Poster 131. A Transcriptomic Analysis of Cartilage-synovium Crosstalk in the Transition from Hip Femoroacetabular Impingement to Osteoarthritis Highlights Neuroregulatory Pathways as Key Drivers of Hip Osteoarthritis Progression
Year: 2026
Type: article
Study design: Observational Study
Abstract: Objectives: Femoroacetabular impingement (FAI) is a common pre-arthritic condition of the hip that contributes to up to 50% of hip osteoarthritis (OA) cases and represents a critical window for early intervention. As a degenerative joint disease with substantial clinical burden, OA is thought to arise, at least in part, from the progressive joint damage initiated during the FAI stage. Although both cartilage and synovium are known to actively participate in OA pathogenesis, the molecular crosstalk between these tissues during the FAI-to-OA transition remains poorly characterized. Previous studies have largely focused on immune or catabolic factors in isolated tissues, overlooking coordinated inter-tissue regulatory mechanisms. Here, the objective of this study is to define shared biological programs across cartilage and synovium in FAI and OA patients using integrative transcriptomic analysis, with a particular focus on neuroregulatory pathways, emerging as critical mediators of hip OA progression. (Figure1) Methods: This study was approved by the institutional review board, and informed consent was obtained from all participants. Cartilage samples were collected from 4 FAI patients (male/female 3/1, age 43 ±10.82y) and 12 OA patients (male/female 9/3, age 59.42 ±10.64y). Synovium samples were collected from 4 FAI samples (male/female 1/3, age 39 ±6.28y) and 4 OA samples (male/female 0/4, age 44.75 ±4.09y). Full-thickness cartilage from the anterolateral head-neck junction and synovial tissue from the anterior fold were processed for bulk RNA sequencing. Synovial fibroblasts (PDPN+CD45−) were isolated via fluorescence-activated cell sorting (FACS) for RNA extraction. Differential expression analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and gene set enrichment analysis (GSEA) were conducted to identify disease-relevant signaling. We further performed gene set variation analysis (GSVA) to quantify neural-related pathway activity. Weighted gene co-expression network analysis (WGCNA) was applied to both tissues to uncover key transcriptomic modules associated with neural signatures and disease state. Candidate genes were prioritized based on module membership, gene significance, and overlap with differentially expressed genes (DEGs) to identify potential cross-tissue regulators. Results: Transcriptomic profiling revealed extensive molecular remodeling in both tissues, with over 3,000 significantly altered transcripts in cartilage and more than 1,000 in synovium. Integration across tissue types identified 123 concordantly upregulated and 25 concordantly downregulated genes in OA versus FAI (Figure 2A-F), reflecting shared pathophysiologic reprogramming. Functional enrichment of these co-dysregulated genes highlighted distinct yet complementary biological processes, with strong convergence on neuroregulatory pathways, including myelination, synaptic signaling, axon guidance, and neuronal differentiation (Figure 2G). GSEA confirmed elevated activity of neurodevelopmental and synaptic remodeling pathways in OA (Figure 2H-I). We next quantified these neural programs at the sample level using GSVA, identifying distinct disease-associated profiles in cartilage and synovium (Figure 2J-K). To further explore the systems-level organization of neural signatures, we performed WGCNA in both tissues (Figure 3A-B). Several modules significantly correlated with GSVA-derived neural scores and OA phenotype (Figure 3C-D). Cross-referencing key modules with tissue-specific DEGs revealed overlapping gene sets with directional consistency (Figure 3E-F). Based on network centrality, module membership, gene significance, and neural pathway annotation, we prioritized a group of top-ranked candidate drivers (Figure 3G-H), potentially orchestrating cartilage-synovium communication during OA progression. Conclusions: This study provides the first multi-tissue transcriptomic dissection of the FAI-to-OA transition with a focus on coordinated cartilage-synovium crosstalk. Unlike previous efforts centered on immune dysregulation or cartilage degeneration alone, we reveal a neuroregulatory axis that is jointly dysregulated in both tissues. Our results highlight previously underappreciated neuro-signaling programs as central to the pathological dialogue between cartilage and synovium and suggest they may underlie both structural deterioration and pain sensitization in early OA. These findings not only improve our understanding of joint-level disease mechanisms but also nominate novel candidates for therapeutic targeting in the pre-OA stage.
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,500
OpenAlex ID: W7204765048
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