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Runx2/Cbfa1, but not loss of myocardin, is required for smooth muscle cell lineage reprogramming toward osteochondrogenesis
Author(s) -
Speer Mei Y.,
Li Xianwu,
Hiremath Pranoti G.,
Giachelli Cecilia M.
Publication year - 2010
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22607
Subject(s) - myocardin , runx2 , reprogramming , calcification , biology , osteopontin , vascular smooth muscle , transdifferentiation , microbiology and biotechnology , transcription factor , endocrinology , medicine , genetics , stem cell , cell , serum response factor , gene , smooth muscle
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 in the 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. J. Cell. Biochem. 110: 935–947, 2010. © 2010 Wiley‐Liss, Inc.