Genetically inspired organoids prevent joint degeneration and alleviate chondrocyte senescence via Col11a1–HIF1α‐mediated glycolysis–OXPHOS metabolism shift

Abstract

Abstract Introduction Developmental dysplasia of hip (DDH) is a hip joint disorder leading to subsequent osteoarthritis. Previous studies suggested collagen XI alpha 1 (COL11A1) as a potential gene in hip dysplasia and chondrocyte degeneration. However, no genetic association has reported COL11A1‐related cellular therapy as treatment of DDH and joint degeneration. Methods and Results We report identified genetic association between COL11A1 locus and DDH with genome‐wide association study (GWAS). Further exome sequencing for familial DDH patients was conducted in different populations to identify potential pathogenic Col11A1 variants for familiar DDH. Further studies demonstrated involvement of COL11A1 expression was down‐regulated in femoral head cartilage of DDH patients and Col11a1‐KO mice with induced DDH. Col11a1‐KO mice demonstrated aggravated joint degeneration and severe OA phenotype. To explore the underlying mechanism of Col11a1 in cartilage and DDH development, we generated scRNA‐seq profiles for DDH and Col11a1‐KO cartilage, demonstrating disrupted chondrocyte homeostasis and cellular senescence caused by Col11a1–HIF1α‐mediated glycolysis–OXPHOS shift in chondrocytes. Genetically and biologically inspired, we further fabricated an intra‐articular injection therapy to preventing cartilage degeneration by generating a Col11a1‐over‐expressed (OE) SMSC mini‐organoids. Col11a1‐OE organoids demonstrated superior chondrogenesis and ameliorated cartilage degeneration in DDH mice via regulating cellular senescence by up‐regulated Col11a1/HIF1α‐mediated glycolysis in chondrocytes. Conclusion We reported association between COL11A1 loci and DDH with GWAS and exome sequencing. Further studies demonstrated involvement of COL11A1 in DDH patients and Col11a1‐KO mice. ScRNA‐seq for DDH and Col11a1‐KO cartilage demonstrated disrupted chondrocyte homeostasis and cellular senescence caused by Col11a1–HIF1α‐mediated glycolysis–OXPHOS shift in chondrocytes. Genetically and biologically inspired, an intra‐articular injection therapy was fabricated to prevent cartilage degeneration with Col11a1‐OE SMSC organoids. Col11a1‐OE organoids ameliorated cartilage degeneration in DDH mice via regulating cellular senescence by up‐regulated Col11a1/HIF1α‐mediated glycolysis in chondrocytes.

Keywords

• cellular senescence
• genetics
• glycolysis
• hip dysplasia
• organoids
• osteoarthritis