Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis

被引：922

作者：

Zhen, Gehua ^{[1
,2
]}

Wen, Chunyi ^{[3
,4
]}

Jia, Xiaofeng ^{[5
]}

Li, Yu ^{[6
]}

Crane, Janet L. ^{[1
,2
]}

Mears, Simon C. ^{[1
]}

Askin, Frederic B. ^{[7
]}

Frassica, Frank J. ^{[1
]}

Chang, Weizhong ^{[1
,2
]}

Yao, Jie ^{[3
]}

Carrino, John A. ^{[1
,8
]}

Cosgarea, Andrew ^{[1
]}

Artemov, Dmitri ^{[8
]}

Chen, Qianming ^{[6
]}

Zhao, Zhihe ^{[6
]}

Zhou, Xuedong ^{[6
]}

Riley, Lee ^{[1
]}

Sponseller, Paul ^{[1
]}

Wan, Mei ^{[1
,2
]}

Lu, William Weijia ^{[3
,4
]}

Cao, Xu ^{[1
,2
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Orthopaed Surg, Baltimore, MD 21218 USA

[2] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD USA

[3] Univ Hong Kong, Li Ka Shing Fac Med, Dept Orthopaed & Traumatol, Pokfulam, Peoples R China

[4] Chinese Acad Sci, Shenzhen Inst Adv Technol, Ctr Human Tissues & Organs Degenerat, Shenzhen, Peoples R China

[5] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA

[6] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Chengdu, Sichuan, Peoples R China

[7] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA

来源：

NATURE MEDICINE | 2013年 / 19卷 / 06期

基金：

美国国家卫生研究院;

关键词：

HYPERTROPHIC DIFFERENTIATION; CARTILAGE DEGRADATION; OSTEOPHYTE FORMATION; ARTICULAR-CARTILAGE; SYNOVIAL-FLUID; MARROW LESIONS; IN-VIVO; KNEE; EXPRESSION; INCREASE;

D O I：

10.1038/nm.3143

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：

Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor beta 1 (TGF-beta 1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF-beta 1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-beta 1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-beta 1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-beta activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-beta type II receptor (TbRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-beta 1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease.

引用

页码：704 / +

页数：11

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