Oncotarget

Research Papers: Pathology:

A novel osteoporosis model with ascorbic acid deficiency in Akr1A1 gene knockout mice

Cheng-Wei Lai, Hsiao-Ling Chen, Min-Yu Tu, Wei-Yu Lin, Theresa Röhrig, Shang-Hsun Yang, Ying-Wei Lan, Kowit-Yu Chong and Chuan-Mu Chen _

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Oncotarget. 2017; 8:7357-7369. https://doi.org/10.18632/oncotarget.14458

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Abstract

Cheng-Wei Lai1,2,*, Hsiao-Ling Chen3,*, Min-Yu Tu1,4,5, Wei-Yu Lin1,2, Theresa Röhrig1,2, Shang-Hsun Yang6, Ying-Wei Lan1,7, Kowit-Yu Chong7,8 and Chuan-Mu Chen1,2,9

1 Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan

2 Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan

3 Department of Bioresources, Da-Yeh University, Changhua, Taiwan

4 Department of Orthopaedic Surgery, Taichung Armed Forces General Hospital, Taichung, Taiwan and National Defense Medical Center, Taipei, Taiwan

5 Department of Biomedical Engineering, Hungkuang University, Taichung, Taiwan

6 Department of Physiology and Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan

7 Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan

8 Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Tao-Yuan, Taiwan

9 Rong-Hsing Translational Medicine Center, and iEGG Center, National Chung Hsing University, Taichung, Taiwan

* These authors have contributed equally to this study

Correspondence to:

Chuan-Mu Chen, email:

Kowit-Yu Chong, email:

Keywords: osteoporosis; Akr1A1 gene; ascorbic acid; knockout mice; micro-CT imaging; trabecular bone; cortical bone; Pathology Section

Received: August 13, 2016 Accepted: December 07, 2016 Published: January 02, 2017

Abstract

The AKR1A1 protein is a member of the aldo-keto reductase superfamily that is responsible for the conversion of D-glucuronate to L-gulonate in the ascorbic acid (vitamin C) synthesis pathway. In a pCAG-eGFP transgenic mouse line that was produced by pronuclear microinjection, the integration of the transgene resulted in a 30-kb genomic DNA deletion, including the Akr1A1 gene, and thus caused the knockout (KO) of the Akr1A1 gene and targeting of the eGFP gene. The Akr1A1 KO mice (Akr1A1eGFP/eGFP) exhibited insufficient serum ascorbic acid levels, abnormal bone development and osteoporosis. Using micro-CT analysis, the results showed that the microarchitecture of the 12-week-old Akr1A1eGFP/eGFP mouse femur was shorter in length and exhibited less cortical bone thickness, enlargement of the bone marrow cavity and a complete loss of the trabecular bone in the distal femur. The femoral head and neck of the proximal femur also showed a severe loss of bone mass. Based on the decreased levels of serum osteocalcin and osteoblast activity in the Akr1A1eGFP/eGFP mice, the osteoporosis might be caused by impaired bone formation. In addition, administration of ascorbic acid to the Akr1A1eGFP/eGFP mice significantly prevented the condition of osteoporotic femurs and increased bone formation. Therefore, through ascorbic acid administration, the Akr1A1 KO mice exhibited controllable osteoporosis and may serve as a novel model for osteoporotic research.


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