Medivir AB, Box 1086, 141 22, Huddinge, Sweden.
Bolder BioPATH Inc, Boulder, CO, USA.
J Transl Med. 2018 Mar 9;16(1):56. doi: 10.1186/s12967-018-1425-7.
MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA).
Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured.
In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55-57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25-37% lower macroscopic scores in the femur condyles and 13-33% lower macroscopic scores in the tibial plateaus.
MIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA.
MIV-711 是一种高效且选择性的组织蛋白酶 K 抑制剂。本文总结了 MIV-711 对前交叉韧带切断（ACLT）兔关节病理学的治疗作用，以及对部分内侧半月板切除术犬关节病理学的预防作用，这两种模型都是骨关节炎（OA）。
手术后 1 周开始，兔子通过口服灌胃每天接受 MIV-711 或载体（每组 n = 7）治疗 7 周。四个治疗组分别为：（1）假手术+载体；（2）ACLT+载体；（3）ACLT+MIV-711，30µmol/kg 和（4）ACLT+MIV-711，100µmol/kg。通过 µCT、组织形态计量学和评分评估软骨下骨和关节软骨结构。接受部分内侧半月板切除术的狗通过口服灌胃每天接受 MIV-711（30µmol/kg）或载体（每组 n = 15）治疗，从半月板切除术前 1 天开始，共 28 天。在宏观和微观水平上评估软骨降解。在两项研究中评估了 MIV-711 的暴露情况，并测量了反映骨吸收（兔子中的 HP-1，狗中的 CTX-I）和软骨降解（CTX-II）的生物标志物。
在 ACLT 兔中，与 ACLT 载体对照组相比，MIV-711 降低了高达 72%（p<0.001）的 HP-1 水平和高达 74%（p<0.001）的 CTX-II 水平。ACLT 手术显著降低了软骨下骨板的总厚度，并减少了股骨和胫骨的小梁骨体积。这些作用被 MIV-711 逆转。ACLT 导致软骨增厚，MIV-711 减轻了这种增厚。MIV-711 不影响骨赘形成或 Mankin 评分。在狗中，MIV-711 降低了 CTX-I 和 CTX-II 水平 86%（p<0.001）和 80%（p<0.001）。与基线相比，滑液 CTX-II 水平降低了 55-57%（p<0.001）。MIV-711 治疗的动物在股骨髁上的宏观评分降低了 25-37%，在胫骨平台上的宏观评分降低了 13-33%。
MIV-711 可预防软骨下骨丢失，并部分减轻两种 OA 动物模型中的软骨病理学。在这些关节病理学的有益作用与已显示在临床上可达到的骨和软骨生物标志物的减少有关。数据支持进一步开发 MIV-711 用于治疗 OA。
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