ABCA6 Regulates Chondrogenesis and Inhibits Joint Degeneration via Orchestrated Cholesterol Efflux and Cellular Senescence
Abstract Patellar dysplasia (PD) can cause patellar dislocation and subsequent osteoarthritis (OA) development. Herein, a novel ABCA6 mutation contributing to a four‐generation family with familiar patellar dysplasia (FPD) is identified. In this study, whole exome sequencing (WES) and genetic linkag...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-03-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202410414 |
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| Summary: | Abstract Patellar dysplasia (PD) can cause patellar dislocation and subsequent osteoarthritis (OA) development. Herein, a novel ABCA6 mutation contributing to a four‐generation family with familiar patellar dysplasia (FPD) is identified. In this study, whole exome sequencing (WES) and genetic linkage analysis across a four‐generation lineage presenting with six cases of FPD are conducted. A disease‐causing mutation in ABCA6 is identified for FPD. Further analyses reveal a consistent correlation between ABCA6 expression downregulation and PD occurrence, chondrocyte degeneration, and OA onset. Moreover, ABCA6‐KO mice demonstrate severe knee joint degeneration and accelerated OA progression. Besides, synovial mesenchymal stem cells (SMSCs) are extracted from WT, ABCA6−/+, and ABCA6−/− mice to create chondrogenic organoids in vitro, confirming ABCA6 deficiency can lead to chondrocyte degeneration via modulating cell cycle and activating cellular senescence. Moreover, transcriptome and metabolomic sequencing analysis on ABCA6‐KO chondrocytes unveils that the ABCA6 deficiency inhibits cholesterol efflux, leading to intracellular cholesterol accumulation and subsequent cellular senescence and impaired chondrogenesis.A disease‐causing mutation of ABCA6 is identified for FPD. ABCA6 is correlated with PD occurrence and subsequent OA progression. ABCA6 can serve as a potential target in chondrogenesis and OA treatment by orchestrated intracellular cholesterol efflux and delayed cellular senescence. |
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| ISSN: | 2198-3844 |