组织蛋白酶K抑制剂ONO-5334及ONO-5334与甲氨蝶呤合用对食蟹猴胶原性关节炎的影响

IF 2.3 Q2 RHEUMATOLOGY International Journal of Rheumatology Pub Date : 2019-02-17 eCollection Date: 2019-01-01 DOI:10.1155/2019/5710340
Hiroyuki Yamada, Hiroshi Mori, Yasutomo Nakanishi, Satoshi Nishikawa, Yasuaki Hashimoto, Yasuo Ochi, Makoto Tanaka, Kazuhito Kawabata
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引用次数: 10

摘要

我们研究了组织蛋白酶K抑制剂ONO-5334单独或与甲氨蝶呤(MTX)联合使用是否可以改善雌性食蟹猴胶原诱导关节炎(CIA)引起的关节破坏。用牛ⅱ型胶原免疫诱导CIA。ONO-5334 (30 mg/kg/天)每日口服一次,MTX (10 mg/体/天)每周两次,共9周。评估近端指间关节(PIP)、远端指间关节(DIP)和掌指关节(MP)的x线(关节破坏评估)和肿胀(炎症)评分。测定尿中I型胶原(CTX-I)和II型胶原(CTX-II) c末端末端肽的浓度。在这种胶原诱导的关节炎猴子模型中,成功地诱导了伴有骨和软骨破坏的关节炎。ONO-5334对关节肿胀无抑制作用,而与对照组相比,MTX和联合用药(ONO-5334 + MTX)组关节肿胀评分均小于50%。ONO-5334使x线评分平均降低64% (p
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Effects of the Cathepsin K Inhibitor ONO-5334 and Concomitant Use of ONO-5334 with Methotrexate on Collagen-Induced Arthritis in Cynomolgus Monkeys.

We examined whether the cathepsin K inhibitor, ONO-5334, administered alone or in combination with methotrexate (MTX), could ameliorate joint destruction evoked by collagen-induced arthritis (CIA) in female cynomolgus monkeys. CIA was induced by immunizing with bovine type II collagen. ONO-5334 (30 mg/kg/day) was orally administered once daily and MTX (10 mg/body/day) twice weekly for 9 weeks. X-ray (evaluation of joint destruction) and swelling (inflammatory) scores of proximal interphalangeal (PIP), distal interphalangeal (DIP), and metacarpophalangeal (MP) joints were evaluated. Urinary concentrations of C-terminal telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) were measured. Arthritis, accompanied by bone and cartilage destruction, was successfully induced in this collagen-induced arthritis monkey model. ONO-5334 showed no suppressive effect on joint swelling, while the joint swelling scores in the MTX and combination (ONO-5334 + MTX) groups were less than 50% compared with the control group. ONO-5334 decreased X-ray score by a mean of 64% (p<0.05 vs the control group), and MTX also decreased in X-ray score by a mean of 46% but with no statistical significance. Combination of ONO-5334 and MTX further decreased the X-ray score by 28% over MTX group (74% reduction vs the control group, p<0.01). Maximum increase in CTX-I (10-fold) and CTX-II (7-fold) compared to baseline was observed at 7 and 3 weeks after the first sensitization, respectively. After treatment with ONO-5334 alone or in combination with MTX, concentrations were maintained near baseline for both markers. In conclusion, ONO-5334 prevented joint destruction but not joint inflammation in this monkey CIA model. Concomitant use of ONO-5334 with MTX reduced architectural joint destruction compared to MTX alone; therefore, ONO-5334 may help to prevent joint destruction in combination with MTX for the treatment of rheumatoid arthritis.

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来源期刊
CiteScore
4.40
自引率
0.00%
发文量
9
审稿时长
24 weeks
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