Deficiency of stress‐associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts

Abstract

Nuclear protein 1 (NUPR1) is a multifunctional stress‐induced protein involved in regulating tumorigenesis, apoptosis, and autophagy. Bone homeostasis is maintained by bone‐resorbing osteoclasts and bone‐forming osteoblasts and osteocytes. We aimed to determine the role of NUPR1 in bone metabolism. Using microcomputed tomography, we found that mice lacking Nupr1 exhibited increased bone volume. Histologic analysis showed that Nupr1 deficiency decreased osteoclast numbers but increased osteoblast numbers and osteoid formation. In vitro culture of bone marrow macrophages showed that receptor activator of NF‐κB ligand‐induced osteoclastogenesis was down‐regulated in Nupr1‐deficient mice. In contrast, primary osteoblasts from Nupr1‐deficient mice revealed that proliferation of osteoblasts and expression of bone matrix proteins were markedly enhanced. In addition, expression of autophagy‐related genes, formation of autophagosomes, and cell survival were up‐regulated in Nupr1‐deficient osteoblasts. In contract, deletion of Nupr1 reduced the formation of osteocyte cellular projection, which is an indicator of mature osteocytes. Importantly, we found that the expression of sclerostin (Sost), an inhibitor of bone formation, was down‐regulated in the osteoblasts and osteocytes of Nupr1‐deficient mice. Conversely, Nupr1 overexpression enhanced Sost expression in primary osteoblasts. Collectively, these results indicate that Nupr1 deficiency increases bone volume by attenuating production of Sost and osteoclastogenesis and enhancing differentiation of osteoblasts.—Shiraki, M., Xu, X., Iovanna, J. L., Kukita, T., Hirata, H., Kamohara, A., Kubota, Y., Miyamoto, H., Mawatari, M., Kukita, A. Deficiency of stress‐associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts. FASEB J. 33, 8836–8852 (2019). http://www.fasebj.org

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“…Whilst secretion is elevated by reduced mechanical load, disruption to endo-lysosomal biogenesis and altered hydrolase function may inhibit the efficient endocytosis and degradation of sclerostin, maintaining its inhibitory effects on Wnt signalling pathways. Interestingly, sclerostin expression is induced by Nupr1 via Runx2 transcription factor [71]. Nupr1, a stress-associated gene, is highly expressed in mature osteoclasts; however, Nupr1-deficient mice show elevated autophagy and apoptosis [71], suggesting that Nupr1 is a protective factor in osteoclast homeostasis or that osteoclasts pre-disposed to elevated Nupr1 will survive spaceflight stressors that induce autophagy and apoptosis.…”

“…Interestingly, sclerostin expression is induced by Nupr1 via Runx2 transcription factor [71]. Nupr1, a stress-associated gene, is highly expressed in mature osteoclasts; however, Nupr1-deficient mice show elevated autophagy and apoptosis [71], suggesting that Nupr1 is a protective factor in osteoclast homeostasis or that osteoclasts pre-disposed to elevated Nupr1 will survive spaceflight stressors that induce autophagy and apoptosis. Investigations on the interplay of stress response, autophagy, and the endo-lysosomal system on sclerostin and osteoclast activity in space environments may reveal new insights to maintaining bone health in spaceflight.…”