Epidermal growth factor receptor plays an anabolic role in bone metabolism in vivo |
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| Authors: | Xianrong Zhang Joseph Tamasi Xin Lu Ji Zhu Haiyan Chen Xiaoyan Tian Tang‐Cheng Lee David W Threadgill Barbara E Kream Yibin Kang Nicola C Partridge Ling Qin |
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| Affiliation: | 1. Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;2. Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA;3. Department of Molecular Biology, Princeton University, Princeton, NJ, USA;4. Division of Radiobiology, Department of Radiology, School of Medicine, University of Utah, Salt Lake City, UT, USA;5. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA;6. Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA;7. Department of Basic Science and Craniofacial Biology, New York University, College of Dentistry, New York, NY, USA |
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| Abstract: | While the epidermal growth factor receptor (EGFR)–mediated signaling pathway has been shown to have vital roles in many developmental and pathologic processes, its functions in the development and homeostasis of the skeletal system has been poorly defined. To address its in vivo role, we constructed transgenic and pharmacologic mouse models and used peripheral quantitative computed tomography (pQCT), micro–computed tomography (µCT) and histomorphometry to analyze their trabecular and cortical bone phenotypes. We initially deleted the EGFR in preosteoblasts/osteoblasts using a Cre/loxP system (Col‐Cre Egfrf/f), but no bone phenotype was observed because of incomplete deletion of the Egfr genomic locus. To further reduce the remaining osteoblastic EGFR activity, we introduced an EGFR dominant‐negative allele, Wa5, and generated Col‐Cre EgfrWa5/f mice. At 3 and 7 months of age, both male and female mice exhibited a remarkable decrease in tibial trabecular bone mass with abnormalities in trabecular number and thickness. Histologic analyses revealed decreases in osteoblast number and mineralization activity and an increase in osteoclast number. Significant increases in trabecular pattern factor and structural model index indicate that trabecular microarchitecture was altered. The femurs of these mice were shorter and smaller with reduced cortical area and periosteal perimeter. Moreover, colony‐forming unit–fibroblast (CFU‐F) assay indicates that these mice had fewer bone marrow mesenchymal stem cells and committed progenitors. Similarly, administration of an EGFR inhibitor into wild‐type mice caused a significant reduction in trabecular bone volume. In contrast, EgfrDsk5/+ mice with a constitutively active EGFR allele displayed increases in trabecular and cortical bone content. Taken together, these data demonstrate that the EGFR signaling pathway is an important bone regulator and that it primarily plays an anabolic role in bone metabolism. © 2011 American Society for Bone and Mineral Research. |
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| Keywords: | EPIDERMAL GROWTH FACTOR RECEPTOR ANIMAL MODELS BONE MASS SKELETAL PHENOTYPE OSTEOBLAST |
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