Hematopoietic or Osteoclast-Specific Deletion of Syk Leads to Increased Bone Mass in Experimental Mice

Dániel Csete, Edina Simon, Ahmad Alatshan, Petra Aradi, Csaba Dobó-Nagy, Z. Jakus, Sz. Benkő, Dávid S. Győri, A. Mócsai

Research output: Contribution to journalArticle

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 (SykΔOC ) or hematopoietic (SykΔHaemo ) 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 SykΔOC and SykΔHaemo 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 Sykflox allele revealed complete and early deletion of Syk from SykΔHaemo osteoclasts whereas Syk was incompletely deleted at a later stage of osteoclast development from SykΔOC cultures. Those results provide an explanation for the in vivo and in vitro difference between the SykΔOC and SykΔHaemo 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.

Original languageEnglish
Number of pages1
JournalFrontiers in immunology
Volume10
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Osteoclasts
Bone Resorption
Fc Receptors
Gene Deletion
Protein-Tyrosine Kinases
Bone Density
B-Lymphocytes
Alleles
Phenotype
Gene Expression
Bone and Bones

Keywords

  • Cre-Lox
  • in vivo
  • mice
  • osteoclasts
  • SYK (spleen tyrosine kinase)
  • tyrosine kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Hematopoietic or Osteoclast-Specific Deletion of Syk Leads to Increased Bone Mass in Experimental Mice. / Csete, Dániel; Simon, Edina; Alatshan, Ahmad; Aradi, Petra; Dobó-Nagy, Csaba; Jakus, Z.; Benkő, Sz.; Győri, Dávid S.; Mócsai, A.

In: Frontiers in immunology, Vol. 10, 01.01.2019.

Research output: Contribution to journalArticle

Csete, Dániel ; Simon, Edina ; Alatshan, Ahmad ; Aradi, Petra ; Dobó-Nagy, Csaba ; Jakus, Z. ; Benkő, Sz. ; Győri, Dávid S. ; Mócsai, A. / Hematopoietic or Osteoclast-Specific Deletion of Syk Leads to Increased Bone Mass in Experimental Mice. In: Frontiers in immunology. 2019 ; Vol. 10.
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AU - Dobó-Nagy, Csaba

AU - Jakus, Z.

AU - Benkő, Sz.

AU - Győri, Dávid S.

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AB - 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 (SykΔOC ) or hematopoietic (SykΔHaemo ) 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 SykΔOC and SykΔHaemo 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 Sykflox allele revealed complete and early deletion of Syk from SykΔHaemo osteoclasts whereas Syk was incompletely deleted at a later stage of osteoclast development from SykΔOC cultures. Those results provide an explanation for the in vivo and in vitro difference between the SykΔOC and SykΔHaemo 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.

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