Role of TNFa in Osteoclast-Mediated Bone Loss

描述（由申请人提供）：炎性侵蚀性关节炎（如类风湿性关节炎（RA））中的骨破坏与促炎细胞因子的产生增加有关，促炎细胞因子通过增加破骨细胞前体（OCP）分化为炎症关节中的成熟破骨细胞来促进局灶性骨吸收。骨免疫学的最新进展表明，破骨细胞不仅是骨吸收细胞，它们还通过自分泌和旁分泌机制产生有助于炎症和自身免疫的因子。然而，破骨细胞产生的因子，可以直接影响RA的发展和进展还没有得到很好的研究。使用微阵列分析，我们确定VEGF-C表达在来自TNF-Tg关节炎小鼠的OCP中显著增加。VEGF-C是淋巴管生成所必需的淋巴生长因子。但其在破骨细胞功能中的作用尚未研究，淋巴系统在RA关节破坏的发病机制中的作用也知之甚少。为了探索VEGF-C在这种情况下的参与，我们进行了一系列初步研究，并证明1）RANKL和TNF诱导OCP和OC中的VEGF-C表达; 2）VEGF-C刺激骨小梁骨吸收; 3）RA关节显著增加淋巴管形成; 4）抑制VEGF-C信号传导降低TNF-Tg小鼠关节炎症的严重程度。基于这些发现，我们假设在炎症关节中，RANKL和TNF激活OCP和OC产生VEGF-C，VEGF-C通过自分泌和旁分泌机制刺激血管生成和破骨细胞生成，同时介导关节炎症和骨侵蚀。这些假设将在3个具体目标中进行检验。在目的1中，我们将研究RANKL和TNF刺激OCP和破骨细胞产生VEGF-C的机制。在目标2中，我们将研究VEGF-C对破骨细胞功能的影响以及所涉及的下游信号通路。在目标3中，我们将使用VEGFR 3阻断方法确定VEGF-C信号传导在RA发病机制中的功能重要性。这些研究将提供关于OCP如何通过淋巴管生成刺激血管翳形成的新信息。最终，他们应该导致新的特定治疗药物的开发，以预防和治疗炎症性糜烂性关节炎患者。公共卫生相关性。本研究旨在通过影响破骨细胞功能和小鼠关节炎模型中的淋巴管生成，探讨骨吸收破骨细胞在类风湿关节炎发生和进展中的作用。这一结果将加深我们对破骨细胞和淋巴生物学的理解，并为开发治疗关节炎的新疗法提供新的方向。

DESCRIPTION (provided by applicant): Bone destruction in inflammatory erosive arthritis, such as rheumatoid arthritis (RA), is associated with increased production of pro-inflammatory cytokines, which promote focal bone resorption by increasing the differentiation of osteoclast precursors (OCP) to mature osteoclasts in inflamed joints. Recent progress in Osteoimmunology indicates that osteoclasts are not only bone resorbing cells; they also produce factors that contribute to inflammation and autoimmunity by autocrine and paracrine mechanisms. However, osteoclast-produced factors that could affect the development and progression of RA directly have not been well studied. Using microarray analysis, we identified that VEGF-C expression is significantly increased in OCPs from TNF- Tg arthritic mice. VEGF-C is a lymphogenic growth factor essential for lymphoangiogenesis. But its role in osteoclast function has not been investigated and little is known about the role of the lymphatic system in the pathogenesis of joint destruction in RA. To explore the involvement of VEGF-C in this setting, we carried out a series preliminary studies and demonstrated that 1) RANKL and TNF induce VEGF-C expression in OCPs and OCs; 2) VEGF-C stimulates osteoclastic bone resorption; 3) RA joints have remarkably increased lymphatic vessel formation; and 4) inhibition of VEGF-C signaling reduces the severity of joint inflammation in TNF-Tg mice. Based on these findings, we hypothesize that in inflammatory joints OCPs and OCs are activated by RANKL and TNF to produce VEGF-C, which mediates joint inflammation and bone erosion simultaneously by stimulating vasculogenesis and osteoclastogenesis via autocrine and paracrine mechanisms. These hypotheses will be tested in 3 specific aims. In Aim 1, we will investigate the mechanisms by which RANKL and TNF stimulate OCPs and osteoclasts to produce VEGF-C. In Aim 2, we will examine the effects of VEGF-C on osteoclast function and the downstream signaling pathways involved. In Aim 3, we will determine the functional importance of VEGF-C signaling in the pathogenesis of RA using a VEGFR3 blockade approach. These studies will provide new information on how OCPs stimulate pannus formation via lymphangiogenesis. Ultimately they should lead to the development of novel specific therapeutic agents to prevent and treat patients with inflammatory erosive arthritis. PUBLIC HEALTH RELEVANCE. The proposed study is aimed to investigate the role of bone resorbing osteoclasts in the development and progression of rheumatoid arthritis by affecting osteoclast function and lymphangiogenesis in mouse models of arthritis. The results will enhance our understanding of osteoclast and lymphatic biology and provide new direction for developing a novel therapy to treat arthritis.