title: Epidermal growth factor receptor plays an anabolic role in bone metabolism in vivo.
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 Egfr(f/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 Egfr(Wa5/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, Egfr(Dsk5/+) 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.
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xianrong
authors.initials: X
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Tamasi
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Ji
authors.initials: J
authors.lastname: Zhu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Tian
authors.forename: Tang-Cheng
authors.initials: TC
authors.lastname: Lee
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Kream
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
authors.forename: Nicola C
authors.initials: NC
authors.lastname: Partridge
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000000981:diagnostic imaging / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging; D019426:Integrases / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology; D010012:Osteogenesis / Q000187:drug effects; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects; D014057:Tomography, X-Ray Computed
chemical_list: D047428:Protein Kinase Inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; C045073:Cre recombinase; D019426:Integrases