Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis
Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis
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DOI：
10.1002/path.2684
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发表时间：
2010-05-01
影响因子：
7.3
通讯作者：
Heymann, Dominique
中科院分区：
文献类型：
--
作者：
Baud'Huin, Marc;Renault, Romain;Heymann, Dominique
白介素34(IL-34)是新近发现的一种调节髓系分化、增殖和存活的因子，通过巨噬细胞集落刺激因子受体(M-CSF受体，c-FMS)发挥作用。M-CSF是c-FMS的主要配体，是破骨细胞形成所必需的，已被认为是骨巨细胞瘤(GCTS)发病的关键因素，GCTS是富含破骨细胞的肿瘤。根据M-CSF在破骨细胞形成和GCTS中的关键作用，首次检测了IL-34在人GCTS中的表达。定量分析14例人GCTS中IL-34mRNA的表达，发现该细胞因子在GCTS、M-CSF和c-FMS中均有表达。免疫组织化学显示破骨细胞样细胞表达IL-34，单核基质细胞呈弱阳性。与成骨细胞相比，骨吸收破骨细胞显示出非常强的IL-34染色，提示其可能通过促进破骨细胞的形成而在GCTS的发病机制中发挥作用。然后在小鼠和人的模型中研究了IL-34在破骨细胞形成中的作用。在所有模型中，IL-34均能支持RANKL诱导的破骨细胞生成，但不存在M-CSF。在IL-34和RANKL存在下产生的多核细胞表达特定的破骨细胞标志物和重新吸收的牙本质。IL-34通过激活c-FMS诱导ERK1/2和Akt的磷酸化，c-FMS酪氨酸激酶抑制剂抑制信号转导。此外，IL-34通过促进破骨细胞前体细胞的黏附和增殖来刺激RANKL诱导的破骨细胞生成，而对破骨细胞的存活无影响。总之，这些数据表明，在RANKL诱导的破骨细胞形成中，IL-34可以完全取代M-CSF，从而确定了这种细胞因子的新的生物学活性，并在GCTS的发病机制中做出了贡献。版权所有(C)2010年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Interleukin-34 (IL-34) is a newly discovered regulator of myeloid lineage differentiation, proliferation, and survival, acting via the macrophage-colony stimulating factor receptor (M-CSF receptor, c-fms). M-CSF, the main ligand for c-fms, is required for osteoclastogenesis and has been already identified as a critical contributor of the pathogenesis of giant cell tumours of bone (GCTs), tumours rich in osteoclasts. According to the key role of M-CSF in osteoclastogenesis and GCTs, the expression of IL-34 in human GCTs was first assessed. Quantitative analysis of IL-34 mRNA expression in 14 human GCTs revealed expression of this cytokine in GCTs as well as M-CSF and c-fms. Immunohistochemistry demonstrated that osteoclast-like cells exhibited a huge immunostaining for IL-34 and that mononuclear stromal cells were slightly positive for this protein. In contrast to osteoblasts, bone-resorbing osteoclasts showed very strong staining for IL-34, suggesting its potential role in the pathogenesis of GCTs by facilitating osteoclast formation. The role of IL-34 in osteoclastogenesis was then studied in murine and human models. IL-34 was able to support RANKL-induced osteoclastogenesis in the absence of M-CSF in all models. Multinucleated cells generated in the presence of IL-34 and RANKL expressed specific osteoclastic markers and resorbed dentine. IL-34 induced phosphorylation of ERK 1/2 and Akt through the activation of c-fms, as revealed by the inhibition of signalling by a specific c-fms tyrosine kinase inhibitor. Furthermore, IL-34 stimulated RANKL-induced osteoclastogenesis by promoting the adhesion and proliferation of osteoclast progenitors, and had no effect on osteoclast survival. Overall, these data reveal that IL-34 can be entirely substituted for M-CSF in RANKL-induced osteoclastogenesis, thus identifying a new biological activity for this cytokine and a contribution to the pathogenesis of GCTs. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.