基質金屬蛋白酶 (MMPs) 可以分解所有的細胞外基質，調控細胞所必須的微環境 (microenviorment)。特別的是，MMPs在細胞計畫性死亡中扮演著令人困惑的角色，會同步顯現出促進凋亡及抗凋亡的作用。MMPs也會因特異性細胞附著的發生，藉由正向或負向調控生存訊息，影響細胞存活與增殖。星狀膠質細胞是主要產生MMPs的神經細胞，可以分泌出MMP-2與MMP-9。而MMP-2與MMP-9也被證實，會調控神經細胞的能動性，並和中樞神經系統的傷害與神經退化性疾病有關。鎘是個由現代工業所產生的重金屬污染物，在許多研究指出會造成神經毒性，並與中樞神經系統中一些神經退化性疾病的形成有關。在先前本實驗室研究發現，當處理的氯化鎘濃度超過20 M，會經由活性氧族群而非凋亡蛋白酵素 (caspase-3) 路徑，引起星狀膠質細胞死亡。在本實驗發現處理低於10 M的氯化鎘24小時後，會造成星狀膠質細胞MMP-2與MMP-9活性下降。而即使移除氯化鎘，抑制的作用仍持續存在。利用反轉錄聚合酶鏈與定量聚合酶鏈分析指出，氯化鎘抑制MMP-2活性是經由抑制MMP-2的轉錄。再經由反轉錄聚合酶鏈的分析發現，MMP-9基因表現上升會隨著氯化鎘處理濃度而增加。近一步發現處理細胞內與胞外鈣離子螯合劑，可以抵除氯化鎘對於MMP-2與MMP-9活性的影響，而證實鎘抑制MMP-2與MMP-9的活性，與鎘引起鈣離子訊息有關 (Yang et al., 2007)。雖然氯化鎘不會顯著改變星狀膠質細胞主要型態，但會降低細胞突起的星狀化。而外加rhMMP-2能移除氯化鎘對於星狀膠質細胞突起星狀化的影響。接著我們也探討甲基汞與鉻對於星狀膠質細胞MMP-2與MMP-9活性的影響。發現鉻對於MMP-2與MMP-9只有輕微的影響，而處理甲基汞0.1、0.5、1 M會導致MMP-2活性上升但對於MMP-9則沒有影響。綜合上述，我們發現氯化鎘會透過所引起的鈣離子訊息抑制星狀膠質細胞MMP-2與MMP-9的活性，而降低細胞突起星狀化，因此可能導致星狀膠質細胞功能的損壞。而不同的重金屬可能透過不同的訊息路徑，調控星狀膠質細胞MMP-2與MMP-9的活性。

Matrix metalloproteinase (MMPs) can process virtually any component of the extracellular matrix (ECM), regulating essentially the cell’s microenvironment. In particular, it seems that MMPs play an intriguing role in program cell death, showing both apoptotic and anti-apoptotic action. MMPs affect cell survival and proliferation both positively and negatively by regulating survival signals generated by specific adhesive events. Astrocytes are the main source of MMPs among neural cells, can secrete MMP-2/MMP-9. The function of MMP-2 and MMP-9 is complex since they have been reported to involve neural cell motility/survival and CNS neurodegenerative diseases. Cadmium (Cd), a heavy metal generated by modern industry, has been reported to induce neurotoxicity, and Cd-induced injury is thought to be associated with CNS neurodegenerative disorders. The previous study from our laboratory has indicated that CdCl2 at the concentrations greater than 20 M induced astrocytic cell death via a caspase 3-independent/ROS-dependent pathway. In this study, we found that treatment of astrocytes with CdCl2 at the concentrations lower than 10 M for 24 h inhibited the activity of MMP-2 and MMP-9. Moreover, this inhibition sustained after CdCl2 removal. RT-PCR and Q-PCR analysis indicated that Cd-induced reduction in MMP-2 activity was resulted from the downregulation of MMP-2 transcription by CdCl2. Interestingly, RT-PCR indicated that MMP-9 mRNA expression was significantly increased by CdCl2 in a dose-dependent manner. Nevertheless, the inhibition of MMP-2/MMP-9 activity was involved in Cd-induced Ca2+ signaling pathway (Yang et al., 2007), because the addition of calcium chelators (EGTA and BAPTA-AM) abolished Cd effect on the MMP-2/MMP-9 activity. Although there was no significant change in the main body shape of astrocytes after CdCl2 treatment, less stellation was observed in Cd-treated astrocytes. We further found that Cd effect on astrocytic stellation was blocked by the addition of rhMMP-2. We also examined the effect of chromium and methylmercury on astrocytic MMP-2/MMP-9 activity. Chromium only slightly affected the MMP-2 activity in astrocytes. However, methylmercury at the concentrations (0.1, 0.5 and 1.0 M) which did not induce astrocytic toxicity increased MMP-2 activity, but had no effect on MMP-9 activity. In summary, our findings demonstrate that Cd-induced Ca2+ signaling contributes to the inhibition of astrocytic MMP-2/MMP-9 activity, and in turn reduces in astrocytic stellation which may impair astrocytic function. Moreover, distinct heavy metals have different effects on astrocytic MMP-2/MMP-9 activity, possibly due to distinctive cellular signaling pathways.

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