Elevated Cytokine Production Restores Bone Resorption by Human Btk-Deficient Osteoclasts
Elevated Cytokine Production Restores Bone Resorption by Human Btk-Deficient Osteoclasts
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DOI：
10.1002/jbmr.210
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发表时间：
2011-01-01
影响因子：
6.2
通讯作者：
Norwood, Nicole J.
中科院分区：
文献类型：
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作者：
Danks, Lynett;Workman, Santa;Norwood, Nicole J.
Bruton氏酪氨酸激酶(BTK)基因突变导致人类B细胞疾病X连锁无丙种球蛋白血症(XLA)，但BTK缺乏对人类骨骼健康的影响尚未被研究过。在这项研究中，我们发现，由于肌动蛋白细胞骨架功能的失调，人BTK缺陷破骨细胞在体外的吸收活性存在缺陷。与预期相反，XLA患者没有表现出骨密度增加或骨转换血清标志物的变化，这表明潜在的代偿机制使骨稳态正常化。与骨转换指标相比，XLA患者血清中炎性细胞因子IL-6、IL-1β和肿瘤坏死因子-α水平显著升高。用XLA患者血清或重组炎性细胞因子IL-6、IL-1β和INF-α补充正常和XLA受试者的破骨细胞培养物，可在体外刺激破骨细胞活性，而加入细胞因子中和抗体则抑制这一刺激作用，证实了XLA患者血清中炎性细胞因子的升高增强了体外破骨细胞的活性。这项研究提供了新的证据，表明BTK信号对分离的破骨细胞中肌动蛋白细胞骨架的最佳组织和腔隙吸收至关重要。然而，在XLA患者中，这些固有的破骨细胞缺陷可以通过增加炎症细胞因子水平、恢复破骨细胞活性和导致骨密度正常化来纠正。(C)2011年美国骨与矿物研究学会。
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-1 beta, and tumor necrosis factor alpha (TNF-alpha) 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-1 beta, and INF-alpha 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. (C) 2011 American Society for Bone and Mineral Research.