Furan-2-carboxylic acid, a natural product isolated and purified from the herbs of Hexagonia speciosa with anti-bacterial effect, is also an orally active selective human cathepsin K inhibitor which may have the therapeutic potential for the treatment of diseases characterized by excessive bone loss including osteoporosis.
Cathepsin K is a cysteine proteinase regulating bone resorbing in osteoclasts. Furan-2-carboxylic acid is a selective inhibitor of human cathepsin K with an IC50 value of 11 nM, which is 39-fold more than against rat cathepsin K. Treatment of furan-2-carboxylic acid in rabbit unfractionated bone cells for 48 hours inhibited osteoclast-mediated release of C-telopeptide of type 1 collagen (CTx) in a concentration-dependent manner from 10 to 1000 nM. Furan-2-carboxylic acid suppressed bone resorption induced by rabbit osteoclasts with an IC50 value of 37 nM without affecting bone mineralization or the activity of cellular alkaline phosphatase in MC3T3-E1 cells. The inhibition of CTx release by furan-2-carboxylic acid was also observed in human PBMC-derived osteoclast-like cells with an IC50 value of 205 nM. Oral administration of furan-2-carboxylic acid significantly downregulated parathyroid hormone-induced bone resorption in thyroparathyroidectomized rats in a six-hour duration at dose-dependent manner from 10 to 100 mg/kg, which was indicated by the change of plasma concentration of calcium. Four-week oral treatment of 100 mg/kg furan-2-carboxylic acid twice daily completely inhibited ovariectomized-induced bone loss in 3-month-old rats as shown in bone densitometry, ash content, and urinary excretion of deoxypyridinoline.
作用机制
Furan-2-carboxylic acid selectively prevents bone resorbing activities of osteoclasts and estrogen deficiency-induced bone loss through the inhibition of cathepsin K activity.
搜索
