肌醇多磷酸 4-磷酸酶 B 作为调节小鼠和人类骨量的分子。
Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans.
机构信息
Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada.
出版信息
Cell Metab. 2011 Oct 5;14(4):466-77. doi: 10.1016/j.cmet.2011.08.013.
Abstract
Osteoporosis is a multifactorial genetic disease characterized by reduction of bone mass due to dysregulation of osteoclast differentiation or maturation. Herein, we identified a regulator of osteoclastogenesis, the murine homolog of inositol polyphosphate 4-phosphatase type IIα (Inpp4bα). Expression of Inpp4bα is detected from early osteoclast differentiation to activation stage. Targeted expression of native Inpp4bα ex vivo repressed whereas phosphatase-inactive Inpp4bα stimulated osteoclast differentiation. Inpp4bα acts on intracellular calcium level that modulates NFATc1 nuclear translocation and activation. In vivo mice deficient in Inpp4b displayed increased osteoclast differentiation rate and potential resulting in decreased bone mass and osteoporosis. Importantly, INPP4B in human was identified as a susceptibility locus for osteoporosis. This study defined Inpp4b as a major modulator of the osteoclast differentiation and as a gene linked to variability of bone mineral density in mice and humans.
摘要
骨质疏松症是一种多因素遗传疾病，其特征是由于破骨细胞分化或成熟失调导致骨量减少。在此，我们鉴定了破骨细胞生成的调节因子，即肌醇多磷酸 4-磷酸酶 IIα（Inpp4bα）的鼠同源物。Inpp4bα 的表达从早期破骨细胞分化到激活阶段都可检测到。天然 Inpp4bα 的靶向表达在体外抑制，而磷酸酶失活的 Inpp4bα 则刺激破骨细胞分化。Inpp4bα 作用于细胞内钙水平，调节 NFATc1 核易位和激活。体内缺乏 Inpp4b 的小鼠表现出破骨细胞分化率和潜能的增加，导致骨量减少和骨质疏松症。重要的是，人类中的 INPP4B 被鉴定为骨质疏松症的易感基因座。本研究将 Inpp4b 定义为破骨细胞分化的主要调节剂，并将其确定为与小鼠和人类骨矿物质密度变异性相关的基因。
相似文献
1
Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans.肌醇多磷酸 4-磷酸酶 B 作为调节小鼠和人类骨量的分子。
Cell Metab. 2011 Oct 5;14(4):466-77. doi: 10.1016/j.cmet.2011.08.013.
2
Inpp4b is a novel negative modulator of osteoclast differentiation and a prognostic locus for human osteoporosis.Inpp4b 是破骨细胞分化的新型负调节剂，也是人类骨质疏松症的一个预后基因座。
Ann N Y Acad Sci. 2013 Mar;1280:52-4. doi: 10.1111/nyas.12014.
3
Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade.Akt 通过调节 GSK3β/NFATc1 信号级联诱导破骨细胞分化。
J Immunol. 2012 Jan 1;188(1):163-9. doi: 10.4049/jimmunol.1101254. Epub 2011 Nov 30.
4
Phospholipase C-related, but catalytically inactive protein (PRIP) up-regulates osteoclast differentiation via calcium-calcineurin-NFATc1 signaling.磷脂酶C相关但无催化活性蛋白（PRIP）通过钙-钙调神经磷酸酶-NFATc1信号通路上调破骨细胞分化。
J Biol Chem. 2017 May 12;292(19):7994-8006. doi: 10.1074/jbc.M117.784777. Epub 2017 Mar 24.
5
Knockdown of TRPV4 suppresses osteoclast differentiation and osteoporosis by inhibiting autophagy through Ca -calcineurin-NFATc1 pathway.TRPV4 敲低通过 Ca -calcineurin-NFATc1 通路抑制自噬来抑制破骨细胞分化和骨质疏松症。
J Cell Physiol. 2019 May;234(5):6831-6841. doi: 10.1002/jcp.27432. Epub 2018 Nov 1.
