Hwang Soyun M, Feigenson Marina, Begun Dana L, Shull Lomeli Carpio, Culley Kirsty L, Otero Miguel, Goldring Mary B, Ta Lauren E, Kakar Sanjeev, Bradley Elizabeth W, Westendorf Jennifer J
Mayo Clinic School of Medicine, Mayo Clinic, Rochester, MN 55905.
Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905.
J Orthop Res. 2018 May;36(5):1487-1497. doi: 10.1002/jor.23781. Epub 2017 Nov 28.
Phlpp protein phosphatases are abnormally abundant within human osteoarthritic articular chondrocytes and may contribute to the development of osteoarthritis. Mice lacking Phlpp1 were previously shown to be resistant to post-traumatic osteoarthritis. Here a small molecule with therapeutic properties that inhibits Phlpp1 and Phlpp2 was tested for its ability to slow post-traumatic OA in mice and to stimulate anabolic pathways in human articular cartilage from OA joints. PTOA was induced in male C57Bl/6 mice by surgically destabilizing the meniscus. Seven weeks after surgery, mice received a single intra-articular injection of the Phlpp inhibitor NSC117079 or saline. Mechanical allodynia was measured with von Frey assays, mobility was tracked in an open field system, and cartilage damage was assessed histologically. A single intra-articular injection of the Phlpp inhibitor NSC117079 attenuated mechanical allodynia and slowed articular cartilage degradation in joints with a destabilized meniscus. Animals treated with the Phlpp inhibitor 7 weeks after injury maintained normal activity levels, while those in the control group traveled shorter distances and were less active 3 months after the joint injury. NSC117079 also increased production of cartilage extracellular matrix components (glycosaminoglycans and aggrecan) in over 90% of human articular cartilage explants from OA patients and increased phosphorylation of Phlpp1 substrates (AKT2, ERK1/2, and PKC) in human articular chondrocytes. Our results indicate that Phlpp inhibitor NSC117079 is a novel osteoarthritis disease modifying drug candidate that may have palliative affects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1487-1497, 2018.
Phlpp蛋白磷酸酶在人类骨关节炎关节软骨细胞中异常丰富，可能促成骨关节炎的发展。先前已证明，缺乏Phlpp1的小鼠对创伤后骨关节炎具有抗性。在此，对一种具有治疗特性、可抑制Phlpp1和Phlpp2的小分子进行了测试，以检验其减缓小鼠创伤后骨关节炎以及刺激骨关节炎关节的人类关节软骨合成代谢途径的能力。通过手术破坏半月板，在雄性C57Bl/6小鼠中诱导创伤后骨关节炎（PTOA）。术后7周，小鼠接受一次关节内注射Phlpp抑制剂NSC117079或生理盐水。用von Frey试验测量机械性异常性疼痛，在旷场系统中追踪活动能力，并通过组织学评估软骨损伤情况。单次关节内注射Phlpp抑制剂NSC117079可减轻机械性异常性疼痛，并减缓半月板不稳定关节的关节软骨降解。受伤7周后接受Phlpp抑制剂治疗的动物保持正常活动水平，而对照组动物在关节损伤3个月后移动距离较短且活动较少。NSC117079还使超过90%的骨关节炎患者的人类关节软骨外植体中软骨细胞外基质成分（糖胺聚糖和聚集蛋白聚糖）的产量增加，并使人类关节软骨细胞中Phlpp1底物（AKT2、ERK1/2和PKC）的磷酸化增加。我们的结果表明，Phlpp抑制剂NSC117079是一种新型的骨关节炎病情改善药物候选物，可能具有缓解作用。© 2017骨科研究协会。由Wiley Periodicals, Inc.出版。《矫形外科学研究》36:1487 - 1497, 2018。
