NF-κB/HIF-2α/VEGF信号通路介导骨关节炎软骨钙化层重构及“骨-软骨对话”的作用及机制研究

Calcified cartilage layer is an important component of cartilage. Now, more evidence indicates that calcified layer remodeling, thickening, tidemark shifting, neovascular invasion, and bone-cartilage crosstalk are involved in the occurrence and Calcified cartilage layer is an important component of cartilage. Now, more evidence indicates that calcified layer remodeling, thickening, tidemark shifting, neovascular invasion, and bone-cartilage crosstalk are involved in the occurrence and development of osteoarthritis. However, the exact processes are not completely understood and become a obstacle in the clinical treatment of osteoarthritis. Recent studies indicated the linear relationship between VEGF and the severity of osteoarthritis and neovascularization.VEGF was associated with regulation of cartilage calcification, permeability of cartilage, change of cartilage anti-angiogenic properties and the articular cartilage remodeling. More study indicated the expression of VEGF through NF-κB/HIF-2α pathway.Therefore, we focus on changes in dense calcified layer and new blood vessels breaking through barrier. Fortunately, our previous study found that VEGF expression was involved in osteoarthritic cartilage, new blood vessels invading the calcified cartilage layer, Moreover, we found that VEGF inhibited chondrocyte proteoglycan and type II collagen protein expression. However, the mechanisms of VEGF-induced remodeling of calcified cartilage layer, vascular endothelial cell proliferation, migration and the articular cartilage remodeling to achieve bone-cartilage crosstalk remains unclear. Accordingly, we propose the hypothesis that blocking the NF-κB/HIF-2α signaling pathway inhibits VEGF-induced calcified layer remodeling and delays the development of osteoarthritis.

软骨钙化层是构成关节软骨重要的组成部分，研究发现钙化层重构、增厚、潮线漂移，新生血管侵入，骨与软骨之间发生了"对话",促进了骨关节炎发生发展，然而其确切的机制仍不明确，成为临床治疗骨关节炎的障碍。最近研究表明VEGF与骨关节炎严重程度及新生血管存在一定的线性关系, NF-κB/HIF-2α信号通路调节VEGF表达，VEGF参与软骨矿化度，增加软骨通透性，改变软骨抗血管特性，引起关节软骨重塑。那么致密的钙化层结构发生了怎样的变化，新生血管如何突破屏障成为本研究重点。我们前期研究发现骨关节炎软骨VEGF表达升高，新生血管侵入软骨钙化层，VEGF抑制软骨细胞蛋白聚糖及Ⅱ型胶原蛋白表达。但是VEGF导致软骨钙化层重构的机制是什么？如何诱导血管内皮细胞增生、迁移，促进新生血管的形成并侵入钙化层，实现对话？阻断NF-κB/HIF-2α信号通能否抑制VEGF诱导的钙化层重构，从而延缓骨关节炎发生发展？

骨关节炎(osteoarthritis, OA)是一种以关节软骨退变、滑膜炎、软骨下骨的改变及骨赘形成为病变基础的疾病,最近许多学者研究发现关节软骨中新生血管出现及血管内皮生长因子（Vascular endothelial growth factor ，VEGF）参与了骨关节炎的发生发展过程, 血清VEGF的水平与关节炎的严重程度密切相关，我们前期的实验研究发现，骨关节炎关节软骨中VEGF 及VEGFR-2 mRNA表达较正常软骨有明显升高。VEGF表达升高的是何种机制来调控的呢？最近研究发现HIF-2α在人及大鼠骨关节炎软骨中表达明显升高，HIF-2α主要表达在软骨周边钙化层高分化的肥大软骨细胞，诱导软骨细胞凋亡，上调VEGF表达，导致软骨基质降解，促进新生成熟的血管形成并侵入。 .HIF-2α可能成为治疗骨关节炎的靶目标，研究证实炎性因子及机械压力都可以引起NF-κB表达，NF-κB作为HIF-2α的上游信号，可以诱导HIF-2α的表达，NF-κB/ HIF-2α/VEGF信号通路参与了软骨退变。我们推断VEGF可能通过NF-κB/ HIF-2α信号通路参与了钙化层软骨的重构，新生血管的形成，而且我们可以大胆设想相对分子量较HGF小的VEGF有可能自由通过钙化层，导致钙化层重构，出现“潮线漂移”，为新生血管的侵入铺平了道路，促进了“骨-软骨对话”，但是其具体机制仍需要我们进一步探讨。.本研究结果进证实钙化层软骨重构在骨关节炎中的作用，VEGF表达及血管形成的呈线性关系，VEGF参与了钙化层软骨的矿化、增寛，引起“潮线漂移”，以及内皮细胞增殖、迁移、血管形成。NF-κB/ HIF-2α/VEGF参与了骨关节炎的发生发展，阻断NF-κB/ HIF-2α通路可以阻止VEGF对钙化层软骨基质转换、重构及血管形成的影响，减少或抑制血管内皮细胞的增殖、迁移并穿越钙化层，减少“骨-软骨异常的对话”，从而延缓骨关节炎的发生发展。.上述问题的探讨将进一步揭示VEGF在骨关节炎血管形成的作用及机制，这有助于进一步深入揭示骨关节炎软骨退变机制，从而推动骨关节炎理论学的发展，为骨关节炎的防治提供新的理论依据。