Hyaluronan inhibits osteoclast differentiation via toll-like receptor 4
Hyaluronan inhibits osteoclast differentiation via toll-like receptor 4
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DOI：
10.1242/jcs.03310
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发表时间：
2007-01-01
影响因子：
4
通讯作者：
Kim, Hong-Hee
中科院分区：
文献类型：
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作者：
Chang, Eun-Ju;Kim, Hyon Jong;Kim, Hong-Hee
破骨细胞是骨吸收的特化细胞，其分化受两个关键因子控制，即巨噬细胞集落刺激因子（M-CSF）和核因子κ B配体受体激活因子（RANKL）。细胞外基质（ECM）是影响细胞命运的重要因素。迄今为止，很少有研究ECM成分和破骨细胞分化之间的关系已被记录。在这项研究中，我们发现了一个有效的抗破骨细胞生成作用的透明质酸（HA），ECM成分存在于骨髓和软结缔组织，在原代小鼠和人类破骨细胞前体细胞培养。HA的抗破骨细胞生成功能依赖于Toll样受体4（TLR 4），而不依赖于CD 44。HA抑制涉及Rac、活性氧和丝裂原活化蛋白激酶的M-CSF依赖性信号通路，导致控制RANK表达的转录因子AP-1和MITF受到抑制。此外，在颅骨骨吸收测定的体内小鼠模型中，HA减少了RANKL诱导的骨侵蚀和破骨细胞生成。我们的研究结果清楚地表明，HA通过TLR 4干扰M-CSF信号转导抑制破骨细胞分化，并指出ECM成分和先天免疫受体之间的相互作用可以在骨代谢的调节中发挥重要作用。
The differentiation of osteoclasts, cells specialized for bone resorption, is governed by two key factors, macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL). The extracellular matrix (ECM) is an important factor influencing cell fate. To date, little investigation on the relationship between ECM components and osteoclast differentiation has been documented. In this study, we uncovered a potent anti-osteoclastogenic effect of hyaluronan (HA), an ECM component present in bone marrow and soft connective tissues, in primary mouse and human osteoclast precursor cell cultures. The anti-osteoclastogenic function of HA was dependent on Toll-like receptor 4 (TLR4) but not on CD44. HA inhibited M-CSF-dependent signaling pathways involving Rac, reactive oxygen species and mitogen-activated protein kinases, resulting in suppression of transcription factors AP-1 and MITF that control RANK expression. Furthermore, in an in vivo mouse model of calvarial bone resorption assays HA reduced RANKL-induced bone erosion and osteoclastogenesis. Our results clearly show that HA inhibits osteoclast differentiation through TLR4 by interfering with M-CSF signaling, and point that the interaction between ECM components and innate immune receptors can play an important role in the regulation of bone metabolism.