Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects.
Osteosarcoma (OS) is the most common primary malignancy of bone. Here, we investigated a possible role of defective osteoblast differentiation in OS tumorigenesis. We found that basal levels of the early osteogenic marker alkaline phosphatase (ALP) activity were low in OS lines. Osteogenic regulators Runx2 and OSX, and the late marker osteopontin (OPN) expressed at low levels in most OS lines, indicating that most OS cells fail to undergo terminal differentiation. Furthermore, OS cells were refractory to osteogenic BMP-induced increases in ALP activity. Osteogenic BMPs were shown to upregulate early target genes, but not late osteogenic markers OPN and osteocalcin (OC). Furthermore, osteogenic BMPs failed to induce bone formation from human OS cells, rather effectively promoted OS tumor growth in an orthotopic OS model. Exogenous expression of early target genes enhanced BMP-stimulated OS tumor growth, whereas osteogenic BMP-promoted OS tumor growth was inhibited by exogenous Runx2 expression. These results suggest that alterations in osteoprogenitors may disrupt osteogenic differentiation pathway. Thus, identifying potential differentiation defects in OS tumors would allow us to reconstruct the tumorigenic events in osteoprogenitors and to develop rational differentiation therapies for clinical OS management.
Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education, Department of Pediatric Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China.
Xiaoji
X
Luo
Jin
J
Chen
Wen-Xin
WX
Song
Ni
N
Tang
Jinyong
J
Luo
Zhong-Liang
ZL
Deng
Katie A
KA
Sharff
Gary
G
He
Yang
Y
Bi
Bai-Cheng
BC
He
Erwin
E
Bennett
Jiayi
J
Huang
Quan
Q
Kang
Wei
W
Jiang
Yuxi
Y
Su
Gao-Hui
GH
Zhu
Hong
H
Yin
Yun
Y
He
Yi
Y
Wang
Jeffrey S
JS
Souris
Liang
L
Chen
Guo-Wei
GW
Zuo
Anthony G
AG
Montag
Russell R
RR
Reid
Rex C
RC
Haydon
Hue H
HH
Luu
Tong-Chuan
TC
He
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002454:Cell Differentiation; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D015675:Osteocalcin / Q000235:genetics; D010012:Osteogenesis / Q000502:physiology*; D053495:Osteopontin / Q000235:genetics; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*
D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D015675:Osteocalcin; D053495:Osteopontin; D000469:Alkaline Phosphatase