摘要：目的：组织蛋白酶K表达于破骨细胞和滑膜成纤维细胞，并降解骨和软骨组织的关键组分。抑制组织蛋白酶K活性可能有益于预防类风湿关节炎(RA)的骨侵蚀和软骨退化。胶原诱导的关节炎(CIA)大鼠模型已成熟用于研究RA的病理学和治疗。我们研究了ONO-KK1-300-01(组织蛋白酶K抑制剂，CKI)对CIA大鼠关节炎和骨密度(BMD)的影响。

方法：将7月龄雌性Sprague Dawley大鼠分成5组：非CIA大鼠(CNT);接受卵巢切除术(OVX)并经CKI处理的CIA大鼠;接受OVX并用载体(Veh)治疗的CIA大鼠;接受假手术并经CKI处理的CIA大鼠;接受假手术并接受Veh治疗的CIA大鼠。CKI以15mg/kg的剂量口服给药，从而引发胶原蛋白致敏，直至4周死亡。我们每周评估后爪厚度和关节炎评分直至大鼠死亡。用软X射线获得切除的左腿的放射线片。如先前Engelhardt等人所述，对骨和软骨的破坏进行分类和评分。采用骨密度测定法测定远干骺端与切除的右股骨骨干之间中点的骨密度。我们还进行了近端左胫骨组织形态测量、关节炎的组织学评估和骨强度测试。

结果：CKI给药后显著减少后爪厚度和关节炎评分，并防止骨密度减低。对比Veh组，CKI组的放射学评分显著下降。在组织形态分析中，CKI组的骨吸收参数显著低于Veh组。CKI显著抑制CIA大鼠的滑膜增生。骨强度测试方面，CKI组的极限应力显著强于Veh组。

结论：我们的研究结果表面在关节炎动物模型中，组织蛋白酶K抑制物可能抑制全身及局部骨丢失、改善关节炎并及减轻骨强度的降低。

附原文：Objectives:Cathepsin K is expressed by osteoclasts and synovial fibroblasts and degrades key components of bone and cartilage. Inhibition of cathepsin K protease activity may be beneficial for the prevention of bone erosion and cartilage degradation in rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) rat model is well established for studying the pathology and treatment of RA. We investigated the effect of ONO-KK1-300-01, a cathepsin K inhibitor (CKI), on arthritis and bone mineral density (BMD) in rats with CIA.Methods:Seven-month-old female Sprague Dawley rats were divided into 5 groups: rats without CIA (CNT); CIA rats that underwent ovariectomy (OVX) and were treated with CKI; CIA rats that underwent OVX and were treated with vehicle (Veh); CIA rats that underwent sham surgery and were treated with CKI; and CIA rats that underwent sham surgery and were treated with Veh. CKI was orally administered at a dose of 15 mg/kg, thus initiating collagen sensitization, until death at 4 weeks. We evaluated hind paw thickness and the arthritis score every week until death. Radiographs of the resected left foot were obtained with a soft X-ray apparatus. Destruction of bone and cartilage was classified and scored as previously described by Engelhardt et al. BMD was measured by bone densitometry at the halfway point between the distal metaphysis and the diaphysis of the resected right femur. We also performed histomorphometry of the proximal left tibia, histological evaluation of arthritis, and a bone strength test.Results:CKI administration significantly reduced hind paw thickness and the arthritis score, and prevented a decrease in BMD. The radiographic score was significantly lower in the CKI group than in the Veh group. In the histomorphometric analysis, bone-resorption parameters were significantly lower in the CKI groups than in the Veh groups. CKI significantly inhibited synovial proliferation in the CIA rats. In the bone strength test, the ultimate stress was significantly higher in the CKI groups than in the Veh groups.Conclusion:Our findings indicate that cathepsin K inhibitors may inhibit systemic and local bone loss, ameliorate arthritis, and attenuate the decrease of bone strength in an animal model of arthritis.

摘自：Yamashita T, Hagino H, Hayashi Iet al. Effect of a cathepsin K inhibitor on arthritis and bone mineral density in ovariectomized rats with collagen-induced arthritis.Bone Rep. 2018 May 30;9:1-10. doi: 10.1016/j.bonr.2018.05.006. eCollection 2018 Dec.