Premium
Epidermal growth factor receptor plays an anabolic role in bone metabolism in vivo
Author(s) -
Zhang Xianrong,
Tamasi Joseph,
Lu Xin,
Zhu Ji,
Chen Haiyan,
Tian Xiaoyan,
Lee TangCheng,
Threadgill David W,
Kream Barbara E,
Kang Yibin,
Partridge Nicola C,
Qin Ling
Publication year - 2011
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.295
Subject(s) - osteoblast , endocrinology , epidermal growth factor receptor , bone remodeling , cortical bone , in vivo , medicine , biology , growth factor , bone marrow , genetically modified mouse , epidermal growth factor , osteoclast , receptor , transgene , anatomy , in vitro , biochemistry , microbiology and biotechnology , gene
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. © 2011 American Society for Bone and Mineral Research.