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

Makoto Shiraki, Xianghe Xu, Juan L. Iovanna, Toshio Kukita, Hirohito Hirata, Asana Kamohara, Yasushi Kubota, Hiroshi Miyamoto, Masaaki Mawatari, Akiko Kukita

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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.

Original languageEnglish
Pages (from-to)8836-8852
Number of pages17
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number8
DOIs
Publication statusPublished - Aug 1 2019

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Osteoblasts
Osteoclasts
Bone
Genes
Bone and Bones
Osteocytes
Osteogenesis
Autophagy
Nuclear Proteins
X-Ray Microtomography
Bone Matrix
Contracts
Macrophages
Heat-Shock Proteins
Cell culture
Metabolism
Cell Survival
Carcinogenesis
Tomography
Homeostasis

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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Deficiency of stress-associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts. / Shiraki, Makoto; Xu, Xianghe; Iovanna, Juan L.; Kukita, Toshio; Hirata, Hirohito; Kamohara, Asana; Kubota, Yasushi; Miyamoto, Hiroshi; Mawatari, Masaaki; Kukita, Akiko.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 8, 01.08.2019, p. 8836-8852.

Research output: Contribution to journalArticle

Shiraki, Makoto ; Xu, Xianghe ; Iovanna, Juan L. ; Kukita, Toshio ; Hirata, Hirohito ; Kamohara, Asana ; Kubota, Yasushi ; Miyamoto, Hiroshi ; Mawatari, Masaaki ; Kukita, Akiko. / Deficiency of stress-associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts. In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019 ; Vol. 33, No. 8. pp. 8836-8852.
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AU - Hirata, Hirohito

AU - Kamohara, Asana

AU - Kubota, Yasushi

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