Elucidating mechano-pathology of osteoarthritis: transcriptome-wide differences in mechanically stressed aged human cartilage explants

Arthritis Research & Therapy

Robert J. P. van der Wal¹  Rob G. H. H. Nelissen¹  Evelyn Houtman²  Rodrigo Coutinho de Almeida²  Eka H. E. D. Suchiman²  Yolande F. M. Ramos²  Margo Tuerlings²  Janne Riechelman²  Ingrid Meulenbelt²  Hailiang Mei³ 

[1] Department of Orthopaedics, Leiden University Medical Center;Section of Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center;Sequencing Analysis Support Core, Leiden University Medical Centre;

关键词: Osteoarthritis;    Cartilage;    Chondrocytes;    Mechanical stress;    Mechano-pathology;    RNA sequencing;   

DOI  :  10.1186/s13075-021-02595-8

来源: DOAJ

【 摘 要 】

Abstract Background Failing of intrinsic chondrocyte repair after mechanical stress is known as one of the most important initiators of osteoarthritis. Nonetheless, insight into these early mechano-pathophysiological processes in age-related human articular cartilage is still lacking. Such insights are needed to advance clinical development. To highlight important molecular processes of osteoarthritis mechano-pathology, the transcriptome-wide changes following injurious mechanical stress on human aged osteochondral explants were characterized. Methods Following mechanical stress at a strain of 65% (65%MS) on human osteochondral explants (n 65%MS = 14 versus n control = 14), RNA sequencing was performed. Differential expression analysis between control and 65%MS was performed to determine mechanical stress-specific changes. Enrichment for pathways and protein-protein interactions was analyzed with Enrichr and STRING. Results We identified 156 genes significantly differentially expressed between control and 65%MS human osteochondral explants. Of note, IGFBP5 (FC = 6.01; FDR = 7.81 × 10−3) and MMP13 (FC = 5.19; FDR = 4.84 × 10−2) were the highest upregulated genes, while IGFBP6 (FC = 0.19; FDR = 3.07 × 10−4) was the most downregulated gene. Protein-protein interactions were significantly higher than expected by chance (P = 1.44 × 10−15 with connections between 116 out of 156 genes). Pathway analysis showed, among others, enrichment for cellular senescence, insulin-like growth factor (IGF) I and II binding, and focal adhesion. Conclusions Our results faithfully represent transcriptomic wide consequences of mechanical stress in human aged articular cartilage with MMP13, IGF binding proteins, and cellular senescence as the most notable results. Acquired knowledge on the as such identified initial, osteoarthritis-related, detrimental responses of chondrocytes may eventually contribute to the development of effective disease-modifying osteoarthritis treatments.

【 授权许可】

Unknown