Nordic Bioscience Biomarkers and Research, Herlev Hovedgade 207, Herlev, DK-2730, Denmark.
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Arthritis Res Ther. 2024 Jul 12;26(1):129. doi: 10.1186/s13075-024-03361-2.
Despite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats.
We evaluated KBP-336's effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology.
After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues.
Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.
尽管有大量研究致力于提供一种治疗骨关节炎的药物（DMOAD），但目前仍没有被批准的 DMOAD。双重淀粉样蛋白和降钙素受体激动剂（DACRA）可提供代谢益处，同时具有抗伤害感受和潜在的结构保护作用。在这些研究中，我们测试了一种名为 KBP-336 的 DACRA 在半月板切除（MNX）大鼠的代谢性骨关节炎模型中的效果。
我们使用 von Frey 测试来评估 KBP-336 对高脂肪饮食（HFD）下接受半月板切除术的 Sprague Dawley（SD）大鼠的疼痛样症状的影响，以测量 50%的足底退缩阈值（PWT），并使用单因素方差分析进行分析。短期体内研究和体外细胞受体表达系统用于说明受体药理学。
在 HFD 喂养 30 周，包括 8 周治疗后，接受 KBP-336 4.5 nmol/Kg/72 h 治疗的雌性 MNX 动物的体重和脂肪组织比接受载体治疗的动物小。在 HFD 喂养 20 周，包括 8 周治疗后，接受 KBP-336 治疗的雄性大鼠的体重低于载体组。在雌性和雄性大鼠中，接受 KBP-336 治疗的 MNX 组的 PWT 均高于接受载体治疗的 MNX 组。为了确定影响疼痛缓解的受体，将 KBP-336 与长效人降钙素（hCTA）进行了比较。对 12 周龄雄性大鼠进行的单次剂量研究表明，hCTA 降低 CTX-I 而不影响食物摄入，证实了其降钙素受体选择性。在 18 周 HFD 的代谢性 OA 模型中，包括 6 周治疗，与接受载体治疗的 MNX 动物相比，hCTA 100 nmol/Kg/24 h 和 KBP-336 0.5、1.5 和 4.5 nmol/Kg/72 h 在 MNX 动物中产生了显著更高的 PWT。hCTA 和 KBP-336 的 0.5 nmol/Kg 体重不影响体重和脂肪组织。
总体而言，KBP-336 改善了代谢性 OA 模型中观察到的疼痛。降钙素受体激活被证明是这种抗伤害感受作用的关键。
