Characterization of a novel murine Sost ERT2 Cre model targeting osteocytes

Transgenic mice are widely used to delete or overexpress genes in a cell specific manner to advance knowledge of bone biology, function and disease. While numerous Cre models exist to target gene recombination in osteoblasts and osteoclasts, few target osteocytes specifically, particularly mature osteocytes. Our goal was to create a spatial and temporal conditional Cre model using tamoxifen to induce Cre activity in mature osteocytes using a Bac construct containing the 5’ and 3’ regions of the Sost gene (Sost ER T2 Cre). Four founder lines were crossed with the Ai9 Cre reporter mice. One founder line showed high and specific activity in mature osteocytes. Bones and organs were imaged and fluorescent signal quantitated. While no activity was observed in 2 day old pups, by 2 months of age some osteocytes were positive as osteocyte Cre activity became spontaneous or ‘leaky’ with age. The percentage of positive osteocytes increased following tamoxifen injection, especially in males, with 43% to 95% positive cells compared to 19% to 32% in females. No signal was observed in any bone surface cell, bone marrow, nor in muscle with or without tamoxifen injection. No spontaneous signal was observed in any other organ. However, with tamoxifen injection, a few positive cells were observed in kidney, eye, lung, heart and brain. All other organs, 28 in total, were negative with tamoxifen injection. However, with age, a muscle phenotype was apparent in the Sost-ER T2 Cre mice. Therefore, although this mouse model may be useful for targeting gene deletion or expression to mature osteocytes, the muscle phenotype may restrict the use of this model to specific applications and should be considered when interpreting data. Animal model: Transgenic mice offer platform to study mature osteocytes A new transgenic mouse allows DNA modifications to be targeted to mature bone cells known as osteocytes, enabling researchers to better study the function of this cell population, although the model has some weaknesses that may restrict its use. Lynda Bonewald from Indiana University, Indianapolis, USA, and colleagues engineered mice to express introduced genetic material only in cells in which a gene called Sost is normally active — namely, osteocytes — and only when experimenters introduce a drug called tamoxifen. In general, transgene activity was contained to the osteocytes, but a full characterization of the mice showed some issues. For one, spontaneously transgene expression occur