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

Abstract

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.

Comprehensive Analysis of Key Genes, Signaling Pathways and miRNAs in Human Knee Osteoarthritis: Based on Bioinformatics

“…Recently, another study observed about 10% overlapping DEGs in OA cartilage and subchondral bone. They identified IL11 and CHADL as two potential therapeutic targets of OA by comparing their identified cartilage-subchondral bone overlapping DEGs with previously identified OA risk genes ( Styrkarsdottir et al, 2018 ; Tuerlings et al, 2021 ).…”

Osteoarthritis year in review: genetics, genomics, epigenetics

“…This year saw several genomics studies examining other tissues of the joint and investigating the relationships between joint tissues. Tuerlings et al examined subchondral bone using RNA sequencing (RNA-seq) to highlight the differentially expressed genes between paired preserved and lesional regions in 18 KOA and 6 HOA patients 29 . Comparison to articular cartilage revealed shared altered genes between joint sites, including the OA susceptibility genes IL11 and CHADL, which are candidates for future studies in in vivo OA models.…”

3D Printing for Bone-Cartilage Interface Regeneration

“…In healthy bones, a balance exists between bone resorption and deposition in response to dynamic adaptation to mechanical loading. In Osteochondral Defects (OCD), this balance is disrupted, leading to changes in the structure of the subchondral trabeculae (T bone), including increased thickness of the subchondral bone plate, formation of new bony structures at the joint edges (osteophytes), and development of subchondral bone cysts (Goldring and Goldring, 2010;Loeser et al, 2012;Funck-Brentano and Cohen-Solal, 2015;Tuerlings et al, 2021). Cartilage defects can be classified, using various methods, according to severity, width, and depth, according to different methods.…”