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Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3

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posted on 13.10.2021, 19:22 by Zheng-Zhao Liu, Chun-Gu Hong, Wen-Bao Hu, Meng-Lu Chen, Ran Duan, Hong-Ming Li, Tao Yue, Jia Cao, Zhen-Xing Wang, Chun-Yuan Chen, Xiong-Ke Hu, Ben Wu, Hao-Ming Liu, Yi-Juan Tan, Jiang-Hua Liu, Zhong-Wei Luo, Yan Zhang, Shan-Shan Rao, Ming-Jie Luo, Hao Yin, Yi-Yi Wang, Kun Xia, Lang Xu, Si-Yuan Tang, Rong-Gui Hu, Hui Xie

Senile osteoporosis (OP) is often concomitant with decreased autophagic activity. OPTN (optineurin), a macroautophagy/autophagy (hereinafter referred to as autophagy) receptor, is found to play a pivotal role in selective autophagy, coupling autophagy with bone metabolism. However, its role in osteogenesis is still mysterious. Herein, we identified Optn as a critical molecule of cell fate decision for bone marrow mesenchymal stem cells (MSCs), whose expression decreased in aged mice. Aged mice revealed osteoporotic bone loss, elevated senescence of MSCs, decreased osteogenesis, and enhanced adipogenesis, as well as optn/ mice. Importantly, restoring Optn by transplanting wild-type MSCs to optn/ mice or infecting optn/ mice with Optn-containing lentivirus rescued bone loss. The introduction of a loss-of-function mutant of OptnK193R failed to reestablish a bone-fat balance. We further identified FABP3 (fatty acid binding protein 3, muscle and heart) as a novel selective autophagy substrate of OPTN. FABP3 promoted adipogenesis and inhibited osteogenesis of MSCs. Knockdown of FABP3 alleviated bone loss in optn/ mice and aged mice. Our study revealed that reduced OPTN expression during aging might lead to OP due to a lack of FABP3 degradation via selective autophagy. FABP3 accumulation impaired osteogenesis of MSCs, leading to the occurrence of OP. Thus, reactivating OPTN or inhibiting FABP3 would open a new avenue to treat senile OP.

Abbreviations: ADIPOQ: adiponectin, C1Q and collagen domain containing; ALPL: alkaline phosphatase, liver/bone/kidney; BGLAP/OC/osteocalcin: bone gamma carboxyglutamate protein; BFR/BS: bone formation rate/bone surface; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A/p21: cyclin-dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CDKN2B/p15: cyclin dependent kinase inhibitor 2B; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; COL1A1: collagen, type I, alpha 1; Ct. BV/TV: cortical bone volume fraction; Ct. Th: cortical thickness; Es. Pm: endocortical perimeter; FABP4/Ap2: fatty acid binding protein 4, adipocyte; H2AX: H2A.X variant histone; HE: hematoxylin and eosin; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MAR: mineral apposition rate; MSCs: bone marrow mesenchymal stem cells; NBR1: NBR1, autophagy cargo receptor; OP: osteoporosis; OPTN: optineurin; PDB: Paget disease of bone; PPARG: peroxisome proliferator activated receptor gamma; Ps. Pm: periosteal perimeter; qRT-PCR: quantitative real-time PCR; γH2AX: Phosphorylation of the Serine residue of H2AX; ROS: reactive oxygen species; RUNX2: runt related transcription factor 2; SA-GLB1: senescence-associated (SA)-GLB1 (galactosidase, beta 1); SP7/Osx/Osterix: Sp7 transcription factor 7; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; Tb. BV/TV: trabecular bone volume fraction; Tb. N: trabecular number; Tb. Sp: trabecular separation; Tb. Th: trabecular thickness; μCT: micro computed tomography.

Funding

This work was supported by National Natural Science Foundation of China [81974127, 81701383, 31700680, 81670807, 81871822, 81522012, 81600699, 81802138, 81702237, 81801395]; Science and Technology Plan Project of Hunan Province [2018RS3029, 2017XK2039]; Guangdong Basic and Applied Basic Research Foundation [2016A030306051, 2017A030310005]; Shenzhen Foundation of Science and Technology [JCYJ20170306092009689]; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019-RC-HL-024]; China Postdoctoral Science Foundation [2017M612596, 2019T120717, 2018M632998]; Fundamental Research Funds for Central Universities of the Central South University [2018zzts895]; Innovation-Driven Project of Central South University [2018CX029,2019CX014]];.

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