Accumulation of advanced oxidation protein products contributes to age-related impairment of gap junction intercellular communication in osteocytes of male mice

Bone & Joint Research

article

Chen Tu¹  Siqi Lai²  Zhiwei Huang¹  Guixing Cai¹  Kai Zhao¹  Jiawen Gao¹  Zhiyong Wu³  Zhaoming Zhong¹ 

[1] Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University;Department of Pathology, Nanfang Hospital, Southern Medical University;College of Traditional Chinese Medicine, Southern Medical University

关键词: AOPPs;    Ageing;    Gap junction;    Osteocyte;    Oxidative stress;    NADPH oxidase;    apocynin;    phosphate;    mechanical properties;    bone mass;    bone loss;    Mitochondria;    Reactive oxygen species;    Cortical bone;   

DOI  :  10.1302/2046-3758.117.BJR-2021-0554.R2

学科分类：骨科学

来源: British Editorial Society Of Bone And Joint Surgery

【 摘 要 】

AimsGap junction intercellular communication (GJIC) in osteocytes is impaired by oxidative stress, which is associated with age-related bone loss. Ageing is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, it is still unknown whether AOPP accumulation is involved in the impairment of osteocytes’ GJIC. This study aims to investigate the effect of AOPP accumulation on osteocytes’ GJIC in aged male mice and its mechanism.MethodsChanges in AOPP levels, expression of connexin43 (Cx43), osteocyte network, and bone mass were detected in 18-month-old and three-month-old male mice. Cx43 expression, GJIC function, mitochondria membrane potential, reactive oxygen species (ROS) levels, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation were detected in murine osteocyte-like cells (MLOY4 cells) treated with AOPPs. The Cx43 expression, osteocyte network, bone mass, and mechanical properties were detected in three-month-old mice treated with AOPPs for 12 weeks.ResultsThe AOPP levels were increased in aged mice and correlated with degeneration of osteocyte network, loss of bone mass, and decreased Cx43 expression. AOPP intervention induced NADPH oxidase activation and mitochondrial dysfunction, triggered ROS generation, reduced Cx43 expression, and ultimately impaired osteocytes’ GJIC, which were ameliorated by NADPH oxidase inhibitor apocynin, mitochondria-targeted superoxide dismutase mimetic (mito-TEMPO), and ROS scavenger N-acetyl cysteine. Chronic AOPP loading accelerated the degradation of osteocyte networks and decreased Cx43 expression, resulting in deterioration of bone mass and mechanical properties in vivo.ConclusionOur study suggests that AOPP accumulation contributes to age-related impairment of GJIC in osteocytes of male mice, which may be part of the pathogenic mechanism responsible for bone loss during ageing.

【 授权许可】

CC BY-NC