Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis

Hsin Chiao Chou; Sung Yen Lin; Liang Yin Chou; Mei Ling Ho; Shu Chun Chuang; Tsung Lin Cheng; Lin Kang; Yi Shan Lin; Yan Hsiung Wang; Chun Wang Wei; Chung Hwan Chen; Chau Zen Wang

doi:10.3390/biomedicines10092173

Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis

Hsin Chiao Chou, Sung Yen Lin, Liang Yin Chou, Mei Ling Ho, Shu Chun Chuang, Tsung Lin Cheng, Lin Kang, Yi Shan Lin, Yan Hsiung Wang, Chun Wang Wei, Chung Hwan Chen, Chau Zen Wang

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摘要

Discoidin domain receptor 1 (DDR1) is a collagen receptor that belongs to the receptor tyrosine kinase family. We have previously shown that DDR1 plays a crucial role during bone development, resulting in dwarfism and a short stature in osteoblast-specific knockout mice (OKO mice). However, the detailed pathophysiological effects of DDR1 on bone development throughout adulthood have remained unclear. This study aims to identify how DDR1 regulates osteoblast and osteocyte functions in vivo and in vitro during bone development in adulthood. The metabolic changes in bone tissues were analyzed using Micro-CT and immunohistochemistry staining (IHC) in vivo; the role of DDR1 in regulating osteoblasts was examined in MC3T3-E1 cells in vitro. The Micro-CT analysis results demonstrated that OKO mice showed a 10% reduction in bone-related parameters from 10 to 14 weeks old and a significant reduction in cortical thickness and diameter compared with flox/flox control mice (FF) mice. These results indicated that DDR1 knockout in OKO mice exhibiting significant bone loss provokes an osteopenic phenotype. The IHC staining revealed a significant decrease in osteogenesis-related genes, including RUNX2, osteocalcin, and osterix. We noted that DDR1 knockout significantly induced osteoblast/osteocyte apoptosis and markedly decreased autophagy activity in vivo. Additionally, the results of the gain- and loss-of-function of the DDR1 assay in MC3T3-E1 cells indicated that DDR1 can regulate the osteoblast differentiation through activating autophagy by regulating the phosphorylation of the mechanistic target of rapamycin (p-mTOR), light chain 3 (LC3), and beclin-1. In conclusion, our study highlights that the ablation of DDR1 results in cancellous bone loss by regulating osteoblast/osteocyte autophagy. These results suggest that DDR1 can act as a potential therapeutic target for managing cancellous bone loss.

原文	English
文章編號	2173
期刊	Biomedicines
卷	10
發行號	9
DOIs	https://doi.org/10.3390/biomedicines10092173
出版狀態	Published - 2022 9月

All Science Journal Classification (ASJC) codes

醫藥（雜項）
一般生物化學，遺傳學和分子生物學

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10.3390/biomedicines10092173

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Chou, H. C., Lin, S. Y., Chou, L. Y., Ho, M. L., Chuang, S. C., Cheng, T. L., Kang, L., Lin, Y. S., Wang, Y. H., Wei, C. W., Chen, C. H., & Wang, C. Z. (2022). Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis. Biomedicines, 10(9), 文章 2173. https://doi.org/10.3390/biomedicines10092173

@article{6bad3e788da24d739159a1a6c6ec1f9a,

title = "Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis",

abstract = "Discoidin domain receptor 1 (DDR1) is a collagen receptor that belongs to the receptor tyrosine kinase family. We have previously shown that DDR1 plays a crucial role during bone development, resulting in dwarfism and a short stature in osteoblast-specific knockout mice (OKO mice). However, the detailed pathophysiological effects of DDR1 on bone development throughout adulthood have remained unclear. This study aims to identify how DDR1 regulates osteoblast and osteocyte functions in vivo and in vitro during bone development in adulthood. The metabolic changes in bone tissues were analyzed using Micro-CT and immunohistochemistry staining (IHC) in vivo; the role of DDR1 in regulating osteoblasts was examined in MC3T3-E1 cells in vitro. The Micro-CT analysis results demonstrated that OKO mice showed a 10% reduction in bone-related parameters from 10 to 14 weeks old and a significant reduction in cortical thickness and diameter compared with flox/flox control mice (FF) mice. These results indicated that DDR1 knockout in OKO mice exhibiting significant bone loss provokes an osteopenic phenotype. The IHC staining revealed a significant decrease in osteogenesis-related genes, including RUNX2, osteocalcin, and osterix. We noted that DDR1 knockout significantly induced osteoblast/osteocyte apoptosis and markedly decreased autophagy activity in vivo. Additionally, the results of the gain- and loss-of-function of the DDR1 assay in MC3T3-E1 cells indicated that DDR1 can regulate the osteoblast differentiation through activating autophagy by regulating the phosphorylation of the mechanistic target of rapamycin (p-mTOR), light chain 3 (LC3), and beclin-1. In conclusion, our study highlights that the ablation of DDR1 results in cancellous bone loss by regulating osteoblast/osteocyte autophagy. These results suggest that DDR1 can act as a potential therapeutic target for managing cancellous bone loss.",

