The functional role of the EGFR/ErbB system for bone development and homeostasis

EGFR activity is primarily determined by the availability of seven peptide growth factors. These ligands have both overlapping and specific functions, conferring the system a high degree of robustness. ErbB2, in contrast, has no known ligand. Nonetheless, ErbB2 is a potent initiator of intracellular signaling pathways by forming heterodimers with the EGFR. Although the EGFR, its ligands, and the structurally related receptor ErbB2/neu have been reported to be expressed in skeletal cells and to affect postnatal somatic growth since many years, their functions in bone cells remain poorly defined.

The purpose of the present project is to characterize further the role the EGFR and ERBB2 in bone biology and pathology by employing the following approaches:

1) Unpublished work from our laboratories revealed that osteoblast-specific overexpression of the EGFR ligand amphiregulin profoundly increased trabecular and cortical bone mass in transgenic mice. We propose to fully characterize the bone phenotype of this mouse line.

2) Knockout mice lacking EGFR or ERBB2 are not viable. To evaluate the relevance of these receptors for bone, we propose to specifically inactivate their genes in osteoblasts by employing already available EGFR and ErbB2 "floxed" mouse lines.

3) In a recently finished project, we showed that EGFR signaling is not required for the anabolic response to intermittent PTH on cancellous and endocortical bone surfaces, but that the EGFR pathway is essential for the PTH-driven periosteal expansion at the femoral shaft. We propose experiments to elucidate the mechanisms behind this site-specific effect of the EGFR in long bones.

Related Papers (Title+Pubmed-Link):
1. Schneider M.R., Dahlhoff M., Andrukhova O., Grill J., Glösmann M., Schüler C., Weber K., Wolf E. and Erben R.G. (2012). Normal epidermal growth factor receptor signaling is dispensable for bone anabolic effects of parathyroid hormone. Bone. 50, 237-244. 1
2. Schneider,M.R., Mayer-Roenne,B., Dahlhoff,M., Proell,V., Weber,K., Wolf,E., and Erben,R.G. (2009a). High Cortical Bone Mass Phenotype in Betacellulin Transgenic Mice is EGFR-Dependent. J. Bone Miner. Res. 24, 455-467. 2
3. Schneider,M.R., Sibilia,M., and Erben,R.G. (2009b). The EGFR network in bone biology and pathology. Trends Endocrinol. Metab. 3
4. Sibilia,M., Wagner,B., Hoebertz,A., Elliott,C., Marino,S., Jochum,W., and Wagner,E.F. (2003). Mice humanised for the EGF receptor display hypomorphic phenotypes in skin, bone and heart. Development 130, 4515-4525. 4



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