應用乙醯胺基葡萄糖水解酶抑制劑減緩退化性關節炎中醣胺多醣之降解

Abstract

退化性關節炎是一種常見的關節病變，其主要病症為關節軟骨組織中的胞外間質被不正常代謝降解，有報導指出在退化性關節炎病人的軟骨組織中，大量的乙醯胺基葡萄糖水解酶會被釋放到細胞外，進而可能降解胞外間質的主成分－醣胺多醣。本實驗室近年來開發出具有高度選擇性的乙醯胺基葡萄糖水解酶抑制劑(三號及四號化合物，Ki值分別為1.2 nM及0.69 nM)，在此研究中，將檢測其在退化性關節炎中減緩醣胺多糖降解的能力。研究結果顯示，在軟骨肉瘤細胞及事先給予發炎刺激的軟骨細胞中投以三號或四號化合物，都能夠有效增加細胞表面醣胺多醣的含量，對於從退化性關節炎病人身上分離得到之病變軟骨細胞給予200 nM三號化合物平均能夠提升三成之細胞表面醣胺多醣含量；除此之外，此二化合物經過證實也在細胞實驗中，對於乙醯胺基葡萄糖水解酶的相似酵素－葡萄胺醣水解酶，具有大於一千八百倍以上之選擇性，可減少用於治療時副作用發生的可能性。本研究成果提供了開發減緩退化性關節炎症狀之藥物的新方向。

Osteoarthritis (OA) is characterized by the degeneration of extracellular matrix glycosaminoglycans (GAGs) in articular cartilage. N-Acetyl-β-D-hexosaminidase (Hex) is reported to be the dominant GAG-degrading glycosidase released by chondrocytes in the synovial fluid of OA patients. On the basis of our previous study, discovery of potent and selective Hex inhibitors (compound 3, Ki = 1.2 nM ; compound 4, Ki = 0.69 nM), herein we demonstrated the levels of cell-associated GAGs to be significantly enhanced by addition of compound 3 or 4 in either human chondrosarcoma cells or IL-1β-treated human chondrocytes. Treatment of 200 nM compound 3 to chondrocytes from patients with OA increased 30% cell-associated GAGs in average. Moreover, the same compounds exhibited more than 1,800-fold higher in vivo selectivity for Hex than for O-GlcNAcase. The efficacy and selectivity of compound 3 and 4 support further investigations in the therapeutic development of OA.