Increased trabecular bone and improved biomechanics in an osteocalcin null rat model created by CRISPR/Cas9 technologyстатья из журнала
Аннотация: Osteocalcin, also known as bone gamma-carboxyglutamate protein (bglap), is expressed by osteoblasts and is commonly used as a clinical marker of bone turnover. A mouse model of osteocalcin deficiency has implicated osteocalcin as a mediator of changes to the skeleton, endocrine system, reproductive organs, and central nervous system. However, differences between mouse and human osteocalcin at both the genome and protein levels have challenged the validity of extrapolating findings from the osteocalcin-deficient mouse model to human disease. The rat osteocalcin gene locus shares greater synteny with that of humans. To further examine the role of osteocalcin in disease, we created a rat model with complete loss of osteocalcin using the CRISPR/Cas9 system. Rat osteocalcin was modified by injection of CRISPR/Cas9 mRNA into the pronuclei of fertilized single cell Sprague Dawley embryos, and animals were bred to homozygosity and compound heterozygosity for the mutant alleles. Dual-energy X-ray absorptiometry (DXA), glucose tolerance testing (GTT), insulin tolerance testing (ITT), micro computed tomography (μCT), and a three-point break biomechanical assay were performed on the excised femurs at five months of age. Complete loss of osteocalcin resulted in bones with significantly increased trabecular thickness, density, and volume. Cortical bone volume and density were not increased in null animals. The bones had improved functional quality as evidenced by an increase in failure load during the biomechanical stress assay. Differences in glucose homeostasis were observed between groups, but there were no differences in body weight or composition. This rat model of complete loss of osteocalcin provides a platform for further understanding the role of osteocalcin in disease, and it is a novel model of increased bone formation with potential utility in osteoporosis and osteoarthritis research.
Год издания: 2016
Авторы: Laura Lambert, Anil K. Challa, Aidi Niu, Lihua Zhou, Janusz Tucholski, Maria S. Johnson, Tim R. Nagy, Alan W. Eberhardt, Patrick N. Estep, Robert A. Kesterson, Jayleen Grams
Издательство: The Company of Biologists
Источник: Disease Models & Mechanisms
Ключевые слова: RNA Research and Splicing, Erythrocyte Function and Pathophysiology, Molecular Biology Techniques and Applications
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Disease Models & Mechanisms (HTML)
DOAJ (DOAJ: Directory of Open Access Journals) (HTML)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)
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