Nupr1 deficiency downregulates HtrA1, enhances SMAD1 signaling, and suppresses age‐related bone loss in male mice
Nupr1 deficiency downregulates HtrA1, enhances SMAD1 signaling, and suppresses age‐related bone loss in male mice
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DOI：
10.1002/jcp.30949
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发表时间：
2023-01
影响因子：
5.6
通讯作者：
Masatoshi Murayama;Hirohito Hirata;M. Shiraki;J. Iovanna;T. Yamaza;T. Kukita;T. Komori;T. Moriishi;Masaya Ueno;T. Morimoto;M. Mawatari;A. Kukita
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作者：
Masatoshi Murayama;Hirohito Hirata;M. Shiraki;J. Iovanna;T. Yamaza;T. Kukita;T. Komori;T. Moriishi;Masaya Ueno;T. Morimoto;M. Mawatari;A. Kukita
核蛋白1 （NUPR1）是一种应激诱导蛋白，可被多种应激激活，如炎症和氧化应激。我们之前报道过，在11周大的小鼠中，Nupr1缺乏通过促进骨形成来增加骨体积。对野生型（WT）和敲除型（Nupr1‐KO）骨细胞差异表达基因的分析显示，高温需求a1 (HTRA1)，一种与成骨和转化生长因子β信号有关的丝氨酸蛋白酶，在Nupr1‐KO骨细胞中显著下调。在体外培养的原代成骨细胞中，Nupr1缺失也显著降低了HtrA1的表达，但增强了SMAD1信号传导。相反，Nupr1过表达增强了成骨细胞中HtrA1的表达，表明Nupr1调节HtrA1的表达，从而抑制成骨细胞的发生。由于HtrA1也参与细胞衰老和年龄相关疾病，我们分析了Nupr1‐KO小鼠中与衰老相关的骨质流失。在6 - 19个月大的WT雄性和雌性小鼠中发现了明显的脊柱小梁骨丢失，而衰老相关的脊柱小梁骨丢失有所减弱，尤其是在Nupr1‐KO雄性小鼠中。此外，细胞衰老相关标志物在6 - 19个月龄的WT雄性小鼠的骨细胞中上调，而在19个月龄的Nupr1 - KO雄性小鼠的骨细胞中明显下调。氧化应激诱导的细胞衰老刺激体外培养的原代成骨细胞中Nupr1和HtrA1的表达，Nupr1过表达增强成骨细胞中p16ink4a的表达。最后，骨关节炎患者骨分离的骨细胞中NUPR1的表达与年龄相关。总之，这些结果表明，Nupr1调节HtrA1介导的成骨细胞分化和衰老。我们的发现揭示了一个新的Nupr1/HtrA1轴，它可能在骨形成和年龄相关的骨质流失中起关键作用。
Nuclear protein 1 (NUPR1) is a stress‐induced protein activated by various stresses, such as inflammation and oxidative stress. We previously reported that Nupr1 deficiency increased bone volume by enhancing bone formation in 11‐week‐old mice. Analysis of differentially expressed genes between wild‐type (WT) and Nupr1‐knockout (Nupr1‐KO) osteocytes revealed that high temperature requirement A 1 (HTRA1), a serine protease implicated in osteogenesis and transforming growth factor‐β signaling was markedly downregulated in Nupr1‐KO osteocytes. Nupr1 deficiency also markedly reduced HtrA1 expression, but enhanced SMAD1 signaling in in vitro‐cultured primary osteoblasts. In contrast, Nupr1 overexpression enhanced HtrA1 expression in osteoblasts, suggesting that Nupr1 regulates HtrA1 expression, thereby suppressing osteoblastogenesis. Since HtrA1 is also involved in cellular senescence and age‐related diseases, we analyzed aging‐related bone loss in Nupr1‐KO mice. Significant spine trabecular bone loss was noted in WT male and female mice during 6−19 months of age, whereas aging‐related trabecular bone loss was attenuated, especially in Nupr1‐KO male mice. Moreover, cellular senescence‐related markers were upregulated in the osteocytes of 6−19‐month‐old WT male mice but markedly downregulated in the osteocytes of 19‐month‐old Nupr1‐KO male mice. Oxidative stress‐induced cellular senescence stimulated Nupr1 and HtrA1 expression in in vitro‐cultured primary osteoblasts, and Nupr1 overexpression enhanced p16ink4a expression in osteoblasts. Finally, NUPR1 expression in osteocytes isolated from the bones of patients with osteoarthritis was correlated with age. Collectively, these results indicate that Nupr1 regulates HtrA1‐mediated osteoblast differentiation and senescence. Our findings unveil a novel Nupr1/HtrA1 axis, which may play pivotal roles in bone formation and age‐related bone loss.