Esser R E, Angelo R A, Murphey M D, Watts L M, Thornburg L P, Palmer J T, Talhouk J W, Smith R E
Marion Merrell Dow Research Institute, Kansas City, Missouri.
Arthritis Rheum. 1994 Feb;37(2):236-47. doi: 10.1002/art.1780370213.
To determine the effects of peptidyl fluoromethyl ketones on the in vitro activity of purified cathepsins B and L, on tissue cysteine proteinase activity, and on cartilage and bone destruction in experimental arthritis.
The effects of the fluoroketones on cathepsins B and L in vitro and the effects of oral administration of fluoroketones on ex vivo cysteine proteinase activity in tissue homogenates were determined by measuring the inhibition of fluorogenic substrate cleavage. To determine the effects on arthritis, animals were injected with adjuvant or type II collagen, treated orally with the fluoroketones, and the severity of arthritis was assessed by clinical, histologic, and radiologic methods.
All of the fluoroketones tested were potent inhibitors of purified cathepsins B and L activity. Oral administration of the fluoroketones reduced tissue cysteine proteinase activity by up to 77%. In addition, fluoroketone treatment significantly reduced the severity of clinical joint disease and decreased the destruction of articular cartilage and bone. Quantitative analysis of radiographic images indicated that treatment significantly reduced soft tissue changes, periosteal proliferation, and bone erosion, but only partially reduced juxtaarticular osteoporosis.
These studies suggest that cysteine proteinase inhibitors may limit tissue destruction in diseases such as rheumatoid arthritis.
确定肽基氟甲基酮对纯化的组织蛋白酶B和L的体外活性、组织半胱氨酸蛋白酶活性以及实验性关节炎中软骨和骨破坏的影响。
通过测量对荧光底物裂解的抑制作用，确定氟酮对组织蛋白酶B和L的体外作用以及口服氟酮对组织匀浆中离体半胱氨酸蛋白酶活性的影响。为了确定对关节炎的影响，给动物注射佐剂或II型胶原，口服氟酮进行治疗，并通过临床、组织学和放射学方法评估关节炎的严重程度。
所有测试的氟酮都是纯化的组织蛋白酶B和L活性的有效抑制剂。口服氟酮可使组织半胱氨酸蛋白酶活性降低多达77%。此外，氟酮治疗显著降低了临床关节疾病的严重程度，并减少了关节软骨和骨的破坏。放射图像的定量分析表明，治疗显著减少了软组织变化、骨膜增生和骨侵蚀，但仅部分减少了关节周围骨质疏松。
这些研究表明，半胱氨酸蛋白酶抑制剂可能会限制类风湿性关节炎等疾病中的组织破坏。
