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| Title: | Col1a1 Promoter-targeted Expression of p20 CCAAT Enhancer-binding Protein β (C/EBPβ), a Truncated C/EBPβ Isoform, Causes Osteopenia in Transgenic Mice |
| Authors: | John, R.Harrison
Huang, Yu-Feng
Wilson, K.Amanda
Penny, L.Kelly
Douglas, J.Adams
Gloria, A.Gronowicz
Stephen, H.Clark |
| Contributors: | 中山醫學大學 |
| Date: | 2005 |
| Issue Date: | 2015-07-17T08:05:48Z (UTC)
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| Abstract: | CCAAT enhancer-binding protein (C/EBP) transcription factors regulate adipocyte differentiation, and recent evidence suggests that osteoblasts and adipocytes share a common pluripotent progenitor in bone marrow. However, little is known about the role of C/EBP transcription factors in the control of osteoblast differentiation or function. In this study, the function of C/EBP transcription factors was disrupted in osteoblast lineage cells by overexpressing a naturally occurring dominant negative C/EBP isoform. Expression of FLp20C/EBPβ was driven by a 3.6-kb Col1a1 promoter/first intron construct, and four transgenic (TG) mouse lines were established. Northern blotting and reverse transcription-PCR indicated that the transgene was targeted to bone, with lower levels of expression in lung, skin, and adipose tissue. TG mice from two lines showed reduced body weight compared with wild type littermates. All TG lines showed evidence of osteopenia, ranging from mild to severe, as evidenced by reduced trabecular bone volume. Severely affected lines also showed reduced cortical bone width. Dynamic histomorphometry demonstrated an associated decrease in mineral apposition and bone formation rates. Long bones and calvariae of TG mice showed reduced COL1A1 and osteocalcin mRNA levels and increased bone sialoprotein mRNA, consistent with an inhibition of terminal osteoblast differentiation. Ex vivo analysis of primary osteoblast differentiation showed similar effects on marker expression and reduced expression of the mature osteoblast marker Col2.3-green fluorescent protein, demonstrating a cell-autonomous effect of the transgene. These data suggested that C/EBP transcription factors may be important determinants of osteoblast function and bone mass.
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CCAAT enhancer-binding proteins (C/EBPs)1 comprise a family of homologous transcription factors characterized by a carboxyl-terminal leucine zipper dimerization domain and an adjacent highly conserved basic DNA binding domain (1, 2). C/EBPs are transcriptional regulators of gene expression, particularly those involved in energy metabolism (3) and immune or inflammatory responses (4–6). Over the past several years, C/EBPs have been shown to control cellular differentiation in several lineages, including hepatocytes (7), granulocytes (8), macrophages (9), and adipocytes (10). C/EBP regulation of adipogenesis represents the best characterized system to date. Collectively, the data from a number of pluripotent and pre-adipocytic cell lines support a model in which C/EBPβ and C/EBPδ activation represents the seminal event in the process, regulating commitment of progenitor cells to the adipocyte lineage (11). Subsequently, C/EBPβ and C/EBPδ induce expression of C/EBPα and peroxisome proliferator-activated receptor-γ, which in turn direct expression of terminal adipocyte marker genes (12–14). Work on C/EBP null mice has confirmed that C/EBPβ and C/EBPδ regulate commitment of progenitor cells to the adipocyte lineage, whereas loss of C/EBPα function interferes with terminal adipocyte differentiation and function (15).
A wealth of recent evidence suggests that the osteoblast and adipocyte lineages are closely related, diverging from a common pluripotent progenitor cell (16–18). However, a possible role for C/EBP transcription factors in osteoblast lineage progression has not been investigated. In the present study, we have used a loss-of-function strategy to test the hypothesis that C/EBP transcription factors play a role in osteoblast differentiation and/or function. Toward this end, a naturally occurring dominant negative C/EBPβ isoform (p20C/EBPβ, LIP) (19) has been targeted to cells of the stromal/osteoblast lineage using a 3.6-kb Col1a1 promoter fragment (pOBCol3.6-FLp20C/EBPβ). Mice expressing this transgene show evidence of osteopenia secondary to reduced bone formation, suggesting a role for C/EBP transcription factors in the regulation of osteogenesis. |
| URI: | https://ir.csmu.edu.tw:8080/ir/handle/310902500/11394 |
| Relation: | March 4, 2005 The Journal of Biological Chemistry, 280, 8117-8124. |
| Appears in Collections: | [牙醫學系暨碩士班] 期刊論文
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