皮质骨疏松是衰老长骨结构最显著的退行性变，是引起老年人骨折的根本原因，其分子机制尚未揭示。研究报道，皮质骨骨祖细胞可调节皮质骨代谢，但易受局部微环境影响。我们前期研究发现，成骨系细胞EGFR信号调节骨合成代谢；而衰老皮质骨骨祖细胞Caveolin-1（Cav1）和FOXO1表达上调、EGFR信号和Ezh2表达下调及细胞老化；EGFR或ERK通路的抑制剂或Cav1均可促进骨祖细胞老化，且Cav1可抑制磷酸化EGFR和Ezh2表达；以JAK1/2阻断剂抑制炎症可显著下调骨FOXO1及Cav1表达。推测：衰老皮质骨微环境通过FOXO1/Cav1下调EGFR/ERK/Ezh2信号，引起骨祖细胞老化和皮质骨疏松。本项目拟通过整体动物和细胞实验，阐明衰老皮质骨微环境通过抑制骨祖细胞EGFR信号从而促进细胞老化，导致皮质骨疏松症的分子机制，为探索靶向调节皮质骨代谢以早期防治皮质骨疏松症提供新思路。

Increased cortical porosity, the most striking characteristic of aging-induced degeneration in long bone, is a root cause for fragility fractures in old people. The mechanism behind the age-induced osteoporosis in cortical bone has been inadequately addressed and thus poorly understood. Increasing evidence indicates that osteoprogenitors in cortical bone are critical in regulating cortical bone metabolism, but they are sensitive to local microenvionments. Our previous work has demonstrated that, epidermal growth factor receptor (EGFR) signaling in osteoblastic lineage cells plays an anabolic role in bone metabolism. Our recent work has also demonstrated that osteoprogenitors from aged cortical bone have down-regulated EGFR signaling and up-regulated expression of the Caveolin-1 and FOXO1, with enhanced senescence. Moreover, inhibitors for EGFR signaling or ERK pathway, and Caveolin-1 can all promote senescence of osteoprogenitors,and Caveolin-1 can suppress the expression of phospho-EGFR and Ezh2; JAK1/2 inhibitor (anti-inflammatory reagent) blocks the expression of FOXO1 and Caveolin-1. Based on our studies and other relative investigations, it can be hypothesized that aging microenvironments in cortical bone might activate FOXO1/Caveolin-1, and thereby the down-regulation of EGFR/ERK/Ezh2 in osteoprogenitors, resulting in the senescence of osteoprogenitors and eventually osteoporosis in cortical cortical bone. This project aims to clarify the underlying molecular mechanism by which aging microenvironments in cortical bone may induce senescence of osteoprogenitors though suppressing EGFR signaling, thereby inducing osteoporosis in cortical bone. Better understanding of cortical bone metabolism by our project may hopefully contribute to development of early therapeutic targets and strategies for osteoporosis in cortical bone.