Decreased body weight in young Osterix-Cre transgenic mice results in delayed cortical bone expansion and accrual

Abstract

Conditional gene inactivation using the Cre/loxP system has lead to significant advances in our understanding of the function of genes in a wide range of disciplines. It is becoming increasingly apparent in the literature, that Cre transgenic mice may themselves have a phenotype. In the following study we describe the bone phenotype of a commonly used Cre transgenic mouse line to study osteoblasts, the Osx-GFP::Cre (Osx-Cre) mice. Cortical and trabecular bone parameters were determined in the femurs of Osx-Cre mice at 6 and 12weeks of age by microtomography (μCT). At 6weeks of age, Osx-Cre mice had reduced body weight by 22% (P<0.0001) and delayed cortical bone expansion and accrual, characterized by decreases in periosteal circumference by 7% (P<0.05) and cortical thickness by 11% (P<0.01), compared to wild type controls. Importantly, the cortical bone phenotype of the skeletally immature Osx-Cre mice at 6weeks of age could be accounted for by their low body weight. The delayed weight gain and cortical growth of Osx-Cre mice was overcome by 12weeks of age, with no differences observed between Osx-Cre and wild type controls. In conclusion, Osx-Cre expressing mice display a delayed growth phenotype in the absence of doxycycline treatment, evidenced by decreased cortical bone expansion and accrual at 6weeks of age, as an indirect result of decreased body weight. While this delay in growth is overcome by adulthood at 12weeks of age, caution together with appropriate data analysis must be considered when assessing the experimental data from skeletally immature Cre/loxP knockout mice generated using the Osx-Cre mouse line to avoid misinterpretation.