ANP32A regulates ATM expression and prevents oxidative stress in cartilage, brain, and bone
ANP32A regulates ATM expression and prevents oxidative stress in cartilage, brain, and bone
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DOI：
10.1126/scitranslmed.aar8426
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发表时间：
2018-09-12
影响因子：
17.1
通讯作者：
Lories, Rik J.
中科院分区：
文献类型：
--
作者：
Cornelis, Frederique M. F.;Monteagudo, Silvia;Lories, Rik J.
骨关节炎是最常见的关节疾病，由于人口老龄化，全球患病率不断上升。目前的治疗仅限于缓解症状，但无法治愈。其多因素病因包括氧化应激和活性氧的过量产生，但这些过程在关节中的调节尚不充分了解。我们报道ANP32A保护软骨免受氧化应激，防止骨关节炎的发展和疾病进展。ANP32A在人和小鼠骨关节炎软骨中表达下调。微阵列分析显示ANP32A通过促进ATM的表达来保护关节，ATM是细胞氧化防御的关键调节因子。抗氧化治疗降低了ANP32A缺陷小鼠的骨关节炎、骨质减少和小脑性共济失调的严重程度，表明软骨中发现的ANP32A/ATM轴也存在于大脑和骨骼中。我们的研究结果表明，调节ANP32A信号可以帮助控制软骨、大脑和骨骼的氧化应激，对骨关节炎、神经系统疾病和骨质疏松症具有治疗意义。
Osteoarthritis is the most common joint disorder with increasing global prevalence due to aging of the population. Current therapy is limited to symptom relief, yet there is no cure. Its multifactorial etiology includes oxidative stress and overproduction of reactive oxygen species, but the regulation of these processes in the joint is insufficiently understood. We report that ANP32A protects the cartilage against oxidative stress, preventing osteoarthritis development and disease progression. ANP32A is down-regulated in human and mouse osteoarthritic cartilage. Micro-array profiling revealed that ANP32A protects the joint by promoting the expression of ATM, a key regulator of the cellular oxidative defense. Antioxidant treatment reduced the severity of osteoarthritis, osteopenia, and cerebellar ataxia features in Anp32a-deficient mice, revealing that the ANP32A/ATM axis discovered in cartilage is also present in brain and bone. Our findings indicate that modulating ANP32A signaling could help manage oxidative stress in cartilage, brain, and bone with therapeutic implications for osteoarthritis, neurological disease, and osteoporosis.