Enhanced osteoclastogenesis in patients with tophaceous gout - Urate crystals promote osteoclast development through interactions with stromal cells
Enhanced osteoclastogenesis in patients with tophaceous gout - Urate crystals promote osteoclast development through interactions with stromal cells
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DOI：
10.1002/art.23488
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发表时间：
2008-06-01
影响因子：
--
通讯作者：
Cornish, Jillian
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文献类型：
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作者：
Dalbeth, Nicola;Smith, Timothy;Cornish, Jillian
客观的。分析痛风骨侵蚀的细胞机制。方法。分析痛风患者的外周血单核细胞 (PBMC) 和滑液单核细胞 (SFMC) 是否存在破骨细胞前体。通过免疫组织化学分析固定的痛风石和骨样品。通过单钠培养小鼠破骨细胞前体RAW 264.7 细胞、骨髓基质ST2 细胞和人滑膜成纤维细胞来研究破骨细胞生成机制。一水尿酸盐 (MSU) 晶体。结果。来自严重糜烂性痛风患者的 PBMC 在含有 RANKL 和单核细胞集落刺激因子 (M-CSF) 的培养物中具有优先形成破骨细胞样细胞的能力。 PBMC来源的抗酒石酸酸性磷酸酶（TRAP）阳性多核细胞的数量与痛风石的数量密切相关（r = 0.6296，P = 0.630）。严重糜烂性痛风和痛风石性痛风患者的 RANKL 和 M-CSF 循环浓度也较高。此外，来自痛风性膝关节积液的 SFMC 培养出的 TRAP 阳性多核细胞数量多于配对的 PBMC（P = 0.004）。免疫组织化学分析表明，痛风石内以及软组织与骨之间的界面处有大量表达破骨细胞标记的多核细胞。 MSU 晶体在体外不会直接促进 RAW 264.7 细胞的破骨细胞形成。然而，MSU 晶体抑制 ST2 细胞和人滑膜成纤维细胞中的骨保护素基因和蛋白表达，而不显着改变 RANKL 基因表达。在 RANKL 存在的情况下，用 MSU 晶体培养的 ST2 细胞的条件培养基促进了 RAW 264.7 细胞的破骨细胞形成。结论。慢性痛风石和糜烂性痛风的特点是破骨细胞发育增强。这些数据为破骨细胞靶向疗法预防慢性痛风骨损伤的研究提供了理论基础。
Objective. To analyze cellular mechanisms of bone erosion in gout.Methods. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) from patients with gout were analyzed for the presence of osteoclast precursors. Fixed tophus and bone samples were analyzed by immunohistochemistry. Mechanisms of osteoclastogenesis were studied by culturing murine preosteoclast RAW 264.7 cells, bone marrow stromal ST2 cells, and human synovial fibroblasts with monosodium. urate monohydrate (MSU) crystals.Results. PBMCs from patients with severe erosive gout had the preferential ability to form osteoclast-like cells in culture with RANKL and monocyte colony-stimulating factor (M-CSF). The number of PBMC-derived tartrate-resistant acid phosphatase (TRAP)positive multinucleated cells strongly correlated with the number of tophi (r = 0.6296, P = 0.630). Patients with severe erosive and tophaceous gout also had higher circulating concentrations of RANKL and M-CSF. Furthermore, greater numbers of TRAP-positive multinucleated cells were cultured from SFMCs derived from gouty knee effusions than from paired PBMCs (P = 0.004). Immunohistochemical Analysis demonstrated numerous multinucleated cells expressing osteoclast markers within tophi and at the interface between soft tissue and bone. MSU crystals did not directly promote osteoclast formation from RAW 264.7 cells in vitro. However, MSU crystals inhibited osteoprotegerin gene and protein expression in ST2 cells and human synovial fibroblasts, without significantly altering RANKL gene expression. Conditioned medium from ST2 cells cultured with MSU crystals promoted osteoclast formation from RAW 264.7 cells in the presence of RANKL.Conclusion. Chronic tophaceous and erosive gout is characterized by enhanced osteoclast development. These data provide a rationale for the study of osteoclast-targeted therapies for the prevention of bone damage in chronic gout.