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Objective  To identify key determinants of the interactive pathophysiologic processes in subchondral bone and cartilage in osteoarthritis (OA).    Methods  We performed RNA sequencing on macroscopically preserved and lesional OA subchondral bone from patients in the Research Arthritis and Articular Cartilage study who underwent joint replacement surgery due to OA (n = 24 sample pairs: 6 hips and 18 knees). Unsupervised hierarchical clustering and differential expression analyses were conducted. Results were combined with data on previously identified differentially expressed genes in cartilage (partly overlapping samples) as well as data on recently identified OA risk genes.    Results  We identified 1,569 genes that were significantly differentially expressed between lesional and preserved subchondral bone, including  CNTNAP2  (fold change [FC] 2.4, false discovery rate [FDR] 3.36 × 10 −5 ) and  STMN2  (FC 9.6, FDR 2.36 × 10 −3 ). Among these 1,569 genes, 305 were also differentially expressed, and with the same direction of effect, in cartilage, including the recently recognized OA susceptibility genes  IL11  and  CHADL . Upon differential expression analysis with stratification for joint site, we identified 509 genes that were exclusively differentially expressed in subchondral bone of the knee, including  KLF11  and  WNT4 . These genes that were differentially expressed exclusively in the knee were enriched for involvement in epigenetic processes, characterized by, e.g.,  HIST1H3J  and  HIST1H3H .    Conclusion   IL11  and  CHADL  were among the most consistently differentially expressed genes OA pathophysiology–related genes in both bone and cartilage .  As these genes were recently also identified as robust OA risk genes, they classify as attractive therapeutic targets acting on 2 OA‐relevant tissues.

arthritis and rheumatology

RNA Sequencing Reveals Interacting Key Determinants of Osteoarthritis Acting in Subchondral Bone and Articular Cartilage: Identification of  IL11  and  CHADL  as Attractive Treatment Targets