An Osteocalcin-deficient mouse strain without endocrine abnormalities

Osteocalcin (OCN), the most abundant non-collagenous protein in the bone matrix, is reported to be a bone-derived endocrine hormone with wide-ranging effects on many aspects of physiology, including glucose metabolism and male fertility. Many of these observations were made using an OCN-deficient mo...

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Published inbioRxiv
Main Authors Diegel, Cassandra R, Hann, Steven, Ayturk, Ugur M, Jennifer Cw Hu, Lim, Kyung-Eun, Droscha, Casey J, Madaj, Zachary B, Foxa, Gabrielle E, Izaguirre, Isaac, Vari Vivarium And Transgenics Core, Paracha, Noorulain, Pidhaynyy, Bohdan, Dowd, Terry L, Robling, Alexander G, Warman, Matthew L, Williams, Bart O
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 13.08.2019
Subjects
Alleles
Bone imaging
Bone mass
Bone matrix
Cancellous bone
Collagen
Cortical bone
CRISPR
Glucose metabolism
Homologous recombination
Hydroxyapatite
Osteocalcin
Rodents
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Summary:Osteocalcin (OCN), the most abundant non-collagenous protein in the bone matrix, is reported to be a bone-derived endocrine hormone with wide-ranging effects on many aspects of physiology, including glucose metabolism and male fertility. Many of these observations were made using an OCN-deficient mouse allele (Osc-) in which the 2 OCN-encoding genes in mice, Bglap and Bglap2, were deleted in ES cells by homologous recombination. Here we describe mice with a new Bglap and Bglap2 double knockout (dko) allele (Bglap/2p.Pro25fs17Ter) that was generated by CRISPR/Cas9-mediated gene editing. Mice homozygous for this new allele do not express full length Bglap or Bglap2 mRNA and have no immunodetectable OCN in their plasma. FTIR imaging of cortical and trabecular bone in these homozygous knockout animals finds alterations in the crystal size and maturity of the bone mineral, hydroxyapatite, compared to wild-type littermates; however, µCT and 3-point bending tests do not find differences from wild-type littermates with respect to bone mass and strength. In contrast to the previously reported OCN-deficient mice with the Osc- allele, blood glucose levels and male fertility in the OCN-deficient mice with Bglap/2pPro25fs17Ter allele did not have significant differences from wild-type littermates. We cannot explain the absence of endocrine effects in mice with this new knockout allele. Potential explanations include effects of each mutated allele on the transcription of neighboring genes, and differences in genetic background and environment. So that our findings can be confirmed and extended by other interested investigators, we are donating this new Bglap and Bglap2 double knockout strain to The Jackson Laboratory for academic distribution.
DOI:10.1101/732800