DAP1 regulates osteoblast autophagy via the ATG16L1-LC3 axis in Graves' disease-induced osteoporosis

被引:0
作者
Gao, Mingdong [1 ,2 ,3 ]
Du, Zouxi [1 ]
Dong, Qianqian [1 ]
Su, Shan [1 ]
Tian, Limin [1 ,3 ,4 ]
机构
[1] Lanzhou Univ, Sch Clin Med 1, Lanzhou 730030, Gansu, Peoples R China
[2] Gansu Prov Hosp, Dept Pediat, Lanzhou 730030, Gansu, Peoples R China
[3] Clin Res Ctr Metab Dis, Lanzhou 730030, Gansu, Peoples R China
[4] Gansu Prov Hosp, Dept Endocrinol, 204 West Donggang Rd, Lanzhou 730030, Gansu, Peoples R China
关键词
Autophagy; Death-associated protein 1; Graves' disease; Osteoblasts; Osteoporosis; PROTEIN; CONSEQUENCES; APOPTOSIS; SUBSTRATE; MEMBRANE; RECEPTOR; LEADS;
D O I
10.1186/s13018-023-04171-z
中图分类号
R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学(修复外科学)];
学科分类号
摘要
Objective This study aimed to uncover a critical protein and its mechanisms in modulating autophagy in Graves' disease (GD)-induced osteoporosis (OP). Methods We discovered the target protein, death-associated protein 1 (DAP1), using bone proteomics analysis. Furthermore, genetic overexpression and knockdown (KD) of DAP1 in bone and MC3T3-E1 cells revealed DAP1 effects on autophagy and osteogenic markers, and autophagic vacuoles in cells were detected using transmission electron microscopy and the microtubule-associated protein 1 light chain 3 alpha (MAP1LC3/LC3) dual fluorescence system. An autophagy polymerase chain reaction (PCR) array kit was used to identify the key molecules associated with DAP1-regulated autophagy. Results DAP1 levels were significantly higher in the bone tissue of GD mice and MC3T3-E1 cells treated with triiodothyronine (T3). DAP1 overexpression reduced LC3 lipidation, autophagic vacuoles, RUNX family transcription factor 2 (RUNX2), and osteocalcin (OCN) expression in MC3T3-E1 cells, whereas DAP1 KD reversed these changes. In vivo experiments revealed that GD mice with DAP1 KD had greater bone mass than control mice. DAP1-overexpressing (OE) cells had lower levels of phosphorylated autophagy-related 16-like 1 (ATG16L1) and LC3 lipidation, whereas DAP1-KD cells had higher levels. Conclusions DAP1 was found to be a critical regulator of autophagy homeostasis in GD mouse bone tissue and T3-treated osteoblasts because it negatively regulated autophagy and osteogenesis in osteoblasts via the ATG16L1-LC3 axis.
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页数:16
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