HIF-1α as a Regulator of BMP2-Induced Chondrogenic Differentiation, Osteogenic Differentiation, and Endochondral Ossification in Stem Cells.
OBJECTIVE
Joint cartilage defects are difficult to treat due to the limited self-repair capacities of cartilage. Cartilage tissue engineering based on stem cells and gene enhancement is a potential alternative for cartilage repair. Bone morphogenetic protein 2 (BMP2) has been shown to induce chondrogenic differentiation in mesenchymal stem cells (MSCs); however, maintaining the phenotypes of MSCs during cartilage repair since differentiation occurs along the endochondral ossification pathway. In this study, hypoxia inducible factor, or (HIF)-1α, was determined to be a regulator of BMP2-induced chondrogenic differentiation, osteogenic differentiation, and endochondral bone formation.


METHODS
BMP2 was used to induce chondrogenic and osteogenic differentiation in stem cells and fetal limb development. After HIF-1α was added to the inducing system, any changes in the differentiation markers were assessed.


RESULTS
HIF-1α was found to potentiate BMP2-induced Sox9 and the expression of chondrogenesis by downstream markers, and inhibit Runx2 and the expression of osteogenesis by downstream markers in vitro. In subcutaneous stem cell implantation studies, HIF-1α was shown to potentiate BMP2-induced cartilage formation and inhibit endochondral ossification during ectopic bone/cartilage formation. In the fetal limb culture, HIF-1α and BMP2 synergistically promoted the expansion of the proliferating chondrocyte zone and inhibited chondrocyte hypertrophy and endochondral ossification.


CONCLUSIONS
The results of this study indicated that, when combined with BMP2, HIF-1α induced MSC differentiation could become a new method of maintaining cartilage phenotypes during cartilage tissue engineering.
Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Nian
N
Zhou
Ning
N
Hu
Jun-Yi
JY
Liao
Liang-Bo
LB
Lin
Chen
C
Zhao
Wei-Ke
WK
Si
Zhong
Z
Yang
Shi-Xiong
SX
Yi
Ting-Xu
TX
Fan
Wei
W
Bao
Xi
X
Liang
Xu
X
Wei
Hong
H
Chen
Cheng
C
Chen
Qiang
Q
Chen
Xin
X
Lin
Wei
W
Huang
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D020219:Chondrogenesis; D005552:Forelimb / Q000196:embryology / Q000254:growth & development*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051457:Hyaline Cartilage / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D010012:Osteogenesis; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse