Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice

被引：246

作者：

Wang, Xiao ^{[1
]}

Li, Fengfeng ^{[2
]}

Xie, Liang ^{[1
]}

Crane, Janet ^{[1
]}

Zhen, Gehua ^{[1
]}

Mishina, Yuji ^{[3
]}

Deng, Ruoxian ^{[1
]}

Gao, Bo ^{[1
]}

Chen, Hao ^{[1
]}

Liu, Shen ^{[1
,2
]}

Yang, Ping ^{[1
]}

Gao, Manman ^{[1
]}

Tu, Manli ^{[1
]}

Wang, Yiguo ^{[1
]}

Wan, Mei ^{[1
]}

Fan, Cunyi ^{[2
]}

Cao, Xu ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Orthoped Surg, Baltimore, MD 21205 USA

[2] Shanghai Sixth Peoples Hosp, Dept Orthoped Surg, Shanghai 200030, Peoples R China

[3] Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

MESENCHYMAL STEM-CELLS; GROWTH-FACTOR-BETA; BONE-MARROW; ENDOTHELIAL-CELLS; SUBCHONDRAL BONE; PROGENITOR CELLS; HUMAN-DISEASES; RECEPTOR; MUTATIONS; ACTIVATION;

D O I：

10.1038/s41467-018-02988-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury. The exact pathogenesis of HO remains unknown. Here we show that TGF-beta initiates and promotes HO in mice. We find that calcified cartilage and newly formed bone resorb osteoclasts after onset of HO, which leads to high levels of active TGF-beta that recruit mesenchymal stromal/progenitor cells (MSPCs) in the HO microenvironment. Transgenic expression of active TGF-beta in tendon induces spontaneous HO, whereas systemic injection of a TGF-beta neutralizing antibody attenuates ectopic bone formation in traumatic and BMP-induced mouse HO models, and in a fibrodysplasia ossificans progressive mouse model. Moreover, inducible knockout of the TGF-beta type II receptor in MSPCs inhibits HO progression in HO mouse models. Our study points toward elevated levels of active TGF-beta as inducers and promoters of ectopic bone formation, and suggest that TGF-beta might be a therapeutic target in HO.

引用

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