Mechanism of synovial cell proliferation and osteoclast differentiation in an in vitro model of bone destruction of cultured rheumatoid synovium

类风湿性关节炎（RA）是一种以骨和软骨破坏导致关节功能丧失为特征的慢性炎症性关节炎。RA的典型组织学特征是滑膜衬里细胞增生伴致密微血管和炎性单核细胞浸润伴淋巴滤泡形成。破骨细胞是人类骨组织中唯一的骨吸收细胞，近年来的研究表明破骨细胞或破骨细胞样细胞参与了RA局灶性骨侵蚀的发病机制。破骨细胞的分化和活化需要两种因子，即核因子κ B受体激活因子配体（RANKL）和巨噬细胞集落刺激因子（M-CSF）。然而，破骨细胞分化的炎症类风湿性滑膜组织的确切机制仍有待建立。最近，我们建立了一种新的类风湿性滑膜骨破坏体外模型^<20）>。该培养体系采用骨细胞 ...更多信息 在无任何诱导剂的情况下，从RA滑膜组织中分化出ast样细胞。利用体外培养的骨破坏模型，我们试图确定哪些因素参与了RA滑膜破骨细胞样细胞的发育。RA滑膜组织培养中OC样细胞的形成远高于OA滑膜组织培养中的OC样细胞，并且培养的类风湿性关节炎滑膜产生更高水平的VEGF。免疫组化检测VEGF受体在巨噬细胞和OC样多核细胞上表达。VEGF受体1-Fc嵌合蛋白以剂量依赖性方式抑制OC样细胞和小窝形成。骨保护素（OPG）和TNF受体Ⅱ-Fc嵌合蛋白也能抑制OC的形成，而MCSF受体-Fc嵌合蛋白则无此作用。与RANKL结合的RANK肽抑制培养的RA滑膜中OC样细胞的形成。我们的数据表明，RANKL依赖性和非依赖性信号可能都参与了体外骨破坏模型中破骨细胞的形成。此外，VEGF可能是破骨细胞介导的RA滑膜骨破坏的关键介质之一。抑制RANKL/RANK和VEGF通路可能成为治疗RA的新策略。少

Rheumatoid arthritis (RA) is a chronic inflammatory arthritis characterized by bone and cartilage destruction leading to loss of joint function. Characteristic histological features of RA are hyperplasia of synovial lining cells with a dense microvasculature and infiltration of inflammatory mononuclear cells with a formation of lymphoid follicles. Osteoclast is an only bone resorbing cells in the human bone tissues and recent studies demonstrated an involvement of osteoclasts or osteoclast-like cells in the pathogenesis of focal bone erosion in RA. Two factors, receptor activator of NF-KB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) are essential for the differentiation and activation of osteoclasts. However, the precise mechanism of osteoclast differentiation in the inflamed rheumatoid synovial tissues remains to be established. Recently, we have established a novel in vitro model of bone destruction by rheumatoid synovium^<20)>. This culture system employed osteocl … More ast-like cells differentiated from RA synovial tissue without any inducers. Using the in vitro culture model of bone destruction, we sought to determine what factors are involved in the development of osteoclast-like cells from RA synovium Formation of OC-like cells in the culture of RA synovial tissue was much higher than that in the culture OA synovial tissue and cultured rheumatoid synovium produced higher level of VEGF. VEGF receptor determined imniunohistochemically was expressed on the macrophages and OC like multinucleated cells. VEGF receptor 1-Fc chimeric protein inhibited OC-like cell and pit formation in a dose-dependent manner. Osteoprotegerin (OPG) and TNF receptor II-Fc chimeric protein also inhibited OC formation, but MCSF receptor-Fc chimeric protein was not effective. The RANK peptide that binds to RANKL inhibited OC-like cell formation in the cultured RA synovium.Our data suggest that both RANKL-dependent and independent signals might be involved in the formation of osteoclasts in the in vitro model of bone destruction. In addition, VEGF might be one of the key mediators of osteoclast-mediated bone destruction by RA synovium. Inhibition of RANKL/RANK and VEGF pathway could be a new strategy for the treatment of RA. Less