6
The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis.Blimp1-Bcl6 轴对于调节破骨细胞分化和骨稳态至关重要。
J Exp Med. 2010 Apr 12;207(4):751-62. doi: 10.1084/jem.20091957. Epub 2010 Apr 5.
7
Kirenol inhibits RANKL-induced osteoclastogenesis and prevents ovariectomized-induced osteoporosis via suppressing the Ca-NFATc1 and Cav-1 signaling pathways.鸢尾黄素通过抑制 Ca-NFATc1 和 Cav-1 信号通路抑制 RANKL 诱导的破骨细胞生成，预防去卵巢诱导的骨质疏松症。
Phytomedicine. 2021 Jan;80:153377. doi: 10.1016/j.phymed.2020.153377. Epub 2020 Oct 12.
8
Osteoporosis regulation by salubrinal through eIF2α mediated differentiation of osteoclast and osteoblast.通过 eIF2α 介导的破骨细胞和成骨细胞分化来调节骨质疏松症。
Cell Signal. 2013 Feb;25(2):552-60. doi: 10.1016/j.cellsig.2012.11.015. Epub 2012 Nov 23.
9
Characterization of the murine Inpp4b gene and identification of a novel isoform.小鼠Inpp4b基因的特征分析及一种新亚型的鉴定。
Gene. 2006 Jul 5;376(1):152-61. doi: 10.1016/j.gene.2006.02.022. Epub 2006 Mar 17.
10
Chaenomelis fructus inhibits osteoclast differentiation by suppressing NFATc1 expression and prevents ovariectomy-induced osteoporosis.木瓜抑制破骨细胞分化，防止去卵巢诱导的骨质疏松症，其作用机制与抑制 NFATc1 表达有关。
BMC Complement Med Ther. 2020 Feb 5;20(1):35. doi: 10.1186/s12906-020-2841-9.
引用本文的文献
1
Inositols and Bone Health: Potential Therapeutic Applications in Osteoporosis Prevention and Treatment.肌醇与骨骼健康：在骨质疏松症预防和治疗中的潜在治疗应用
Nutrients. 2025 Jun 13;17(12):1999. doi: 10.3390/nu17121999.
2
A molecular systems perspective on calcium oscillations beyond ion fluxes.超越离子通量的钙振荡的分子系统视角。
Curr Opin Cell Biol. 2025 Jun;94:102523. doi: 10.1016/j.ceb.2025.102523. Epub 2025 Apr 30.
3
<sc>d</sc>-Chiro-Inositol in Clinical Practice: A Perspective from the Experts Group on Inositol in Basic and Clinical Research (EGOI).《临床实践中的 D-手性肌醇：基础与临床研究手性肌醇专家组（EGOI）的观点》。
Gynecol Obstet Invest. 2024;89(4):284-294. doi: 10.1159/000536081. Epub 2024 Feb 19.
4
Inositol phosphatase INPP4B sustains ILC1s and intratumoral NK cells through an AKT-driven pathway.肌醇磷酸酶 INPP4B 通过 AKT 驱动的途径维持 ILC1s 和肿瘤内 NK 细胞。
J Exp Med. 2024 Mar 4;221(3). doi: 10.1084/jem.20230124. Epub 2024 Jan 10.
5
Regulation of EZH2 Expression by INPP4B in Normal Prostate and Primary Prostate Cancer.INPP4B对正常前列腺组织和原发性前列腺癌中EZH2表达的调控
Cancers (Basel). 2023 Nov 15;15(22):5418. doi: 10.3390/cancers15225418.
6
Vitamin K-dependent carboxylation regulates Ca flux and adaptation to metabolic stress in β cells.维生素 K 依赖性羧化作用调节β细胞中的钙流和代谢应激适应。
Cell Rep. 2023 May 30;42(5):112500. doi: 10.1016/j.celrep.2023.112500. Epub 2023 May 11.