author = "Chou, {Hsin Chiao} and Lin, {Sung Yen} and Chou, {Liang Yin} and Ho, {Mei Ling} and Chuang, {Shu Chun} and Cheng, {Tsung Lin} and Lin Kang and Lin, {Yi Shan} and Wang, {Yan Hsiung} and Wei, {Chun Wang} and Chen, {Chung Hwan} and Wang, {Chau Zen}",

note = "Funding Information: This study was funded by the Guangdong Basic and Applied Basic Research Foundation (Grant Number 2021B1515230003); the Guangdong Natural Science Fund, China (Grant Numbers 2019A1515012061 and 2022A1515012558); the Guangzhou Science and Technology Program Project, China (Grant Numbers 201904010486 and 202102020829); Doctoral Research Initiation Fund from Guangzhou Institute of Pediatrics, Guangzhou Women and Children{\textquoteright}s Medical Center (Grant Number 1600104); and Postdoctoral Research Initiation Fund from Guangzhou Institute of Pediatrics, Guangzhou Women and Children{\textquoteright}s Medical Center (Grant Numbers 3001162 and 3001178-04). Funding Information: This study was supported in part by the Kaohsiung Medical University, Taiwan (KMU-TC111A02-0, KMU-TC111A02-1, NPUST-KMU-111-P005, KMTTH-110-R008, and KMUTC111IFSP03), and the Ministry of Science and Technology, Taiwan (MOST110-2320-B-037-003, MOST108-2314-B-037-059-MY3, MOST109-2314-B-037-026, MOST110-2314-B-037-029-MY3, MOST110-2314-B-037-025, MOST 111-2314-B-037-106, MOST 111-2320-B-037-008-MY2, and MOST111-2314-B037-056). The Orthopedic Research Center and Regeneration Medicine and Cell Therapy Research Center in Kaohsiung Medical University is acknowledged for research resources and equipment. The funders had no conflicts of interest in the study design, the data collection and analysis, the decision to publish, or the manuscript preparation. Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = sep,

doi = "10.3390/biomedicines10092173",

language = "English",

volume = "10",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI AG",

number = "9",

}

TY - JOUR

T1 - Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis

AU - Chou, Hsin Chiao

AU - Lin, Sung Yen

AU - Chou, Liang Yin

AU - Ho, Mei Ling

AU - Chuang, Shu Chun

AU - Cheng, Tsung Lin

AU - Kang, Lin

AU - Lin, Yi Shan

AU - Wang, Yan Hsiung

AU - Wei, Chun Wang

AU - Chen, Chung Hwan

AU - Wang, Chau Zen

N1 - Funding Information: This study was funded by the Guangdong Basic and Applied Basic Research Foundation (Grant Number 2021B1515230003); the Guangdong Natural Science Fund, China (Grant Numbers 2019A1515012061 and 2022A1515012558); the Guangzhou Science and Technology Program Project, China (Grant Numbers 201904010486 and 202102020829); Doctoral Research Initiation Fund from Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center (Grant Number 1600104); and Postdoctoral Research Initiation Fund from Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center (Grant Numbers 3001162 and 3001178-04). Funding Information: This study was supported in part by the Kaohsiung Medical University, Taiwan (KMU-TC111A02-0, KMU-TC111A02-1, NPUST-KMU-111-P005, KMTTH-110-R008, and KMUTC111IFSP03), and the Ministry of Science and Technology, Taiwan (MOST110-2320-B-037-003, MOST108-2314-B-037-059-MY3, MOST109-2314-B-037-026, MOST110-2314-B-037-029-MY3, MOST110-2314-B-037-025, MOST 111-2314-B-037-106, MOST 111-2320-B-037-008-MY2, and MOST111-2314-B037-056). The Orthopedic Research Center and Regeneration Medicine and Cell Therapy Research Center in Kaohsiung Medical University is acknowledged for research resources and equipment. The funders had no conflicts of interest in the study design, the data collection and analysis, the decision to publish, or the manuscript preparation. Publisher Copyright: © 2022 by the authors.

