorly understood. In the absence of specific evidence, SSc synovitis is treated by analogy with rheumatoid arthritis (RA). Here, we present the first comprehensive molecular characterization of SSc synovitis, integrating histology, single-cell RNA sequencing, and spatial multi-omics of synovial biopsies from SSc patients, RA patients, and non-inflammatory controls with in vitro validation. We show that SSc synovitis is characterized by distinct pathomechanisms from RA. Histologically, most SSc biopsies displayed a pauci-immune pathotype with sparse immune infiltrates and predominant stromal cells. At molecular level, synovial fibroblasts in SSc were characterized by a disease-specific type I interferon (IFN) response program, in contrast to the TNF-dominant profile of RA, accompanied by dysregulation of the complement cascade. This IFN program extended across multiple synovial cell types, including monocyte-derived macrophages and endothelial cells, and was spatially organized into focal myeloid niches and a diffuse stromal program. Systemically, elevated serum IFN-2a levels were associated with the presence of clinical synovitis in an independent cohort of SSc patients. We furthermore show that similar IFN-driven programs are shared between skin and synovium in SSc. Genes downregulated by IFNAR1 blockade in SSc skin were enriched in SSc synovium, supporting IFN receptor blockade as a multi-organ target therapeutic strategy. These findings reframe SSc synovitis as a less destructive, IFN-driven stromal condition distinct from RA and provide a mechanistic basis for dedicated clinical trials for joint inflammation in SSc. One Sentence SummarySSc synovitis is a pauci-immune, IFN-driven stromal condition distinct from RA, supporting IFNAR1 blockade as a therapeutic strategy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/733140v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@d85bb5org.highwire.dtl.DTLVardef@6cffe6org.highwire.dtl.DTLVardef@148eb4org.highwire.dtl.DTLVardef@1a4cd83_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Synovial fibroblast niche shapes the efficacy - safety dynamics of JAK inhibition in rheumatoid arthritis

Synovial fibroblasts (SF) drive joint pathology in rheumatoid arthritis (RA). Difficult-to-treat RA frequently exhibits a fibroblast-rich synovial pathotype, enriched in DKK3{square} and CD34{square} SF, highlighting a critical therapeutic gap. Through multicohort transcriptomic analysis of synovial tissues and mechanistic in vitro studies, we identified SF as principal targets of Janus kinase (JAK) inhibition in RA. We demonstrated that JAK inhibitors (JAKi) can target multiple core aspects of fibroblast pathobiology - therapeutic refractoriness, cartilage destruction, and inflammation - offering a mechanistic rationale for JAKi superiority in difficult-to-treat RA. JAK1 was the dominantly expressed JAK across synovial pathotypes and SF subsets, including DKK3{square} and CD34{square} populations. A STAT1-interferon type I gene program was enriched in matrix-destructive PRG4{square} SF, consistent with JAKi efficacy in erosive RA. In contrast, canonical IL-6 signaling predominated in IL6-expressing inflammatory CXCL12high and HLA-DR+ SF, and was reproduced in cytokine-stimulated cultured SF, underscoring the autocrine nature of synovial IL-6 signaling. These data inferred a heightened JAKi sensitivity of PRG4{square}, CXCL12high, and HLA-DR+ SF subsets, informing precision therapeutic strategies. We uncovered a strong synergy between TNF and IL-6 trans-signaling, profoundly amplifying fibroblast inflammation. In high and synergistic cytokine milieu, STAT1/3 phosphorylation and IL-6 secretion persisted in SF despite tofacitinib treatment, revealing tofacitinibs functional ceiling. This could explain reduced tofacitinib efficacy and adherence in patients with high baseline arthritis activity. Finally, inflamed SF partially uncoupled STAT3 activation from sustained JAK1 phosphorylation, limiting inflammatory output. Similar uncoupling in tofacitinib-treated SF, likely drove rapid STAT1/3 reactivation following tofacitinib washout. These data aligned with JAKi withdrawal complications and clinical recommendations for gradual JAKi tapering. Collectively, our study identifies SF as key cellular targets of JAK inhibition and delineates cytokine- and drug-driven mechanisms that may constrain the efficacy and safety profiles of JAKi in RA.

molecular biology↗

bioRxiv2023

Liposomal aggregates sustain the release of rapamycin and protect cartilage from friction

Fibrosis, low-grade inflammation, and increased friction are together with degradation of cartilage key culprits for debilitating pain in osteoarthritis (OA), which is one of the most common chronic diseases of todays aging population. Intraarticular administration of bio-lubricants loaded with a pharmaceutically active component recently showed promise to improve therapy. Liposomes have emerged as exceptional lubricant biomaterial, but their small size leads to rapid clearance from the synovium, causing a need for more frequent administration. We recently developed a liposomal drug delivery system based on aggregation of negatively charged liposomes with physiologically present divalent cations. Here, we expanded our platform by replacing calcium with zinc, reported to exert anti-inflammatory action. The liposomal aggregates extend the release of rapamycin (RAPA) beyond the free liposomes and have a diameter of nearly 100 m, which was previously established to improve retention in synovial joints. Electron microscopy showed that RAPA alters the irregular morphology of liposomal clusters, which are irreversible upon dilution. RAPA recently showed great promise both in vitro and in vivo at protecting the joints from inflammation and cartilage from further degradation. Our study adds to this by showing that RAPA is also able to dampen the fibrotic response in human OA synovial fibroblasts. Finally, the tribological properties were assessed on nano- and macro-scales on silicon surface and ex vivo porcine cartilage, which showed an excellent protective ability of the system against friction on both scales. Taken together, our study shows that liposomal aggregates have the potential of improving local OA therapy.

pharmacology and toxicology↗

bioRxiv2022

A comprehensive single-cell atlas of freshly dissociated human synovium in inflammatory arthritis with an optimized dissociation protocol for prospective fresh synovial biopsy collection

Single-cell RNA-sequencing is advancing our understanding of synovial pathobiology in inflammatory arthritis. Here, we optimized the protocol for the dissociation of fresh synovial biopsies and created a reference single-cell map of fresh human synovium in inflammatory arthritis. We utilized the published method for dissociating cryopreserved synovium and optimized it for dissociating small fresh synovial biopsies. The optimized protocol enabled the isolation of a good yield of consistently highly viable cells, minimizing the dropout rate of prospectively collected biopsies. Our reference synovium map comprised over 100000 unsorted single-cell profiles from 25 synovial tissues of patients with inflammatory arthritis. Synovial cells formed 11 lymphoid, 15 myeloid and 16 stromal cell clusters, including IFITM2+ synovial neutrophils. Using this reference map, we successfully annotated published synovial scRNA-seq datasets. Our dataset uncovered endothelial cell diversity and identified SOD2highSAA1+SAA2+ and SERPINE1+COL5A3+ fibroblast clusters, expressing genes linked to cartilage breakdown (SDC4) and extracellular matrix remodelling (LOXL2, TGFBI, TGFB1), respectively. We broadened the characterization of tissue resident FOLR2+COLEC12high and LYVE1+SLC40A1+ macrophages, inferring their extracellular matrix sensing and iron recycling activities. Our research brings an efficient synovium dissociation protocol and a reference annotation resource of fresh human synovium, while expanding the knowledge about synovial cell diversity in inflammatory arthritis.

genomics↗