AIMS Gap 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. METHODS Changes 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. RESULTS The 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. CONCLUSION Our 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. Cite this article: Bone Joint Res 2022;11(7):413-425.

中文翻译：

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高级氧化蛋白产物的积累导致雄性小鼠骨细胞间隙连接细胞间通讯的年龄相关损伤。

AIMS 骨细胞中的间隙连接细胞间通讯 (GJIC) 受到氧化应激的损害，氧化应激与年龄相关的骨质流失有关。衰老伴随着高级氧化蛋白产物 (AOPP) 的积累。然而，AOPP 的积累是否与骨细胞 GJIC 的损害有关尚不清楚。本研究旨在探讨AOPP积累对老年雄性小鼠骨细胞GJIC的影响及其机制。方法 检测 18 月龄和 3 月龄雄性小鼠的 AOPP 水平、连接蛋白 43 (Cx43) 表达、骨细胞网络和骨量的变化。Cx43 表达、GJIC 功能、线粒体膜电位、活性氧 (ROS) 水平、在用 AOPP 处理的鼠类骨细胞样细胞（MLOY4 细胞）中检测到烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶活化。在用 AOPP 治疗 12 周的三个月大的小鼠中检测到 Cx43 表达、骨细胞网络、骨量和机械性能。结果 老年小鼠的 AOPP 水平升高，并与骨细胞网络退化、骨量减少和 Cx43 表达降低相关。AOPP 干预诱导 NADPH 氧化酶激活和线粒体功能障碍，触发 ROS 生成，降低 Cx43 表达，最终损害骨细胞的 GJIC，NADPH 氧化酶抑制剂夹竹桃麻素、线粒体靶向超氧化物歧化酶模拟物 (mito-TEMPO) 和 ROS 清除剂 N 可改善这些情况-乙酰半胱氨酸。慢性 AOPP 负荷加速了骨细胞网络的降解并降低了 Cx43 的表达，导致体内骨量和机械性能恶化。结论 我们的研究表明，AOPP 积累导致雄性小鼠骨细胞中 GJIC 的年龄相关性损伤，这可能是导致衰老过程中骨丢失的致病机制的一部分。引用这篇文章：Bone Joint Res 2022;11(7):413-425。