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Sci Transl Med. 2018 Sep 12;10(458). pii: eaar8426. doi: 10.1126/scitranslmed.aar8426.

ANP32A regulates ATM expression and prevents oxidative stress in cartilage, brain, and bone.

Author information

1
Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
2
Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
3
Integrated research on Developmental determinants of Ageing and Longevity (IDEAL), 2300 RC Leiden, Netherlands.
4
Department of Orthopaedics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
5
Human Movement Biomechanics, Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium.
6
Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium. rik.lories@kuleuven.be.
7
Division of Rheumatology, University Hospitals Leuven, 3000 Leuven, Belgium.

Abstract

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. Microarray 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.

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