Identification of CITED2 as a negative regulator of fracture healing

Jonathan Y. Lee, Peter J. Taub, Liang Wang, Amelia Clark, Ling L. Zhu, Edward R. Maharam, Daniel J. Leong, Melissa Ramcharan, Zhengzhi Li, Zhonghou Liu, Yuan Zheng Ma, Li Sun, Mone Zaidi, Robert J. Majeska, Hui B. Sun

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)641-645
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume387
Issue number4
DOIs
StatePublished - Oct 2 2009
Externally publishedYes

Keywords

  • Angiogenesis
  • Bone fracture healing
  • CITED2
  • ECM remodeling
  • Matrix metalloproteinases
  • Osteogenesis

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Lee, J. Y., Taub, P. J., Wang, L., Clark, A., Zhu, L. L., Maharam, E. R., Leong, D. J., Ramcharan, M., Li, Z., Liu, Z., Ma, Y. Z., Sun, L., Zaidi, M., Majeska, R. J., & Sun, H. B. (2009). Identification of CITED2 as a negative regulator of fracture healing. Biochemical and Biophysical Research Communications, 387(4), 641-645. https://doi.org/10.1016/j.bbrc.2009.07.029