7
Tumor Suppressor Role of INPP4B in Chemoresistant Retinoblastoma.肌醇多磷酸-4-磷酸酶β（INPP4B）在化疗耐药性视网膜母细胞瘤中的肿瘤抑制作用
J Oncol. 2023 Mar 8;2023:2270097. doi: 10.1155/2023/2270097. eCollection 2023.
8
Traditional Chinese medicine promotes bone regeneration in bone tissue engineering.中医促进骨组织工程中的骨再生。
Chin Med. 2022 Jul 20;17(1):86. doi: 10.1186/s13020-022-00640-5.
9
A signaling axis is a critical mediator of regulatory network in T lymphopoiesis.一条信号轴是T淋巴细胞生成调控网络的关键介质。
iScience. 2022 Mar 25;25(4):104160. doi: 10.1016/j.isci.2022.104160. eCollection 2022 Apr 15.
10
The Aqueous Extract of Eucommia Leaves Promotes Proliferation, Differentiation, and Mineralization of Osteoblast-Like MC3T3-E1 Cells.杜仲叶水提取物促进成骨样MC3T3-E1细胞的增殖、分化和矿化。
Evid Based Complement Alternat Med. 2021 Jun 19;2021:3641317. doi: 10.1155/2021/3641317. eCollection 2021.
本文引用的文献
1
Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis.1-磷酸鞘氨醇可动员破骨细胞前体并调节骨稳态。
Nature. 2009 Mar 26;458(7237):524-8. doi: 10.1038/nature07713. Epub 2009 Feb 8.
2
The PTEN-PI3K pathway: of feedbacks and cross-talks.PTEN-PI3K信号通路：反馈与相互作用
Oncogene. 2008 Sep 18;27(41):5527-41. doi: 10.1038/onc.2008.247.
3
Replication of associations between LRP5 and ESRRA variants and bone density in premenopausal women.LRP5基因与ESRRA基因变异和绝经前女性骨密度之间关联的重复验证
Osteoporos Int. 2008 Dec;19(12):1769-75. doi: 10.1007/s00198-008-0617-z. Epub 2008 Apr 17.
4
A second generation human haplotype map of over 3.1 million SNPs.一张包含超过310万个单核苷酸多态性的第二代人类单倍型图谱。
Nature. 2007 Oct 18;449(7164):851-61. doi: 10.1038/nature06258.
5
Skeletal remodeling in health and disease.健康与疾病中的骨骼重塑
Nat Med. 2007 Jul;13(7):791-801. doi: 10.1038/nm1593.
6
LRP5 coding polymorphisms influence the variation of peak bone mass in a normal population of French-Canadian women.低密度脂蛋白受体相关蛋白5（LRP5）编码多态性影响法裔加拿大女性正常人群中骨峰值的变化。
Bone. 2007 May;40(5):1299-307. doi: 10.1016/j.bone.2007.01.004. Epub 2007 Jan 19.
7
Characterization of the murine Inpp4b gene and identification of a novel isoform.小鼠Inpp4b基因的特征分析及一种新亚型的鉴定。
Gene. 2006 Jul 5;376(1):152-61. doi: 10.1016/j.gene.2006.02.022. Epub 2006 Mar 17.
8
Autoamplification of NFATc1 expression determines its essential role in bone homeostasis.NFATc1 表达的自动扩增决定了其在骨稳态中的关键作用。
J Exp Med. 2005 Nov 7;202(9):1261-9. doi: 10.1084/jem.20051150.
9
Mechanistic insight into osteoclast differentiation in osteoimmunology.骨免疫学中破骨细胞分化的机制性见解。
J Mol Med (Berl). 2005 Mar;83(3):170-9. doi: 10.1007/s00109-004-0612-6. Epub 2005 Jan 26.
10
Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study.通过全基因组连锁扫描确定的男性和女性骨矿物质密度调控位点：FAMOS研究。
Hum Mol Genet. 2005 Apr 1;14(7):943-51. doi: 10.1093/hmg/ddi088. Epub 2005 Mar 3.
Zotero 插件