Elevated cytokine production restores bone resorption by human Btk-deficient osteoclasts

Lynett Danks, Sarita Workman, David Webster, Nicole J Horwood

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Mutations in Bruton's tyrosine kinase (Btk) cause the B-cell disorder X-linked agammaglobulinaemia (XLA) in humans, but the effect of Btk deficiency in human bone health has not been investigated previously. In this study, we show that human Btk-deficient osteoclasts are defective at resorption activity in vitro owing to a dysregulation of the actin cytoskeletal function. Contrary to expectation, XLA patients did not exhibit increased bone density or alterations in serum markers of bone turnover, indicating that a potential compensation mechanism normalizes bone homeostasis. In contrast to the bone turnover markers, the levels of inflammatory cytokines interleukin 6 (IL-6), IL-1β, and tumor necrosis factor α (TNF-α) were significantly elevated in XLA patients' serum compared with control individuals. Supplementation of osteoclast cultures from normal and XLA subjects with serum from XLA patients or recombinant inflammatory cytokines IL-6, IL-1β, and TNF-α resulted in a stimulation of osteoclast activity in vitro, whereas the addition of cytokine-neutralizing antibodies inhibited this stimulatory effect, confirming that elevated inflammatory cytokines in XLA serum heightened osteoclast activity in vitro. This study provides novel evidence that Btk signaling is crucial for optimal actin cytoskeletal organization and lacunar resorption in isolated osteoclasts. In XLA patients, however, these inherent osteoclast defects are corrected by increased inflammatory cytokine levels, restoring osteoclast activity and leading to the normalization of bone density.

Original languageEnglish
Pages (from-to)182-192
Number of pages11
JournalJournal of Bone and Mineral Research
Volume26
Issue number1
Early online date16 Aug 2010
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Acid Phosphatase/metabolism
  • Actins/metabolism
  • Adult
  • Agammaglobulinaemia Tyrosine Kinase
  • Agammaglobulinemia/blood
  • Biomarkers/metabolism
  • Bone Density
  • Bone Resorption/complications
  • Cells, Cultured
  • Cytokines/biosynthesis
  • Dentin/metabolism
  • Genetic Diseases, X-Linked/blood
  • Humans
  • Inflammation Mediators/blood
  • Isoenzymes/metabolism
  • Middle Aged
  • Osteoclasts/enzymology
  • Protein-Tyrosine Kinases/deficiency
  • Tartrate-Resistant Acid Phosphatase

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