目的:淋巴系统在维持组织液稳态和对炎症的免疫反应中起着至关重要的作用。半乳糖凝集素-8(Gal-8)调节病理性淋巴管生成,但其对颞下颌关节(TMJ)中与炎症相关的髁突骨丢失的影响尚未得到充分研究。
方法:我们使用TNFα转基因(TNFTG)小鼠及其野生型(WT)同窝比较了它们在TMJ中的炎症表型。接下来,淋巴内皮细胞(LECs)用于检查其对破骨细胞形成的影响,促炎因子表达,和有或没有硫基半乳糖苷的炎性淋巴管生成(TDG,Gal-8抑制剂)治疗。最后,使用两种小鼠模型(TNFTG关节炎模型和强迫张口模型)来探索TDG作为治疗炎症相关髁突骨质丢失的潜在药物。
结果:与WT小鼠相比,淋巴管内皮受体1(LYVE1)+/podoplanin(PDPN)+和Gal-8+/PDPN+的淋巴区域,TRAP阳性破骨细胞数,TNFTG小鼠髁突骨质流失增加。TDG对LEC中Gal-8的抑制作用,减少TNFα诱导的破骨细胞形成,促炎因子表达,和炎性淋巴管生成。此外,Gal-8通过与PDPN结合促进TNFα激活的AKT/ERK/NF-κB途径。最后,TDG的给药减弱炎性淋巴管生成,抑制破骨细胞活性,并减少TNFTG关节炎小鼠和强迫张口小鼠的髁突骨质流失。
结论:我们的发现揭示了Gal-8促进病理性淋巴管生成在炎症相关髁突骨质丢失中的重要作用。
The lymphatic system plays a crucial role in the maintenance of tissue fluid homeostasis and the immunological response to inflammation. Galectin-8 (Gal-8) regulates pathological lymphangiogenesis but the effects of which on inflammation-related condylar bone loss in temporomandibular joint (TMJ) have not been well studied.
We used TNFα-transgenic (TNFTG) mice and their wildtype (WT) littermates to compare their inflammatory phenotype in TMJs. Next, lymphatic endothelial cells (LECs) were used to examine the effects of which on osteoclast formation, pro-inflammatory factor expression, and inflammatory lymphangiogenesis with or without thiodigalactoside (TDG, a Gal-8 inhibitor) treatment. At last, two murine models (TNFTG arthritic model and forced mouth opening model) were used to explore TDG as a potential drug for the treatment of inflammation-related condylar bone loss.
In comparison to WT mice, lymphatic areas of lymphatic vessel endothelial receptor 1 (LYVE1)+/podoplanin (PDPN)+ and Gal-8+/PDPN+, TRAP-positive osteoclast number, and condylar bone loss are increased in TNFTG mice. Inhibition of Gal-8 in LECs by TDG, reduces TNFα-induced osteoclast formation, pro-inflammatory factor expression, and inflammatory lymphangiogenesis. In addition, Gal-8 promotes TNFα-activated AKT/ERK/NF-κB pathways by binding to PDPN. Finally, the administration of TDG attenuates inflammatory lymphangiogenesis, inhibits osteoclast activity, and reduces condylar bone loss in TNFTG arthritic mice and forced mouth opening mice.
Our findings reveal the important role of Gal-8-promoted pathological lymphangiogenesis in inflammation-related condylar bone loss.