The high bone mass phenotype of Lrp5-mutant mice is not affected by megakaryocyte depletion
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The high bone mass phenotype of Lrp5-mutant mice is not affected by megakaryocyte depletion. / Yorgan, Timur; David, Jean-Pierre; Amling, Michael; Schinke, Thorsten.
In: BIOCHEM BIOPH RES CO, Vol. 497, No. 2, 04.03.2018, p. 659-666.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The high bone mass phenotype of Lrp5-mutant mice is not affected by megakaryocyte depletion
AU - Yorgan, Timur
AU - David, Jean-Pierre
AU - Amling, Michael
AU - Schinke, Thorsten
N1 - Copyright © 2018. Published by Elsevier Inc.
PY - 2018/3/4
Y1 - 2018/3/4
N2 - Bone remodeling is a continuously ongoing process mediated by bone-resorbing osteoclasts and bone-forming osteoblasts. One key regulator of bone formation is the putative Wnt co-receptor Lrp5, where activating mutations in the extracellular domain cause increased bone formation in mice and humans. We have previously reported that megakaryocyte numbers are increased the bone marrow of mice carrying a high bone mass mutation (HBM) of Lrp5 (Lrp5G170V). Since megakaryocytes can promote bone formation, we addressed the question, if the bone remodeling phenotype of Lrp5G170Vmice is affected by megakaryocyte depletion. For that purpose we took advantage of a mouse model carrying a mutation of the Mpl gene, encoding the thrombopoietin receptor. These mice (Mplhlb219) were crossed with Lrp5G170Vmice to generate animals carrying both mutations in a homozygous state. Using μCT, undecalcified histology and bone-specific histomorphometry of 12 weeks old littermates we observed that megakaryocyte number was remarkably decreased in Mplhlb219/Lrp5G170Vmice, yet the high bone mass phenotype of Lrp5G170Vmice was not significantly affected by the homozygous Mpl mutation. Finally, when we analyzed 24 weeks old wildtype and Mplhlb219mice we did not observe a statistically significant alteration of bone remodeling in the latter ones. Taken together, our results demonstrate that an increased number of bone marrow megakaryocytes does not contribute to the increased bone formation caused by Lrp5 activation.
AB - Bone remodeling is a continuously ongoing process mediated by bone-resorbing osteoclasts and bone-forming osteoblasts. One key regulator of bone formation is the putative Wnt co-receptor Lrp5, where activating mutations in the extracellular domain cause increased bone formation in mice and humans. We have previously reported that megakaryocyte numbers are increased the bone marrow of mice carrying a high bone mass mutation (HBM) of Lrp5 (Lrp5G170V). Since megakaryocytes can promote bone formation, we addressed the question, if the bone remodeling phenotype of Lrp5G170Vmice is affected by megakaryocyte depletion. For that purpose we took advantage of a mouse model carrying a mutation of the Mpl gene, encoding the thrombopoietin receptor. These mice (Mplhlb219) were crossed with Lrp5G170Vmice to generate animals carrying both mutations in a homozygous state. Using μCT, undecalcified histology and bone-specific histomorphometry of 12 weeks old littermates we observed that megakaryocyte number was remarkably decreased in Mplhlb219/Lrp5G170Vmice, yet the high bone mass phenotype of Lrp5G170Vmice was not significantly affected by the homozygous Mpl mutation. Finally, when we analyzed 24 weeks old wildtype and Mplhlb219mice we did not observe a statistically significant alteration of bone remodeling in the latter ones. Taken together, our results demonstrate that an increased number of bone marrow megakaryocytes does not contribute to the increased bone formation caused by Lrp5 activation.
KW - Journal Article
U2 - 10.1016/j.bbrc.2018.02.127
DO - 10.1016/j.bbrc.2018.02.127
M3 - SCORING: Journal article
C2 - 29454962
VL - 497
SP - 659
EP - 666
JO - BIOCHEM BIOPH RES CO
JF - BIOCHEM BIOPH RES CO
SN - 0006-291X
IS - 2
ER -