PY - 2022/9

Y1 - 2022/9

N2 - Discoidin domain receptor 1 (DDR1) is a collagen receptor that belongs to the receptor tyrosine kinase family. We have previously shown that DDR1 plays a crucial role during bone development, resulting in dwarfism and a short stature in osteoblast-specific knockout mice (OKO mice). However, the detailed pathophysiological effects of DDR1 on bone development throughout adulthood have remained unclear. This study aims to identify how DDR1 regulates osteoblast and osteocyte functions in vivo and in vitro during bone development in adulthood. The metabolic changes in bone tissues were analyzed using Micro-CT and immunohistochemistry staining (IHC) in vivo; the role of DDR1 in regulating osteoblasts was examined in MC3T3-E1 cells in vitro. The Micro-CT analysis results demonstrated that OKO mice showed a 10% reduction in bone-related parameters from 10 to 14 weeks old and a significant reduction in cortical thickness and diameter compared with flox/flox control mice (FF) mice. These results indicated that DDR1 knockout in OKO mice exhibiting significant bone loss provokes an osteopenic phenotype. The IHC staining revealed a significant decrease in osteogenesis-related genes, including RUNX2, osteocalcin, and osterix. We noted that DDR1 knockout significantly induced osteoblast/osteocyte apoptosis and markedly decreased autophagy activity in vivo. Additionally, the results of the gain- and loss-of-function of the DDR1 assay in MC3T3-E1 cells indicated that DDR1 can regulate the osteoblast differentiation through activating autophagy by regulating the phosphorylation of the mechanistic target of rapamycin (p-mTOR), light chain 3 (LC3), and beclin-1. In conclusion, our study highlights that the ablation of DDR1 results in cancellous bone loss by regulating osteoblast/osteocyte autophagy. These results suggest that DDR1 can act as a potential therapeutic target for managing cancellous bone loss.

AB - Discoidin domain receptor 1 (DDR1) is a collagen receptor that belongs to the receptor tyrosine kinase family. We have previously shown that DDR1 plays a crucial role during bone development, resulting in dwarfism and a short stature in osteoblast-specific knockout mice (OKO mice). However, the detailed pathophysiological effects of DDR1 on bone development throughout adulthood have remained unclear. This study aims to identify how DDR1 regulates osteoblast and osteocyte functions in vivo and in vitro during bone development in adulthood. The metabolic changes in bone tissues were analyzed using Micro-CT and immunohistochemistry staining (IHC) in vivo; the role of DDR1 in regulating osteoblasts was examined in MC3T3-E1 cells in vitro. The Micro-CT analysis results demonstrated that OKO mice showed a 10% reduction in bone-related parameters from 10 to 14 weeks old and a significant reduction in cortical thickness and diameter compared with flox/flox control mice (FF) mice. These results indicated that DDR1 knockout in OKO mice exhibiting significant bone loss provokes an osteopenic phenotype. The IHC staining revealed a significant decrease in osteogenesis-related genes, including RUNX2, osteocalcin, and osterix. We noted that DDR1 knockout significantly induced osteoblast/osteocyte apoptosis and markedly decreased autophagy activity in vivo. Additionally, the results of the gain- and loss-of-function of the DDR1 assay in MC3T3-E1 cells indicated that DDR1 can regulate the osteoblast differentiation through activating autophagy by regulating the phosphorylation of the mechanistic target of rapamycin (p-mTOR), light chain 3 (LC3), and beclin-1. In conclusion, our study highlights that the ablation of DDR1 results in cancellous bone loss by regulating osteoblast/osteocyte autophagy. These results suggest that DDR1 can act as a potential therapeutic target for managing cancellous bone loss.

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U2 - 10.3390/biomedicines10092173

DO - 10.3390/biomedicines10092173

M3 - Article

AN - SCOPUS:85138649882

SN - 2227-9059

VL - 10

JO - Biomedicines

JF - Biomedicines

IS - 9

M1 - 2173

ER -

Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis

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