Efficacy and mechanism of action of KHBJ-9B, a new herbal medicine, and its major compound triterpenoids in human cartilage culture and in a rabbit model of collagenase-induced osteoarthritis
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- 作者：Jeong-Eun Huh ; Yong-Hyeon Baek ; Seong-Ryong Ryu ; Jae-Dong Lee ; Do-Young Choi ; Dong-Suk Park
- 关键词：KHBJ-9B ; Triterpenoids ; Cartilage protection ; Anti-inflammation ; Osteoarthritis
- 刊名：International Immunopharmacology
- 出版年：2009
- 出版时间：February 2009
- 年：2009
- 卷：9
- 期：2
- 页码：230-240
- 全文大小：1364 K
文摘
KHBJ-9B has been formulated by n-butanol fraction from 2 herbs known to have cartilage protection and anti-inflammatory effects. We elected to determine the osteoarthritic efficacy and mechanism of KHBJ-9B on human osteoarthritis cartilage explants culture and in a rabbit model of collagenase-induced osteoarthritis (CIA). The major chemical composition and quantification of KHBJ-9B was determined by high performance liquid chromatography. The efficacy of KHBJ-9B and its major compounds on cartilage protective effects such as inhibition of GAG release and type II collagen degradation, and their cytotoxicity in IL-1β-treated human cartilage culture were examined. The mechanism of action of KHBJ-9B and its major compounds were evaluated by measuring inflammatory cytokines (IL-1β and TNF-α) and matrix proteinases (ADAMTS-4, ADAMTS-5, MMP-1, MMP-13 and TIMP-3) in IL-1β-treated human cartilage cultures. Also, the therapeutic effect of KHBJ-9B was confirmed using a collagenase-induced osteoarthritis (CIA) rabbit model. KHBJ-9B and 3 combined triterpenoids potently inhibited the release of proteoglycan and type II collagen in a dose dependent manner without cytotoxicity in IL-1β-treated human cartilage explants culture, whereas its single major compounds (betulin, pimaradienoic acid and betulinic acid) and COX-2 inhibitor (NS398) showed little inhibition even at high concentrations. KHBJ-9B and the combination of 3 triterpenoids markedly inhibited the level of IL-1β and TNF-α, and down-regulated the level of aggrecanases, ADAMTS-4, ADAMTS-5, MMP-1 and MMP-13, and up-regulated TIMP-3 in human cartilage explants culture. However, standard compounds and NS398 do not much affect the level of TNF-α, aggrecanases, and TIMP-3 in cartilage explants culture. In in vivo studies, KHBJ-9B significantly suppressed the stiffness level and global histologic score. Cartilage loss was significantly inhibited in the knee joint in a dose dependent manner, and this was associated with the finding that loss of proteoglycan, degradation of aggrecan and type II collagen was markedly reduced. These results suggest that the effect of KHBJ-9B is bigger than the effects of its single major compounds of triterpenoids or celecoxib inhibitors on cartilage protection and anti-inflammation in human cartilage and in in vivo model of osteoarthritis, and thus has potential for use in osteoarthritis treatment.