The high bone mass phenotype of Lrp5-mutant mice is not affected by megakaryocyte depletion.

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 Lrp5G170V mice 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 Lrp5G170V mice 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 /Lrp5G170V mice, yet the high bone mass phenotype of Lrp5G170V mice was not significantly affected by the homozygous Mpl mutation. Finally, when we analyzed 24 weeks old wildtype and Mplhlb219 mice 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.