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

EGFR活性主要由七种肽生长因子的可用性决定。这些配体具有重叠和特定的功能，赋予系统高度的鲁棒性。ErbB 2没有已知的配体。尽管如此，ErbB 2通过与EGFR形成异源二聚体，是细胞内信号传导途径的有效起始剂。尽管EGFR及其配体和结构相关的受体ErbB 2/neu多年来已被报道在骨骼细胞中表达并影响出生后的体细胞生长，但它们在骨细胞中的功能仍然不清楚。 本项目的目的是通过采用以下方法来进一步表征EGFR和ERBB 2在骨生物学和病理学中的作用：1）来自我们实验室的未发表的工作显示，成骨细胞特异性过表达EGFR配体双调蛋白显著增加转基因小鼠的小梁和皮质骨量。我们建议充分表征该小鼠系的骨表型。2)缺乏EGFR或ERBB 2的敲除小鼠不能存活。为了评估这些受体与骨的相关性，我们建议通过采用现有的EGFR和ErbB 2“floxed”小鼠系，在成骨细胞中特异性地表达它们的基因。3)在最近完成的一个项目中，我们发现EGFR信号传导不是松质骨和皮质内骨表面对间歇性PTH的合成代谢反应所必需的，但EGFR途径对PTH驱动的股骨干骨膜扩张至关重要。我们提出实验来阐明EGFR在长骨中的这种位点特异性作用背后的机制。

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further the role the EGFR and ERBB2 in bone biology and pathology by employing the following approaches: 1) Unpublished work from our laboratories revealed that osteoblast-specific overexpression of the EGFR ligand amphiregulin profoundly increased trabecular and cortical bone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 sitespecific effect of the EGFR in long bones.