Csete, Dániel Simon, Edina Alatshan, Ahmad Aradi, Petra Dobó-Nagy, Csaba Jakus, Zoltán Benkő, Szilvia Győri, Dávid S. Mócsai, Attila Image_3_Hematopoietic or Osteoclast-Specific Deletion of Syk Leads to Increased Bone Mass in Experimental Mice.TIF <p>Syk is a non-receptor tyrosine kinase critically involved in signaling by various immunoreceptors including B-cell-receptors and activating Fc-receptors. We have previously shown that Syk also mediates immunoreceptor-like signals required for the in vitro development and function of osteoclasts. However, the perinatal lethality of Syk<sup>−/−</sup> mice precluded the analysis of the role of Syk in in vivo bone metabolism. To overcome that problem, we generated mice with osteoclast-specific (Syk<sup>ΔOC</sup>) or hematopoietic (Syk<sup>ΔHaemo</sup>) Syk deficiency by conditional deletion of Syk using Cre recombinase expressed under the control of the Ctsk or Vav1 promoter, respectively. Micro-CT analysis revealed increased bone trabecular density in both Syk<sup>ΔOC</sup> and Syk<sup>ΔHaemo</sup> mice, although hematopoietic Syk deficiency caused a more severe phenotype than osteoclast-specific Syk deficiency. Osteoclast-specific Syk deficiency reduced, whereas hematopoietic Syk deficiency completely blocked in vitro development of osteoclasts. Both interventions inhibited the resorptive activity of osteoclasts and osteoclast-specific gene expression. Kinetic analysis of Syk protein levels, Cre expression and the genomic deletion of the Syk<sup>flox</sup> allele revealed complete and early deletion of Syk from Syk<sup>ΔHaemo</sup> osteoclasts whereas Syk was incompletely deleted at a later stage of osteoclast development from Syk<sup>ΔOC</sup> cultures. Those results provide an explanation for the in vivo and in vitro difference between the Syk<sup>ΔOC</sup> and Syk<sup>ΔHaemo</sup> mutant strains and suggest late activation of, and incomplete target gene deletion upon, osteoclast-specific Cre expression driven by the Ctsk promoter. Taken together, our results indicate that Syk plays an indispensable role in osteoclast-mediated in vivo bone resorption and suggest that Syk-specific inhibitors may provide therapeutic benefit in inflammatory and other diseases characterized by excessive osteoclast-mediated bone resorption.</p> SYK (spleen tyrosine kinase);tyrosine kinase;osteoclasts;Cre-Lox;in vivo;mice 2019-04-30
    https://frontiersin.figshare.com/articles/figure/Image_3_Hematopoietic_or_Osteoclast-Specific_Deletion_of_Syk_Leads_to_Increased_Bone_Mass_in_Experimental_Mice_TIF/8056859
10.3389/fimmu.2019.00937.s003