Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-κB

被引：227

作者：

Yu, Bo ^{[1
]}

Chang, Jia ^{[1
]}

Liu, Yunsong ^{[2
]}

Li, Jiong ^{[1
]}

Kevork, Kareena ^{[1
]}

Al-Hezaimi, Khalid ^{[3
]}

Graves, Dana T. ^{[4
]}

Park, No-Hee ^{[5
,6
]}

Wang, Cun-Yu ^{[1
,7
,8
]}

机构：

[1] Univ Calif Los Angeles, Sch Dent, Lab Mol Signaling, Div Oral Biol & Med, Los Angeles, CA 90024 USA

[2] Peking Univ, Dept Prosthodont, Sch & Hosp Stomatol, Beijing 100871, Peoples R China

[3] King Saud Univ, Div Periodontol, Coll Dent, Engn AB Res Ctr Growth Factors & Bone Regenerat, Riyadh, Saudi Arabia

[4] Univ Penn, Sch Dent Med, Dept Periodont, Philadelphia, PA 19104 USA

[5] Univ Calif Los Angeles, Sch Dent, Div Diagnost & Surg Sci, Los Angeles, CA 90024 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Broad Stem Cell Res Ctr, Los Angeles, CA USA

[8] Univ Calif Los Angeles, Henry Samueli Sch Engn & Appl Sci, Dept Bioengn, Los Angeles, CA USA

来源：

NATURE MEDICINE | 2014年 / 20卷 / 09期

关键词：

ACTIVATED PROTEIN-KINASE; BONE LOSS; OSTEOCLAST DEVELOPMENT; POSTMENOPAUSAL WOMEN; ESTROGEN DEFICIENCY; BETA-CATENIN; STEM-CELLS; EXPRESSION; OSTEOPOROSIS; MECHANISMS;

D O I：

10.1038/nm.3586

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Aging-related bone loss and osteoporosis affect millions of people worldwide. Chronic inflammation associated with aging promotes bone resorption and impairs bone formation. Here we show that Wnt4 attenuates bone loss in osteoporosis and skeletal aging mouse models by inhibiting nuclear factor-kappa B (NF-kappa B) via noncanonical Wnt signaling. Transgenic mice expressing Wnt4 from osteoblasts were significantly protected from bone loss and chronic inflammation induced by ovariectomy, tumor necrosis factor or natural aging. In addition to promoting bone formation, Wnt4 inhibited osteoclast formation and bone resorption. Mechanistically, Wnt4 inhibited NF-kappa B activation mediated by transforming growth factor-beta-activated kinase-1 (Tak1) in macrophages and osteoclast precursors independently of beta-catenin. Moreover, recombinant Wnt4 alleviated bone loss and inflammation by inhibiting NF-kappa B in vivo in mouse models of bone disease. Given its dual role in promoting bone formation and inhibiting bone resorption, our results suggest that Wnt4 signaling could be an attractive therapeutic target for treating osteoporosis and preventing skeletal aging.

引用

页码：1009 / 1017

页数：9

共 58 条

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