Identification of CITED2 as a negative regulator of fracture healing.
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-1alpha, 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.
Lee
Jonathan Y
JY
Leni and Peter W. May Department of Orthopaedics, Mount Sinai School of Medicine, NY, USA.
Taub
Peter J
PJ
Wang
Liang
L
Clark
Amelia
A
Zhu
Ling L
LL
Maharam
Edward R
ER
Leong
Daniel J
DJ
Ramcharan
Melissa
M
Li
Zhengzhi
Z
Liu
Zhonghou
Z
Ma
Yuan-Zheng
YZ
Sun
Li
L
Zaidi
Mone
M
Majeska
Robert J
RJ
Sun
Hui B
HB
D000818:Animals; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D017102:Fracture Healing / Q000235:genetics*; D005786:Gene Expression Regulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C517260:CITED2 protein, rat; D014157:Transcription Factors