決定蝕骨細胞的分化過程中，透過綜合複雜轉錄調控網絡內的多個因子，當其失去平衡時，與退化性關節炎、風濕性關節炎和骨質疏鬆有關聯性。微型核糖核酸(microRNAs, miRs)為短鏈、內生性的核糖核酸，能調節基因的表現，透過在後轉錄階段，鍵結目標基因的訊息核糖核酸的3端未轉譯區域。近年，有文獻指出低氧環境(Hypoxia)、miRs和自噬作用(Autophagy)於蝕骨細胞分化過程中似乎有關聯性。然而，Hypoxia、miRs和Autophagy三者間如何調控蝕骨細胞之分化仍然尚待釐清。本研究，我們嘗試描述蝕骨細胞的分化過程中，牽涉到多個因子間(Hypoxia、miRs和Autophagy)的互相調控。舉例來說，初期實驗數據顯示，當利用RANKL跟M-CSF將巨噬細胞RAW264.7分化至蝕骨細胞過程中，探討有無低氧環境下，對其分化之影響，結果發現在低氧環境下，相對於正常環境Autophagy基因之表現較高，且能正調控大部份的Autophagy相關基因。並且，蝕骨細胞分化過程中，逐步降低表現的miRs，透過生物資訊學的分析，與Autophagy相關基因的3端未轉譯區域有鍵結的可能性。針對本研究的目的而言，我們期望能釐清蝕骨細胞分化過程機制中的一些重要調控因子，包含了Hypoxia、miRs和Autophagy。根據此原理，也許能參考並且治療或預防退化性關節炎、風濕性關節炎和骨質疏鬆。
Osteoclastogenesis commitment is governed by the integration of multiple-factors in a complicated transcriptional network and loss of balance have implicated osteoarthritis (OA)、rheumatoid arthritis (RA) and osteoporosis. MicroRNAs (miRs) are short- and endogenous-nucleotides RNA, and acts as critical regulator through pairing 3’UTR of target gene in post-transcriptional level. Recently, increasing number of reports have shown correlation between hypoxia, miRs and autophagy in osteoclastogenesis. However, the global connection between hypoxia, miRs, and autophagy in osteoclastogenesis remains undefined.Here we demonstrate that osteoclastogenesis is dependent regulate-network on multiple-factors including hypoxia, miRs and autophagy. For example, our primary data remained that marcophages RAW264.7 differentiated to osteoclasts (OCs) byRANKL and M-CSF under hypoxia condition have varied effects on expression of autophagy genes on the commitment of osteoclastogenesis. In addition, several candidates of down-regulated miRs have showed potential binding site on 3’UTR of autophagy genes by bio-informatic prediction.To this end, this project will show the mechanism of osteoclastogenesis by critical regulator including hypoxia, miRs and autophagy. Base on this principle that probably have potential prevention/therapy in osteoarthritis (OA)、rheumatoid arthritis (RA) and osteoporosis.
