Integrative single cell RNA ‐sequencing and spatial transcriptomics uncovers distinct macrophage‐fibroblast cross‐talk in human hip synovium between patients with femoroacetabular impingement and osteoarthritis

Objectives Femoroacetabular impingement (FAI) and synovitis have been recognized as essential factors for developing osteoarthritis (OA) in the hip joints. However, little is known about altered synovial cellular compositions, their associated transcriptomic profiles, and cell‐cell interactions in FAI and hip OA. Methods Synovial samples from a sex‐matched cohort of FAI and hip OA patients (n = 6/condition) were analyzed using integrative single‐cell RNA sequencing and spatial transcriptomics. Results Compared to FAI, epiregulin (EREG)‐enriched lining synovial fibroblast‐like synoviocytes (FLS) were significantly increased in hip OA. EREG + FLS are pro‐inflammatory due to elevated expression of CXCL1 , IL8 , and MMPs . Pseudotime analysis predicts that EREG + FLS are derived from DPP4 + PI16 + sublining FLS, likely regulated by NFIX and REL, as well as ELK3 and ETV6 transcription factors under FAI or OA conditions, respectively. Importantly, the only putative cell‐cell interaction is fibroblast growth factor 2 (FGF2) – syndecan 4 (SDC4) communication between COL1A1 + IGFBP5 + fibrotic macrophages (MΦ) and EREG + FLS. This interaction may induce expression of IL6, IL8, and MMP1 in hip OA synovium. The gene ontology (GO) analysis of activated genes downstream of FGF2‐SDC4 signaling revealed that inflammation and angiogenesis were upregulated in hip OA, while positive gene transcription and skeletal muscle differentiation were dominant in FAI. Moreover, we also found that EREG + CCL20 + MMP3 hi lining FLS along with most MΦ and monocyte populations are unique to hip OA patients compared to knee OA and RA patients. Conclusion The findings of this study offer a groundwork in tailoring novel targets and therapies for FAI and hip OA patients.