Browsing by Author "Ayturk, Ugur M."

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    Independent validation of experimental results requires timely and unrestricted access to animal models and reagents
    (Public Library of Science, 2020-06-26) Diegel, Cassandra R.; Hann, Steven; Ayturk, Ugur M.; Hu, Jennifer C. W.; Lim, Kyung-Eun; Droscha, Casey J.; Madaj, Zachary B.; Foxa, Gabrielle E.; Izaguirre, Isaac; Robling, Alexander G; Warman, Matthew L.; Williams, Bart O.; Anatomy and Cell Biology, School of Medicine
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    An osteocalcin-deficient mouse strain without endocrine abnormalities
    (PLOS, 2020-05-28) Diegel, Cassandra R.; Hann, Steven; Ayturk, Ugur M.; Hu, Jennifer C. W.; Lim, Kyung-eun; Droscha, Casey J.; Madaj, Zachary B.; Foxa, Gabrielle E.; Izaguirre, Isaac; Core, VAI Vivarium and Transgenics; Paracha, Noorulain; Pidhaynyy, Bohdan; Dowd, Terry L.; Robling, Alexander G.; Warman, Matthew L.; Williams, Bart O.; Anatomy and Cell Biology, School of Medicine
    Osteocalcin (OCN), the most abundant noncollagenous 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 serum. FTIR imaging of cortical bone in these homozygous knockout animals finds alterations in the collagen maturity and carbonate to phosphate ratio in the cortical bone, compared with 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, serum glucose levels and male fertility in the OCN-deficient mice with the 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. Possible explanations include the effects of each mutated allele on the transcription of neighboring genes, or 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 Laboratories for academic distribution.
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    The role of Meteorin-like in skeletal development and bone fracture healing
    (Wiley, 2022) Huang, Rong; Balu, Abhinav R.; Molitoris, Kristin H.; White, James P.; Robling, Alexander G.; Ayturk, Ugur M.; Baht, Gurpreet S.; Anatomy, Cell Biology and Physiology, School of Medicine
    Meteorin‐like protein (Metrnl), homologous to the initially identified neurotrophic factor Meteorin, is a secreted, multifunctional protein. Here we used mouse models to investigate Metrnl's role in skeletal development and bone fracture healing. During development Metrnl was expressed in the perichondrium and primary ossification center. In neonates, single cell RNA‐seq of diaphyseal bone demonstrated strongest expression of Metrnl transcript by osteoblasts. In vitro, Metrnl was osteoinductive, increasing osteoblast differentiation and mineralization in tissue culture models. In vivo, loss of Metrnl expression resulted in no change in skeletal metrics in utero, at birth, or during postnatal growth. Six‐week‐old Metrnl‐null mice displayed similar body length, body weight, tibial length, femoral length, BV/TV, trabecular number, trabecular thickness, and cortical thickness as littermate controls. In 4‐month‐old mice, lack of Metrnl expression did not change structural stiffness, ultimate force, or energy to fracture of femora under 3‐point‐bending. Last, we investigated the role of Metrnl in bone fracture healing. Metrnl expression increased in response to tibial injury, however, loss of Metrnl expression did not affect the amount of bone deposited within the healing tissue nor did it change the structural parameters of healing tissue. This work identifies Metrnl as a dispensable molecule for skeletal development. However, the osteoinductive capabilities of Metrnl may be utilized to modulate osteoblast differentiation in cell‐based orthopedic therapies.