Runx2/Cbfa1, but not loss of myocardin, is required for smooth muscle cell lineage reprogramming toward osteochondrogenesis.
Runx2/Cbfa1, but not loss of myocardin, is required for smooth muscle cell lineage reprogramming toward osteochondrogenesis.
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DOI：
10.1002/jcb.22607
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发表时间：
2010-07-01
影响因子：
4
通讯作者：
Giachelli, Cecilia M.
中科院分区：
文献类型：
--
作者：
Speer, Mei Y.;Li, Xianwu;Hiremath, Pranoti G.;Giachelli, Cecilia M.
血管钙化是心血管疾病发病率和死亡率的主要危险因素。平滑肌细胞（SMCs）可能通过重编程形成骨软骨，在血管软骨化生和钙化中发挥重要作用。为了研究SM谱系重编程和基质钙化是否可逆，以及逆转这一过程所需的调节因素是什么，我们使用了从4周龄基质Gla蛋白敲除小鼠（MGP−/− SMC）钙化动脉中分离的细胞。我们发现，在有利于SMC分化的培养基中培养时，具有骨软骨形成表型的血管细胞恢复了SMC特性（SM 22 α和SM α-肌动蛋白阳性），并下调了骨软骨形成基因表达（Runx 2/Cbfa 1和骨桥蛋白）。随着时间的推移，MGP−/− SMC不再表达骨软骨形成蛋白，并且与野生型SMC无法区分。此外，表型开关的恢复平滑肌细胞的骨软骨形成状态重新诱导的促钙化因子，无机磷酸盐。最后，心肌素（一种SM特异性转录共激活因子）和Runx 2/Cbfa 1（一种骨软骨形成转录因子）的功能丧失和获得研究表明，Runx 2/Cbfa 1的上调，而不是心肌素的丧失，在磷酸盐诱导的SMC谱系重编程和钙化中发挥关键作用。这些结果首次证明了血管SMC响应于局部环境线索而恢复成骨软骨形成状态的可逆性，并且肌心素强化的SMC谱系分配不足以阻断血管钙化。另一方面，Runx 2/Cbfa 1被发现是在该过程中确定的决定性因素。
Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. Smooth muscle cells (SMCs) may play an important role in vascular cartilaginous metaplasia and calcification via reprogramming to the osteochondrogenic state. To study whether SM lineage reprogramming and thus matrix calcification is reversible and what the necessary regulatory factors are to reverse this process, we used cells isolated from calcifying arterial medias of 4-week-old matrix Gla protein knockout mice (MGP−/− SMCs). We found that vascular cells with an osteochondrogenic phenotype regained SMC properties (positive for SM22α and SM α-actin) and down-regulated osteochondrogenic gene expression (Runx2/Cbfa1 and osteopontin) upon culture in medium that favors SMC differentiation. Over time, the MGP−/− SMCs no longer expressed osteochondrogenic proteins and became indistinguishable from wild-type SMCs. Moreover, phenotypic switch of the restored SMCs to the osteochondrogenic state was re-induced by the pro-calcific factor, inorganic phosphate. Finally, loss- and gain-of-function studies of myocardin, a SM-specific transcription co-activator, and Runx2/Cbfa1, an osteochondrogenic transcription factor, revealed that upregulation of Runx2/Cbfa1, but not loss of myocardin, played a critical role in phosphate-induced SMC lineage reprogramming and calcification. These results are the first to demonstrate reversibility of vascular SMCs to an osteochondrogenic state in response to local environmental cues, and that myocardin-enforced SMC lineage allocation was not sufficient to block vascular calcification. On the other hand, Runx2/Cbfa1 was found to be a decisive factor identified in the process.
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影响因子：
6.1
作者：
Chen, Neal X.;Duan, Danxia;Moe, Sharon M.
通讯作者：
Moe, Sharon M.
影响因子：
20.1
作者：
Li, XW;Yang, HY;Giachelli, CM
通讯作者：
Giachelli, CM
DOI：
10.1073/pnas.1233635100
发表时间：
2003-08-05
影响因子：
11.1
作者：
Li, SJ;Wang, DZ;Olson, EN
通讯作者：
Olson, EN
影响因子：
19.6
作者：
Moe, SM;O'Neill, KD;Kopecky, K
通讯作者：
Kopecky, K
影响因子：
5.3
作者：
Hayashi, Ken'ichiro;Nakamura, Seiji;Sobue, Kenji
通讯作者：
Sobue, Kenji