導眠靜為一種苯二氮類藥物，是目前普遍常用於手術、鎮靜及治療失眠的藥物，這種苯二氮類藥物主要是透過GABA去抑制神經的傳導作用。在過去的研究發現，當懷孕初期的婦女如果服用導眠靜將會導致新生兒出現先天性泌尿道畸形、唇顎裂、或是因為成骨發育不全而有侏儒症的風險。並且最近的研究更證實了，導眠靜會抑制成人骨質間質幹細胞硬骨的分化。由於大部分脊椎動物的骨盆、上下肢的骨骼，都是由軟骨內骨形成的這個模式而分化而來的，成熟肥大的軟骨細胞內會開始產生骨化反應而分化成骨細胞在由骨內骨形成的方式形成硬骨。因此我們想探討在體外實驗中，導眠靜對於人類骨髓間質幹細胞的軟骨分化是否會造成影響。首先我們先透過使用包含乙型轉移生長因子誘導軟骨分化的培養液，以建立軟骨化的系統。結果顯示出不論是使用微顆粒狀的培養方式或是使用平面高密度的培養方式，乙型轉移生長因子都能成功的促進軟骨分化。我們接著使用含乙型轉移生長因子之促進軟骨分化的培養液與導眠靜同時處理細胞，以觀察導眠靜對於人類骨髓間質幹細胞的軟骨分化的影響。除了以阿爾新藍(Alcian blue)染軟骨的黏多醣(glycosaminoglycans)外，我們也利用 RT-PCR及西方轉漬法觀察 SOX9、聚蛋白聚醣(aggrecan)或是第二型膠原蛋白的表現。結果發現導眠靜確實會抑制乙型轉移生長因子誘發之軟骨的分化能力。接著我們想探討分子的機轉，發現無論是使用中樞或是周邊苯二氮類接受體拮抗劑之後，都可以部分回復導眠靜抑制軟骨分化的能力，同時我們也以核醣核酸干擾技術將周邊苯二氮受體去做敲減 (knockdown)，與上述會得到類似的結果，顯示導眠靜會透過周邊苯二氮類接受體以影響人類骨髓間質幹細胞的軟骨分化的能力。
在未來的研究，我們希望能夠更進一步去探討導眠靜是如何透過分子的機轉去抑制軟骨的分化能力，這項研究或許能夠證明並解釋為何導眠靜會引發肌肉骨骼系統相關的先天性畸形。

Midazolam, a benzodiazepine derivative, is widely used for sedation and surgery. Benzodiazepines enhance neural inhibition through modulation of gamma-aminobutyric acid receptor. Previous studies have demonstrated that Midazolam is associated with increased risk of congenital malformations, such as dwarfism when used in early pregnancy. Recent study demonstrated that Midazolam negatively regulates osteogenic differentiation in human bone marrow-derived mesenchymal stem cells. Given the hypertrophic chondrocytes is able to differentiate to osteoblast and osteocytes and contribute to endochondral bone formation, the effect of Midazolam on the chondrogenesis remains unclear. In the present study, we applied a human mesenchymal stem cell line, the KP cell line to serve as an in vitro model to study the effect of Midazolam on chondrogenesis. We first successfully set up an in vitro chondrogenic model by using TGF--driven, chemically-defined induction medium. Our results showed that we were able to induce chondrogenesis either in micromass culture or 2D high density culture. Treatment of Midazolam inhibited chondrogenesis, which was examined by the Alcian blue staining, as well as the expression of chondrogenic markers, such as Sox9, aggrecan and type II collagen. Inhibition of Midazolam by peripheral benzodiazepine receptor (PBR) antagonist or small interfering RNA could partially rescue Midazolam’s inhibitory effects on chondrogenesis. In addition, Midazolam was also found to suppress TGF-β-induced Smad3 phosphorylation. This study may provide a possible explanation on how Midazolam induces congenital malformations of musculoskeletal system.

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