Epidermal growth factor receptor plays an anabolic role in bone metabolism in vivo

Xianrong Zhang,Tang‐Cheng Lee,Xin Lu,Nicola C Partridge,Barbara E Kream,David W Threadgill,Joseph Tamasi,Haiyan Chen,Ji Zhu,Ling Qin,Xiaoyan Tian,Yibin Kang

doi:10.1002/jbmr.295

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.

Highlights

The epidermal growth factor receptor (EGFR) is a 170-kDa glycoprotein on the cell surface of a variety of cell types and is characterized by its ligand-dependent tyrosine kinase activity
EGFR is extremely critical for embryonic development and organogenesis, and mice with systemic Egfr knockout are either embryonic lethal or die shortly after birth owing to placental defects and multiorgan abnormalities,(13) making it impossible to study the role of EGFR signaling in bone development and remodeling postnatally
A bone phenotype was observed in several previous reports investigating either Egfr null mice at birth[14,15] or transgenic mice ubiquitously overexpressing its ligands, EGF[26] or BTC,(17) under the control of ubiquitous actin promoters

Summary

Introduction

The epidermal growth factor receptor (EGFR) is a 170-kDa glycoprotein on the cell surface of a variety of cell types and is characterized by its ligand-dependent tyrosine kinase activity. The EGFR, known as Her or ErbB1, is closely related to three other receptors, Her (ErbB2), Her (ErbB3), and Her (ErbB4). These receptors are composed of an extracellular ligand–binding domain with cystein-rich regions, a transmembrane domain, and an intracellular domain with tyrosine kinase activity. While mAbs target the extracellular ligand–binding domain of EGFR and promote its internalization, TKIs block EGFR activity by competing with adenosine triphosphate (ATP) for binding to the receptor’s kinase pocket. Three TKIs, gefitinib from AstraZeneca, erlotinib from OSI Pharmaceuticals, and lapatinib from GlaxoSmithKline, have received regulatory approval for use in cancer patients.[2]

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