Document Detail


Advanced molecular profiling in vivo detects novel function of dickkopf-3 in the regulation of bone formation.
MedLine Citation:
PMID:  17002559     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A bioinformatics-based analysis of endochondral bone formation model detected several genes upregulated in this process. Among these genes the dickkopf homolog 3 (Dkk3) was upregulated and further studies showed that its expression affects in vitro and in vivo osteogenesis. This study indicates a possible role of Dkk3 in regulating bone formation. INTRODUCTION: Endochondral bone formation is a complex biological process involving numerous chondrogenic, osteogenic, and angiogenic proteins, only some of which have been well studied. Additional key genes may have important roles as well. We hypothesized that to identify key genes and signaling pathways crucial for bone formation, a comprehensive gene discovery strategy should be applied to an established in vivo model of osteogenesis. MATERIALS AND METHODS: We used in vivo implanted C3H10T1/2 cells that had been genetically engineered to express human bone morphogenetic protein-2 (BMP2) in a tetracycline-regulated system that controls osteogenic differentiation. Oligonucleotide microarray data from the implants (n = 4 repeats) was analyzed using coupled two-way clustering (CTWC) and statistical methods. For studying the effects of dickkopf homolog 3 (Dkk3) in chondrogenesis and osteogenesis, C3H10T1/2 mesenchymal progenitors were used. RESULTS: The CTWC revealed temporal expression of Dkk3 with other chondrogenesis-, osteogenesis-, and Wnt-related genes. Quantitative RT-PCR confirmed the expression of Dkk3 in the implants. C3H10T1/2 cells that expressed Dkk3 in the presence of BMP2 displayed lower levels of alkaline phosphatase and collagen I mRNA expression than control C3H10T1/2 cells that did not express Dkk3. Interestingly, the levels of collagen II mRNA expression, Alcian blue staining, and glucose aminoglycans (GAGs) production were not influenced by Dkk3 expression. In vivo microCT and bioluminescence imaging revealed that co-expression of Dkk3 and BMP2 by implanted C3H10T1/2 cells induced the formation of significantly lower quantities of bone than cells expressing only BMP2. CONCLUSIONS: A bioinformatics analysis enabled the identification of Dkk3 as a pivotal gene with a novel function in endochondral bone formation. Our results showed that Dkk3 might have inhibitory effects on osteogenesis, but no effect on chondrogenesis, indicating that Dkk3 plays a regulatory role in endochondral bone formation. Further mechanistic studies are required to reveal the mechanism of action of Dkk3 in endochondral bone formation.
Authors:
Hadi Aslan; Osnat Ravid-Amir; Brian M Clancy; Saeid Rezvankhah; Debra Pittman; Gadi Pelled; Gadi Turgeman; Yoram Zilberman; Zulma Gazit; Andrea Hoffmann; Gerhard Gross; Eytan Domany; Dan Gazit
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research     Volume:  21     ISSN:  0884-0431     ISO Abbreviation:  J. Bone Miner. Res.     Publication Date:  2006 Dec 
Date Detail:
Created Date:  2006-12-20     Completed Date:  2007-01-26     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8610640     Medline TA:  J Bone Miner Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1935-45     Citation Subset:  IM    
Affiliation:
Skeletal Biotechnology Laboratory, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone Morphogenetic Protein 2
Bone Morphogenetic Proteins / biosynthesis*,  genetics
Cell Line
Chondrogenesis / physiology
Computational Biology / methods
Gene Expression Profiling / methods
Humans
Intercellular Signaling Peptides and Proteins / biosynthesis*,  genetics
Mice
Osteogenesis / physiology*
Reverse Transcriptase Polymerase Chain Reaction / methods
Transforming Growth Factor beta / biosynthesis*,  genetics
Up-Regulation / physiology*
Chemical
Reg. No./Substance:
0/BMP2 protein, human; 0/Bmp2 protein, mouse; 0/Bone Morphogenetic Protein 2; 0/Bone Morphogenetic Proteins; 0/Dkk3 protein, mouse; 0/Intercellular Signaling Peptides and Proteins; 0/Transforming Growth Factor beta

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