TY - JOUR
T1 - Identification of CITED2 as a negative regulator of fracture healing
AU - Lee, Jonathan Y.
AU - Taub, Peter J.
AU - Wang, Liang
AU - Clark, Amelia
AU - Zhu, Ling L.
AU - Maharam, Edward R.
AU - Leong, Daniel J.
AU - Ramcharan, Melissa
AU - Li, Zhengzhi
AU - Liu, Zhonghou
AU - Ma, Yuan Zheng
AU - Sun, Li
AU - Zaidi, Mone
AU - Majeska, Robert J.
AU - Sun, Hui B.
N1 - Funding Information:
This study was supported by grants to H.S. from the National Institutes of Health (AR050968, AR047628). L.S. and M.Z. acknowledge the support of the National Institutes of Health (AG23176, DK70526 and DK80459).
PY - 2009/10/2
Y1 - 2009/10/2
N2 - The transcription regulator CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) is known to suppress genes mediating angiogenesis and extracellular matrix (ECM) remodeling. However, it is unclear whether CITED2 has a role in controlling skeletal repair or remodeling. We tested the hypothesis that CITED2 functions in bone fracture healing by suppressing the expression of genes critical to ECM remodeling, angiogenesis and osteogenesis, importantly the matrix metalloproteinases (MMPs). Three hours following mandibular osteotomy or sham surgery of adult rats, osteotomy fronts were harvested and the expression of CITED2 and genes associated with fracture healing was ascertained by quantitative PCR. In parallel, gain-of-function studies examined the effect of overexpressing CITED2 on the expression and activity of several MMPs. In the fractured mandible, CITED2 expression was inversely related to the expression of MMP-2, -3, -9, -13, VEGF, HIF-1α, M-CSF, RANK-L, and OPG. Consistent with this, the over-expression of CITED2 in osteoblasts inhibited the expression and activity of MMP-2, -3, -9, and -13. Taken together, the studies suggest that CITED2 is a critical upstream regulator of fracture healing. The suppression of CITED2 early after fracture may allow an optimal initiation of the healing response.
AB - The transcription regulator CITED2 (CBP/p300-Interacting-Transactivator-with-ED-rich-tail-2) is known to suppress genes mediating angiogenesis and extracellular matrix (ECM) remodeling. However, it is unclear whether CITED2 has a role in controlling skeletal repair or remodeling. We tested the hypothesis that CITED2 functions in bone fracture healing by suppressing the expression of genes critical to ECM remodeling, angiogenesis and osteogenesis, importantly the matrix metalloproteinases (MMPs). Three hours following mandibular osteotomy or sham surgery of adult rats, osteotomy fronts were harvested and the expression of CITED2 and genes associated with fracture healing was ascertained by quantitative PCR. In parallel, gain-of-function studies examined the effect of overexpressing CITED2 on the expression and activity of several MMPs. In the fractured mandible, CITED2 expression was inversely related to the expression of MMP-2, -3, -9, -13, VEGF, HIF-1α, M-CSF, RANK-L, and OPG. Consistent with this, the over-expression of CITED2 in osteoblasts inhibited the expression and activity of MMP-2, -3, -9, and -13. Taken together, the studies suggest that CITED2 is a critical upstream regulator of fracture healing. The suppression of CITED2 early after fracture may allow an optimal initiation of the healing response.
KW - Angiogenesis
KW - Bone fracture healing
KW - CITED2
KW - ECM remodeling
KW - Matrix metalloproteinases
KW - Osteogenesis
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U2 - 10.1016/j.bbrc.2009.07.029
DO - 10.1016/j.bbrc.2009.07.029
M3 - Article
C2 - 19607804
AN - SCOPUS:68549088687
SN - 0006-291X
VL - 387
SP - 641
EP - 645
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -