凝血酶調節素蛋白 (thrombomodulin, TM) 是一種包含五個功能區的第I型穿膜醣蛋白，TM表達於多種細胞類型，並參與調控細胞功能。噬骨細胞是由單核細胞或巨噬細胞分化而成的多核細胞，主要功能為進行骨質吸收，從其分化到執行細胞功能之過程稱為蝕骨細胞新生作用 (osteoclastogenesis) 。牙齦卟啉單胞菌 (Porphyromonas. gingivalis) 的脂多醣 (Pg-LPS) 會造成嚴重發炎症狀、蝕骨細胞新生及牙槽骨侵蝕，是主要導致慢性牙周炎的致病因子。先前的研究已知，凝血酶調節素蛋白第一功能區 (TMD1) 能降低發炎反應和核因子κ-B受體激活配體 (RANKL) 所引起的蝕骨細胞新生作用和骨質流失。因此，重組凝血酶調節素蛋白第一功能區 (rTMD1) 可能抑制牙齦卟啉單胞菌的脂多醣與核因子κ-B受體激活配體同時誘導的發炎反應和蝕骨細胞新生作用。利用rTMD1處理小鼠巨噬細胞 (RAW 264.7) 時，牙齦卟啉單胞菌的脂多醣與核因子κ-B受體激活配體同時誘導所提升的促發炎因子、蝕骨細胞標誌基因、蝕骨細胞形成、蝕骨細胞骨質吸收活性均受到抑制。rTMD1也可抑制牙齦卟啉單胞菌的脂多醣誘導的M1型巨噬細胞形成。實驗及果顯示rTMD1透過阻斷p38及細胞外調節蛋白激酶在小鼠巨噬細胞的胞內信息傳遞，達到抑制腫瘤壞死因子-α與核因子κ-B受體激活配體同時誘導的蝕骨細胞新生作用。綜合本研究結果，rTMD1能夠抑制牙齦卟啉單胞菌的脂多醣與核因子κ-B配體受體激活配體同時誘導的蝕骨細胞新生作用，因此rTMD1具有發展成為牙周疾病治療藥物的潛力。

Thrombomodulin (TM), a type I transmembrane glycoprotein containing five functional domains, is expressed in many cell types and is involved in various biological functions. Osteoclastogenesis is a process that monocytes/macrophages differentiate into osteoclasts, the bone resorbing multinucleated cells for bone resorption. Porphyromonas gingivalis (P. gingivalis) derived lipopolysaccharide (Pg-LPS), a major pathogenic risk factor, functions to increase the inflammation, osteoclastogenesis, alveolar bone resorption, and causes chronic periodontitis. Previous studies have demonstrated that the TM lectin-like domain (TMD1) could function to reduce inflammatory response and the receptor activator of nuclear factor kappa-Β ligand (RANKL)-upregulated osteoclastogenesis and bone loss. Therefore, we hypothesized that the recombinant TMD1 (rTMD1) could suppress Pg-LPS- plus RANKL-induced inflammation and osteoclastogenesis. By treating the RAW 264.7 cells, a murine macrophage cell line, with rTMD1, we found that the Pg-LPS- plus RANKL-induced upregulations of pro-inflammatory cytokines, osteoclast marker genes, osteoclast formation, and bone resorption activity were all inhibited. The Pg-LPS-induced formation of M1-type macrophages, which contribute to promoting inflammation and osteoclastogenesis, was reduced by rTMD1 treatment. Furthermore, rTMD1 suppressed the intracellular signaling of p38 and extracellular regulated protein kinases in RAW 264.7 cells to inhibit osteoclastogenesis induced by RANKL and tumor necrosis factor-α. In conclusion, rTMD1 functions to suppress Pg-LPS-induced osteoclastogenesis, and may provide a potential treatment strategy for periodontal diseases.

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