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

Danks, Lynett, Workman, Sarita, Webster, David and Horwood, Nicole J ORCID: https://orcid.org/0000-0002-6344-1677 (2011) Elevated cytokine production restores bone resorption by human Btk-deficient osteoclasts. Journal of Bone and Mineral Research, 26 (1). pp. 182-192. ISSN 0884-0431

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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.

Item Type:	Article
Additional Information:	© 2011 American Society for Bone and Mineral Research.
Uncontrolled Keywords:	metabolism,metabolism,adult,agammaglobulinaemia tyrosine kinase,blood,metabolism,bone density,complications,cells, cultured,biosynthesis,metabolism,blood,humans,blood,metabolism,middle aged,enzymology,deficiency,tartrate-resistant acid phosphatase,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	06 Mar 2019 10:30
Last Modified:	25 Sep 2024 13:57
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70136
DOI:	10.1002/jbmr.210

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