類風濕性關節炎(rheumatoid arthritis)屬於一種慢性發炎疾病，罹患率佔全球總人口數的百分之一。風濕性關節炎會引起關節液增多，白血球浸潤及關節變形等發炎反應，最終導致骨頭破壞。細胞激素於發炎過程中扮演重要的角色，可促使發炎反應更加嚴重並造成關節的損傷。介白素-20(interleukin-20; IL-20)屬於介白素-10家族並發現參與許多複雜的發炎性疾病，如乾癬、粥狀動脈硬化與腎臟疾病。然而IL-20與類風濕性關節炎的關係以及 IL-20是否與骨頭破壞的機轉有相關連性，目前仍然是未知的，因此本研究想要探討 IL-20是否與類風濕性關節炎以及骨質疏鬆症有關聯性。研究利用酵素連結免疫吸附分析法(enzyme-linked immunosorbent assay)得知，類風濕性關節炎病人之關節液中可偵測到高表現量的IL-20。此外，IL-20不僅作用在關節纖維母細胞上，促使關節纖維母細胞表現大量IL-6、IL-8及MCP-1等細胞激素，也同時促進嗜中性白血球(neutrophil)趨化到關節組織。在大鼠關節炎動物模式中，將IL-20可溶性接受器(sIL-20R1)質體，利用電穿孔(electroporation)方式送入大鼠大腿內側肌肉使其表現。研究首次證實，抑制IL-20可以顯著地減緩關節炎的嚴重程度。接著，利用專一性拮抗IL-20的單株抗體，藉由皮下注射送入關節炎大鼠模式也可以明顯地減緩關節炎的腫脹，防止軟骨破壞，預防骨質流失，降低相關促發炎細胞激素的產生。實驗進一步得知，在關節炎大鼠模式中同時給予拮抗IL-20的單株抗體與TNF的阻斷劑(etanercept)，可以達到更顯著地效用。因此，IL-20在類風濕性關節炎的致病機轉中扮演著重要的角色。除此之外，本研究更深入探討IL-20是否參與調控蝕骨細胞(osteoclast)的成熟與分化(osteoclastogenesis)，拮抗IL-20的單株抗體是否也具有減緩骨質疏鬆的效用。實驗得知，骨質減少(osteopenia)與骨質疏鬆症(osteoporosis)病患以及卵巢摘除小鼠的血清中皆可偵測到高表現量的IL-20。同時，IL-20藉由影響蝕骨前驅細胞(osteoclast precursor cells)的RANK以及造骨細胞(osteoblast)的RANKL表現來調控蝕骨細胞的成熟與分化。細胞實驗顯示，拮抗IL-20的單株抗體可以完全抑制蝕骨細胞的分化。在卵巢摘除建立的小鼠骨質疏鬆模式中也證實，拮抗IL-20的單株抗體可以減緩骨質流失。此外，在我們建立的IL-20第一型接受器(IL-20R1)基因剔除鼠中，首次證實IL-20R1基因剔除鼠比野生型小鼠具有更高的骨密度。而且剔除IL-20R1基因可以完全抑制IL-20所調控的蝕骨細胞成熟與分化。利用卵巢摘除術，更驗證了IL-20R1基因剔除鼠可以對抗卵巢摘除所誘導的骨質疏鬆，可以避免與減緩骨質的流失。由本研究得知，IL-20扮演一個促進發炎的細胞激素並參與在關節炎的發病過程。我們更鑑別出IL-20在蝕骨細胞的成熟與分化扮演重要的角色。經由動物實驗證實，拮抗IL-20的單株抗體可以明顯地減緩關節炎的嚴重程度，降低相關促發炎細胞激素的產生。同時也可以預防骨頭遭受破壞，減緩骨質流失。綜合以上研究結果，我們認為拮抗IL-20的單株抗體在治療類風濕性關節炎以及骨質疏鬆症是極具潛力的。本研究的結果也可讓未來對於類風濕性關節炎以及骨質疏鬆症的治療多了一個新方向。

Rheumatoid arthritis (RA) is a chronic inflammatory arthritis and affects about 1% of the population, which is characterized by synovial hyperplasia, inflammation, and joint destruction. IL-20 is a proinflammatory cytokine of the IL-10 family that is involved in psoriasis, atherosclerosis, and renal diseases. However, little is known about the role of IL-20 in RA and bone destruction. We wanted to determine whether IL-20 was involved in RA and osteoporosis. ELISA showed that RA patients expressed significantly higher levels of IL-20 in synovial fluid. IL-20 not only induced RASFs to secrete MCP-1, IL-6, and IL-8, but also promoted neutrophil chemotaxis. Furthermore, electroporating soluble IL-20R1 into collagen-induced arthritis (CIA) rats significantly reduced the severity of arthritis. Moreover, an alternative IL-20 antagonist, anti-IL-20 monoclonal antibody (mAb) 7E, also significantly reduced the severity of arthritis by decreasing hind-paw thickness; prevented cartilage damage and bone loss; and reduced the expression of IL-20, IL-1β, IL-6, RANKL and MMPs in synovial tissue. The combination of 7E with etanercept significantly ameliorated the progression of arthritis in CIA rats. Therefore, IL-20 may act as a promoting factor during the progression of RA. We also explored the function of IL-20 in osteoclastogenesis and the therapeutic potential of 7E for treating osteoporosis. Higher serum IL-20 levels were detected in patients with osteoporosis and in ovariectomized (OVX) mice. IL-20 mediates osteoclastogenesis by upregulating RANK in osteoclast precursor cells and RANKL in osteoblasts. 7E treatment completely inhibited osteoclast differentiation induced by M-CSF and RANKL in vitro, and protected mice from OVX-induced bone loss in vivo. Furthermore, IL-20R1-deficient mice had significantly higher bone mineral density (BMD) than did wild-type controls. IL-20R1-deficiency also abolished IL-20-induced osteoclastogenesis and increased BMD in OVX mice. In summary, IL-20 is a proinflammatory cytokine and contributed to the pathogenesis of RA. IL-20 is also involved in the pathogenesis of osteoporosis. We have identified a pivotal role of IL-20 in osteoclast differentiation, and we conclude that anti-IL-20 mAb significantly decreased the severity of arthritis, reduced the production of proinflammatory cytokines, and prevented bone destruction in CIA rats and OVX mice, all of which suggested its therapeutic potential in RA and osteoporosis.

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