We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Hematopoietic or Osteoclast-Specific Deletion of Syk Leads to Increased Bone Mass in Experimental Mice.
- Authors
Csete, Dániel; Simon, Edina; Alatshan, Ahmad; Aradi, Petra; Dobó-Nagy, Csaba; Jakus, Zoltán; Benkő, Szilvia; Győri, Dávid S.; Mócsai, Attila
- Abstract
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 −/− 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 Δ OC ) or hematopoietic (Syk Δ Haemo ) 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 Δ OC and Syk Δ Haemo 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 flox allele revealed complete and early deletion of Syk from Syk Δ Haemo osteoclasts whereas Syk was incompletely deleted at a later stage of osteoclast development from Syk Δ OC cultures. Those results provide an explanation for the in vivo and in vitro difference between the Syk Δ OC and Syk Δ Haemo 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.
- Subjects
B cell receptors; OSTEOCLASTS; BONE metabolism; GENE expression; ALLELES
- Publication
Frontiers in Immunology, 2019, pN.PAG
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2019.00937