Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
Mayo Graduate School, Mayo Clinic, Rochester, MN 55905, USA.
Osteoarthritis Cartilage. 2016 Jun;24(6):1021-8. doi: 10.1016/j.joca.2015.12.014. Epub 2015 Dec 31.
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability. OA is characterized by articular chondrocyte deterioration, subchondral bone changes and debilitating pain. One strategy to promote cartilage regeneration and repair is to accelerate proliferation and matrix production of articular chondrocytes. We previously reported that the protein phosphatase Phlpp1 controls chondrocyte differentiation by regulating the activities of anabolic kinases. Here we examined the role of Phlpp1 in OA progression in a murine model. We also assessed PHLPP1 expression and promoter methylation.
Knee joints of WT and Phlpp1(-/-) mice were surgically destabilized by transection of the medial meniscal ligament (DMM). Mice were assessed for signs of OA progression via radiographic and histological analyses, and pain assessment for mechanical hypersensitivity using the von Frey assay. Methylation of the PHLPP1 promoter and PHLPP1 expression were evaluated in human articular cartilage and chondrocyte cell lines.
Following DMM surgeries, Phlpp1 deficient mice showed fewer signs of OA and cartilage degeneration. Mechanical allodynia associated with DMM surgeries was also attenuated in Phlpp1(-/-) mice. PHLPP1 was highly expressed in human articular cartilage from OA patients, but was undetectable in cartilage specimens from femoral neck fractures (FNFxs). Higher PHLPP1 levels correlated with less PHLPP1 promoter CpG methylation in cartilage from OA patients. Blocking cytosine methylation or treatment with inflammatory mediators enhanced PHLPP1 expression in human chondrocyte cell lines.
Phlpp1 deficiency protects against OA progression while CpG demethylation and inflammatory cytokines promote PHLPP1 expression.
骨关节炎（OA）是最常见的关节炎类型，也是导致残疾的主要原因。OA 的特征是关节软骨细胞恶化、软骨下骨改变和使人衰弱的疼痛。促进软骨再生和修复的一种策略是加速关节软骨细胞的增殖和基质产生。我们之前报道过，蛋白磷酸酶 Phlpp1 通过调节合成代谢激酶的活性来控制软骨细胞分化。在这里，我们在小鼠模型中研究了 Phlpp1 在 OA 进展中的作用。我们还评估了 PHLPP1 的表达和启动子甲基化。
通过切断内侧半月板韧带（DMM）对 WT 和 Phlpp1（-/-）小鼠的膝关节进行手术不稳定化。通过放射学和组织学分析评估 OA 进展的迹象，并通过 von Frey 测定法评估机械性超敏反应的疼痛评估。评估人关节软骨和软骨细胞系中 PHLPP1 启动子的甲基化和 PHLPP1 的表达。
在 DMM 手术后，Phlpp1 缺陷型小鼠表现出较少的 OA 和软骨退化迹象。与 DMM 手术相关的机械性痛觉过敏在 Phlpp1（-/-）小鼠中也减弱。PHLPP1 在 OA 患者的人关节软骨中表达较高，但在股骨颈骨折（FNFx）的软骨标本中无法检测到。较高的 PHLPP1 水平与 OA 患者软骨中 PHLPP1 启动子 CpG 甲基化程度较低相关。阻断胞嘧啶甲基化或用炎性介质处理可增强人软骨细胞系中 PHLPP1 的表达。
Phlpp1 缺乏可预防 OA 进展，而 CpG 去甲基化和炎性细胞因子可促进 PHLPP1 的表达。
