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So far, there has been no effective cure for osteoporotic cortical bone, the most significant change in long bone structure during aging and the main cause of bone fragility fractures, because its underlying molecular and cellular mechanisms remain largely unknown. We used 3‐ and 15‐mo‐old mice as well as 15‐mo‐old mice treated with vehicle and gefitinib to evaluate structural, cellular, and molecular changes in cortical bone. We found that the senescence of osteoprogenitors was increased, whereas the expression of phosphorylated epidermal growth factor receptor (EGFR) on the endosteal surface of cortical bone down‐regulated in middle‐aged 15‐mo‐old mice compared with young 3‐mo‐old mice. Further decreasing EGFR signaling by gefitinib treatment in middle‐aged mice resulted in promoted senescence of osteoprogenitors and accelerated cortical bone degeneration. Moreover, inhibiting EGFR signaling suppressed the expression of enhancer of zeste homolog 2 (Ezh2), the repressor of cell senescence‐inducer genes, through ERK1/2 pathway, thereby promoting senescence in osteoprogenitors. Down‐regulated EGFR signaling plays a physiologically significant role during aging by reducing Ezh2 expression, leading to the senescence of osteoprogenitors and the decline in bone formation on the endosteal surface of cortical bone.—Liu, G., Xie, Y., Su, J., Qin, H., Wu, H., Li, K., Yu, B., Zhang, X. The role of EGFR signaling in age‐related osteoporosis in mouse cortical bone. FASEB J. 33, 11137–11147 (2019). http://www.fasebj.org

Background Prenatal dexamethasone exposure (PDE) induces low birth weight and retardation of fetal bone development which are associated with lower peak bone mass in adult offspring. Here we evaluated whether and how PDE affects postnatal long bone growth in mouse offspring. Methods Pregnant mice were injected subcutaneously with dexamethasone (1.2 mg/kg/day) every morning from gestational days (GD) 12–14. Femurs and tibias of 2-, 4-, 6-, and 12-week-old female offspring were harvested for histological, immunofluorescence, flow cytometric analysis, or microcomputed tomography (μCT) measurement. Results PDE leads to impaired bone remodeling as well as decreased bone mass in the long bone of female mouse offspring. During postnatal bone growth, significant decrease of CD45−CD29+CD105+Sca-1+ bone marrow mesenchymal stem cells (BMSCs) and CD45−Nestin+ cells, loss of type H vessels, and increment of cellular senescence were found in metaphysis of long bone in mouse offspring after PDE. We further show that eliminating the excessive senescent cells with dasatinib (5 mg/kg/day) and quercetin (50 mg/kg/day) during GD 12–14 rescues the above toxic effect of PDE on the postnatal long bone growth in female mouse offspring. Conclusion Cellular senescence mediates the toxic effect of PDE on postnatal long bone growth in mouse offspring, and inhibition of cellular senescence may be proposed for treating the retardation of bone growth caused by PDE.