Kavli Affiliate: Robert B. Darnell
| Authors: Michael R. Mazzucco, Bella Mehta, Jenelys Ruiz-Ortiz, Caryn Hale, Fuadur Omi, Purva Singh, Ruoxi Yuan, Samantha Lessard, Eun Kyung Song, Mengrui Zhang, Shady Younis, William H. Robinson, Daniel Ramirez, Edward DiCarlo, Wei Wang, Thomas Carroll, Jose Rodriguez, Peter Sculco, Xiaoshun Li, YiYuan Wu, Robert B. Darnell, Martin Lotz, Rachel E. Miller, Tristan Maerz, Anne-Marie Malfait, Miguel Otero and Dana E. Orange
| Summary:
Objectives: To identify synovial transcriptional clusters in human knee osteoarthritis (OA) and determine how these relate to synovial histologic features, cell-type-associated gene expression, and cartilage degeneration severity. Methods: Bulk RNA sequencing (RNA-seq) of synovial tissue from n = 135 patients with knee OA was analyzed using consensus clustering. Clusters were compared by clinical and histologic features, including cartilage degeneration severity (OARSI score). Single-cell RNA-seq (n = 18) and spatial transcriptomics were used to relate cartilage degeneration-associated gene expression patterns to synovial cell populations. Results: Four synovial transcriptional clusters that differed in synovial histologic features and cartilage degeneration severity were identified. Greater cartilage degeneration was associated with enrichment of lining fibroblast- and inflammatory myeloid-associated gene expression, whereas lesser cartilage degeneration was associated with enrichment of sublining fibroblast, endothelial, mural cell, and adipocyte-associated gene expression. Conclusions: Human knee OA synovium segregates into transcriptional clusters associated with cartilage degeneration severity. Synovial transcriptional heterogeneity corresponds to cell-type-associated gene expression.