Collins Fraser L, Williams Jessica O, Bloom Anja C, Singh Ravinder K, Jordan Lauren, Stone Michael D, McCabe Laura R, Wang Eddie C Y, Williams Anwen S
Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom; Department of Physiology, Michigan State University, East Lansing, MI, USA.
Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Bone. 2017 Apr;97:94-104. doi: 10.1016/j.bone.2017.01.002. Epub 2017 Jan 4.
Reduced bone density and secondary osteoporosis, resulting in increased risk of fracture, is a significant complicating factor in the inflammatory arthritides. While the exact etiology of systemic bone loss is not fully elucidated, recent insights into the tumor necrosis factor super family (TNFSF) revealed a potential role for death receptor 3 (DR3/TNFRSF25) and one of its ligands, TNF-like protein 1A (TL1A/TNFSF15). The mechanisms by which DR3/TL1A signalling modulates bone loss are unclear. We investigated the effect of DR3/TL1A signalling upon osteoclast-dependent chemokine and MMP production to unravel novel mechanisms whereby this pathway regulates OC formation and OC-dependent bone resorption. Collagen induced arthritis (CIA) was established in DR3 and DR3 mice, joints were sectioned and analysed histologically for bone damage while systemic trabecular bone loss distal to the affected joints was compared by micro-CT. Ablation of DR3 protected DBA/1 mice against the development and progression of CIA. In DR3, joints of the ankle and mid-foot were almost free of bone erosions and long bones of mice with CIA were protected against systemic trabecular bone loss. In vitro, expression of DR3 was confirmed on primary human CD14 osteoclast precursors by flow cytometry. These cells were treated with TL1A in osteoclast differentiation medium and TRAP osteoclasts, bone resorption, levels of osteoclast-associated chemokines (CCL3, CCL2 and CXCL8) and MMP-9 measured. TL1A intensified human osteoclast differentiation and bone resorption and increased osteoclast-associated production of CCL3 and MMP-9. Our data reveals the DR3 pathway as an attractive therapeutic target to combat adverse bone pathology associated with inflammatory arthritis. We demonstrate that DR3 is critical in the pathogenesis of murine CIA and associated secondary osteoporosis. Furthermore, we identify a novel mechanism by which the DR3/TL1A pathway directly enhances human OC formation and resorptive activity, controlling expression and activation of CCL3 and MMP-9.
骨密度降低和继发性骨质疏松会导致骨折风险增加，这是炎性关节炎的一个重要复杂因素。虽然全身性骨质流失的确切病因尚未完全阐明，但最近对肿瘤坏死因子超家族（TNFSF）的深入研究揭示了死亡受体3（DR3/TNFRSF25）及其配体之一肿瘤坏死因子样蛋白1A（TL1A/TNFSF15）的潜在作用。DR3/TL1A信号传导调节骨质流失的机制尚不清楚。我们研究了DR3/TL1A信号传导对破骨细胞依赖性趋化因子和基质金属蛋白酶产生的影响，以揭示该途径调节破骨细胞形成和破骨细胞依赖性骨吸收的新机制。在DR3和DR3基因敲除小鼠中建立胶原诱导性关节炎（CIA），对关节进行切片并进行组织学分析以评估骨损伤，同时通过显微CT比较受影响关节远端的全身性小梁骨丢失情况。敲除DR3可保护DBA/1小鼠免受CIA的发生和发展。在DR3基因敲除小鼠中，踝关节和中足关节几乎没有骨侵蚀，患有CIA的小鼠的长骨也受到保护，免受全身性小梁骨丢失。在体外，通过流式细胞术在原代人CD14破骨细胞前体上证实了DR3的表达。这些细胞在破骨细胞分化培养基中用TL1A处理，并测量抗酒石酸酸性磷酸酶阳性破骨细胞、骨吸收、破骨细胞相关趋化因子（CCL3、CCL2和CXCL8）水平以及基质金属蛋白酶-9。TL1A增强了人破骨细胞的分化和骨吸收，并增加了破骨细胞相关的CCL3和基质金属蛋白酶-9的产生。我们的数据表明DR3途径是对抗与炎性关节炎相关的不良骨病理的一个有吸引力的治疗靶点。我们证明DR3在小鼠CIA发病机制及相关继发性骨质疏松中起关键作用。此外，我们确定了一种新机制，通过该机制DR3/TL1A途径直接增强人破骨细胞的形成和吸收活性，控制CCL3和基质金属蛋白酶-9的表达和激活。
