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Bone Res. 2019 Feb 21;7:6. doi: 10.1038/s41413-018-0037-4. eCollection 2019.

Characterization of a novel murine Sost ERT2 Cre model targeting osteocytes.

Author information

1
1Department of Oral and Craniofacial Sciences, University of Missouri-Kansas City School of Dentistry, Kansas City, MO USA.
2
7Present Address: Pharmaceutical Sciences Department, Universite de Bordeaux, Bio-Tis, INSERM Unité 1026 BioTis, 146 Rue Léo Saignat, 33076 Bordeaux, France.
3
2Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN USA.
4
3Bone-Muscle Collaborative Sciences, College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, USA.
5
4Department of Biomedical Sciences, University of Missouri-Kansas City School of Medicine, Kansas City, MO USA.
6
5University of Texas Health Science Center, San Antonio, TX USA.
7
6Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN USA.

Abstract

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 ERT2 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-ERT2 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.

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