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


ABSTRACT:

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.

SUBMITTER: Gao M 

PROVIDER: S-EPMC10512661 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Gao Mingdong M   Du Zouxi Z   Dong Qianqian Q   Su Shan S   Tian Limin L  

Journal of orthopaedic surgery and research 20230921 1


<h4>Objective</h4>This study aimed to uncover a critical protein and its mechanisms in modulating autophagy in Graves' disease (GD)-induced osteoporosis (OP).<h4>Methods</h4>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 m  ...[more]

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