在類風溼性關節炎中，由蝕骨細胞所調控的骨骼侵蝕是一個相當關鍵的過程。先前文獻已證實血管翳係由發炎刺激過度增生的纖維母細胞及浸潤的巨噬細胞所構成，而蝕骨細胞可以由血管翳中M2類型的巨噬細胞分化而來，因此滑膜成纖維母細胞被認為在蝕骨細胞分化(蝕骨生成)中扮演相當重要的角色。NF-κB配體受體致活劑(簡稱RANKL)已經被證明會影響免疫系統以及蝕骨細胞生成作用。Pentraxin 3 (簡稱PTX3)是一種具有多功能的發炎介質，其在類風濕性關節炎患者的關節液中PTX3的表現量也較正常人來的高。實驗室先前的研究指出在巨噬細胞中PTX3會受到轉錄因子CCAAT /增強子結合蛋白δ（簡稱CEBPD）的正向調控而增加。而滑膜纖維母細胞會因為受到PTX3的刺激，而促使RANKL的分泌量大幅增加。實驗室尚未發表的結果中也證明，PTX3可以與X受體結合，進而促進乳腺癌細胞的轉移和浸潤。因此為了瞭解PTX3是否可以與纖維母細胞上的X受體相互作用，我們針對PTX3對於M2類型巨噬細胞分化成蝕骨細胞的影響進行探討。此外實驗室先前已開發一種PTX3多肽抑制劑RI37，但此RI37對於PTX3所參與的蝕骨細胞分化的影響仍未知。在本篇的研究結果中指出在NIH3T3細胞株中，PTX3可以透過活化AKT、ERK、NF-κB訊息傳遞路徑來誘發RANKL的表現。而這些AKT、ERK、NF-κB的活化誘導CEBPD的表現，進而促進RANKL的表現。此外，在NIH3T3細胞株處理RI37的情況下，發現RI37可以抑制PTX3所誘導的下游AKT、ERK、NF-κB的活化以及RANKL的表現。

Osteoclast-mediated bone resorption is a crucial event in rheumatoid arthritis (RA). Several studies suggested that osteoclasts can be differentiated from M2-like macrophages in pannus, the thickened and inflamed synovial membrane at peripheral joints. In addition, synovial fibroblasts were suggested to play an imperative role in osteoclast differentiation (osteoclastogenesis). Receptor activator of nuclear factor kappa B ligand (RANKL) has been identified to affect the immune system and control osteoclastogenesis. Pentraxin 3 (PTX3) is a multipotent inflammatory mediator, which is highly elevated in the joint fluid of RA patients. Transcription factor CCAAT/enhancer binding protein delta (CEBPD) can positively regulate PTX3 transcription in macrophages, and the secretion of RANKL in synovial fibroblasts is significantly increased following PTX3 stimulation. Our previous and unpublished studies showed that PTX3 could bind to X receptor and promote migration/invasion of breast cancer cells. We were therefore interested to test whether PTX3 could interact with X receptor in fibroblasts and dissected the consequent effects and contribution in osteoclast differentiation from M2-like macrophages. In addition, a PTX3 peptide inhibitor RI37 has been developed and we were further to examine its effect on osteoclast differentiation. Herein, we demonstrated that PTX3 could induce AKT, ERK 1/2 and NF-κB signaling and further contributed to CEBPD-mediated RANKL expression in fibroblasts. Furthermore, RI37 could inhibit PTX3-induced AKT, ERK 1/2 and NF-κB activation and consequently attenuated RANKL expression in fibroblasts.

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