A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells.
Pluripotent mesenchymal stem cells (MSCs) are bone marrow stromal progenitor cells that can differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. Several signaling pathways have been shown to regulate the lineage commitment and terminal differentiation of MSCs. Here, we conducted a comprehensive analysis of the 14 types of bone morphogenetic protein (BMPs) for their abilities to regulate multilineage specific differentiation of MSCs. We found that most BMPs exhibited distinct abilities to regulate the expression of Runx2, Sox9, MyoD, and PPARgamma2. Further analysis indicated that BMP-2, BMP-4, BMP-6, BMP-7, and BMP-9 effectively induced both adipogenic and osteogenic differentiation in vitro and in vivo. BMP-induced commitment to osteogenic or adipogenic lineage was shown to be mutually exclusive. Overexpression of Runx2 enhanced BMP-induced osteogenic differentiation, whereas knockdown of Runx2 expression diminished BMP-induced bone formation with a decrease in adipocyte accumulation in vivo. Interestingly, overexpression of PPARgamma2 not only promoted adipogenic differentiation, but also enhanced osteogenic differentiation upon BMP-2, BMP-6, and BMP-9 stimulation. Conversely, MSCs with PPARgamma2 knockdown or mouse embryonic fibroblasts derived from PPARgamma2(-/-) mice exhibited a marked decrease in adipogenic differentiation, coupled with reduced osteogenic differentiation and diminished mineralization upon BMP-9 stimulation, suggesting that PPARgamma2 may play a role in BMP-induced osteogenic and adipogenic differentiation. Thus, it is important to understand the molecular mechanism behind BMP-regulated lineage divergence during MSC differentiation, as this knowledge could help us to understand the pathogenesis of skeletal diseases and may lead to the development of strategies for regenerative medicine.
Kang
Quan
Q
Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, and The Children's Hospital, Chongqing Medical University, Chongqing, People's Republic of China.
Song
Wen-Xin
WX
Luo
Qing
Q
Tang
Ni
N
Luo
Jinyong
J
Luo
Xiaoji
X
Chen
Jin
J
Bi
Yang
Y
He
Bai-Cheng
BC
Park
Jong Kyung
JK
Jiang
Wei
W
Tang
Yi
Y
Huang
Jiayi
J
Su
Yuxi
Y
Zhu
Gao-Hui
GH
He
Yun
Y
Yin
Hong
H
Hu
Zhenming
Z
Wang
Yi
Y
Chen
Liang
L
Zuo
Guo-Wei
GW
Pan
Xiaochuan
X
Shen
Jikun
J
Vokes
Tamara
T
Reid
Russell R
RR
Haydon
Rex C
RC
Luu
Hue H
HH
He
Tong-Chuan
TC
D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010012:Osteogenesis / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D033581:Stem Cell Transplantation
D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D047495:PPAR gamma; D020033:Protein Isoforms; C493716:Runx2 protein, mouse