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