ANP32A represses Wnt signaling across tissues tissues thereby protecting against joint and heart disease
ANP32A represses Wnt signaling across tissues tissues thereby protecting against joint and heart disease
Abstract Wnt signaling is key to diverse homeostatic and pathological processes. This cascade is hyper-activated in osteoarthritis, the most common joint disease. Yet, fundamental aspects of Wnt signaling remain undiscovered. Here, we report that ANP32A negatively regulates Wnt signaling across tissues. In cartilage, loss of Anp32a triggered Wnt hyper-activation. Mechanistically, ANP32A directly interacted with Wnt pathway components and inhibited Wnt target genes via histone acetylation masking. Wnt antagonist treatment reduced severity of osteoarthritis in Anp32a-deficient mice preventing osteophyte formation, contrasting with cartilage-protective effects of ANP32A on oxidative stress. Hence, dual therapy targeting Wnt signaling and oxidative stress in Anp32a-deficient mice ameliorated more osteoarthritis features than individual treatments. Anp32a loss also resulted in Wnt hyper-activation in the heart with cardiac hypertrophy, and in the hippocampus, shedding light on mechanisms for reported links between ANP32A and Alzheimer’s disease. Collectively, this work reveals that ANP32A is a translationally relevant repressor of Wnt signaling, impacting homeostasis and disease across tissues.
Wang Xiangdong、Quintiens Jolien、Sermon An、de Almeida Rodrigo C.、Meulenbelt Ingrid、Peeters Tine、Cornelis Frederique M. F.、Lories Rik J.、de Roover Astrid、Monteagudo Silvia
Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and RegenerationLaboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration||Division of Rheumatology, University Hospitals LeuvenDepartment of Trauma Surgery, University Hospitals Leuven||Department of Development and RegenerationDepartment of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical CenterDepartment of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center||Integrated research on Developmental determinants of Ageing and Longevity (IDEAL)Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and RegenerationLaboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and RegenerationLaboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration||Division of Rheumatology, University Hospitals LeuvenLaboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and RegenerationLaboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration
基础医学分子生物学生理学
Cardiac hypertrophy/ Cartilage / Osteoarthritis/ Rheumatology/ Wnt signaling
Wang Xiangdong,Quintiens Jolien,Sermon An,de Almeida Rodrigo C.,Meulenbelt Ingrid,Peeters Tine,Cornelis Frederique M. F.,Lories Rik J.,de Roover Astrid,Monteagudo Silvia.ANP32A represses Wnt signaling across tissues tissues thereby protecting against joint and heart disease[EB/OL].(2025-03-28)[2025-05-29].https://www.biorxiv.org/content/10.1101/2021.04.04.438364.点此复制
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