探討berberine在治療骨質疏鬆症的機轉

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题名:	探討berberine在治療骨質疏鬆症的機轉
作者:	譚思濰(Tan, Tzu-Wei);湯智昕(Tang, Chih-Hsin)
贡献者:	醫學院醫學系學士班藥理學科
日期:	2012-07-31
上传时间:	2012-06-15 11:36:50 (UTC+8)
摘要:	骨質疏鬆症在二十世紀末已受到世界各國高度的重視。骨質疏鬆症及骨質疏鬆性骨折在西方國家極其普遍，特別是白色人種的老年婦女發病率最高。台灣已漸漸步入高齡化社會，由此聯想，將有更多人發生骨質疏鬆症。停經後骨質疏鬆(postmenopausal osteoporosis) 是老年婦女常患的一種代謝性骨病變。隨著國人平均壽命的延長，停經後骨質疏鬆的發病率呈上升趨勢。現代醫學對停經後骨質疏鬆的治療方法主要是給予?磷酸鹽(bisphosphonate)，但長期使用有一定的副作用。目前最常使用者為 Alendronate，其主要之作用是抑制破骨細胞之合成及其活性，在骨質疏鬆症之治療是一星期給予一次之Alendronate 可以得到不錯的治療效果，但其會造成噁心、嘔吐、食道刺激或潰瘍而產生胸痛，因而影響了服藥的順從性。而這一類藥物最大的副作用則是：停藥後會造成反彈而嚴重的骨質疏鬆症，而且長期使用骨質易脆。因此如果發展促進造骨細胞作用的藥物應可以治療骨質疏鬆症，由我們初步的結果發現在18 個中草藥純化合物之中berberine 具有最強增加造骨細胞分泌alkaline phosphatase activity（為評估造骨細胞造骨能力的指標），另外berberine 也可以增加造骨細胞bone morphogenetic protein-2 (BMP-2) 的表現，因此在第一年的計劃中我們將研究是否berberine 可以增加造骨細胞的活性而對破骨細胞並無影響，另外BMP-2 是否為最重要參與在berberine 所增加造骨的過程之中。分析berberine 所增加BMP-2 的表現經由那些訊息傳遞路徑參與，應是一個治療骨質疏鬆症的指標。由我們初步的結果發現berberine 促進c-Fos/c-Jun 結合至BMP-2 promoter 上AP-1 binding site 之上，而對於ERE 及Sp1 位置的結合並無影響。因此在第二年的時間中我們將要研究是否AP-1 為最重要的轉錄因子參與在berberine 所增加造骨作用及BMP-2 的表現當中。此外，我們也將分析那一些訊息傳遞分子參與在由berberine 所增加BMP-2 的表現及AP-1 的轉錄作用之中。本計劃第三年將進一步利用活體動物模式探討berberine在治療骨質疏鬆症的可能性。由我們初步結果發現局部給予berberine 可以增加局部脛骨的骨密度。因此本計劃除了利用局部給藥的動物模式觀察是否berberine 可以增加骨質及BMP-2 的表現，另外也將利用去除卵巢的動物模式觀察是否berberine 具有治療骨質疏鬆症的可能性。這些結果將有助於瞭解骨質流失的機轉及抗骨質疏鬆藥物發展的基礎。 Bone is a complex tissue and contains several cell types which are continuously undergoing a process of renewal and repair termed “bone remodeling”. Two major cell types responsible for bone remodeling are osteoclasts, which resorb bone, and osteoblasts, which form new bone. When resorption and formation of bone are not coordinated and bone breakdown overrides bone building, osteoporosis results. Bisphosphonates (eg: Alendronate), which inhibits osteoclast formation, are the most widely used lass for the therapy of osteoporosis. It has been reported that alendronate may cause some side effects including chest pain, difficulty breathing and vomiting. It also induces more serious osteoporosis after the withdrawal of therapy. Based on data base search, we speculate that development of bone formation agent may be a good strategy in osteporosis therapy. Our preliminary data show that berberine increased alkaline phosphatase activity in cultured osteoblasts. In addition, berberine also increased the bone morphogenetic protein-2 (BMP-2) expression in osteoblasts. Involvement of BMP-2 by berberine in bone formation effect will be examined in the first year of this research plan The analysis of cell signaling for berberine in osteoblasts is crucial for the development of novel approaches for treatment of osteoporosis. Our preliminary data show that c-Fos and c-Jun, but not estrogen receptor (ER) and SP-1, was found to associate with the BMP-2 promoter after treatment with berberine in osteoblast. Whether AP-1 signaling pathway is involved in berberine-mediated osteoblastic activity and BMP-2 expression in osteoblasts will be examined in the second year of this plan. In the third year, we will examine the anti-osteoporosis effect by berberine in vivo. Female rat (4 week-old) were used for this study. Rats were ovariectomized bilaterally under anesthesia and control rats were sham-operated for comparison. After oral administration of berberine for 8 weeks, the bone mineral density (BMD) and bone mineral content (BMC) were measured with a dual-energy X-ray absorptiometer (DXA). The blood marker of ALP and osteoclast activity will also be evaluated. The present study will provide a new strategy to treat osteoporosis. The results will be also helpful for the development of Chinese Medicine.
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