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

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

doi:10.18632/oncotarget.14458

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.

Highlights

According to the National Institutes of Health (NIH) consensus statement in 2000, osteoporosis is defined as a skeletal disorder characterized by compromised bone strength, predisposing individuals to an increased risk of fracture [1]
In the Akr1A1eGFP/eGFP KO mice, Akr1A1 mRNA and protein expression was abolished in the livers, and mRNA expression was reduced by 50% in Akr1A1eGFP/+ mice compared with wild-type (WT) mice (Figure 1B and 1C)
During the generation of the pCAG-eGFP transgenic mice via pronuclear microinjection, the Akr1A1 gene was disrupted by the integration of the transgene and completely abolished the gene expression (Figure 1)

Summary

Introduction

According to the National Institutes of Health (NIH) consensus statement in 2000, osteoporosis is defined as a skeletal disorder characterized by compromised bone strength, predisposing individuals to an increased risk of fracture [1]. The World Health Organization (WHO) defines a diagnosis of osteoporosis as a peak bone mass (T-score) BMD of 2.5 standard deviations below the mean (T-score < -2.5), and a T-score between -1 to -2.5 is considered osteopenia [5]. Osteoporosis can occur in all populations at all ages because of bone loss and insufficient bone formation. Individuals who are deficient in nutrients (e.g., calcium, vitamin D and vitamin C), hormones (e.g., sex and growth hormones), and exercise, during the critical bone formation period, may have a reduced peak bone mass throughout young adulthood and are at an increased risk of osteoporosis [1]

Methods

Results

Conclusion