Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
Osteoarthritis Cartilage. 2024 Jun;32(6):680-689. doi: 10.1016/j.joca.2024.01.008. Epub 2024 Mar 1.
Phlpp1 inhibition is a potential therapeutic strategy for cartilage regeneration and prevention of post-traumatic osteoarthritis (PTOA). To understand how Phlpp1 loss affects cartilage structure, cartilage elastic modulus was measured with atomic force microscopy (AFM) in male and female mice after injury.
Osteoarthritis was induced in male and female Wildtype (WT) and Phlpp1 mice by destabilization of the medial meniscus (DMM). At various timepoints post-injury, activity was measured, and knee joints examined with AFM and histology. In another cohort of WT mice, the PHLPP inhibitor NSC117079 was intra-articularly injected 4 weeks after injury.
Male WT mice showed decreased activity and histological signs of cartilage damage at 12 but not 6-weeks post-DMM. Female mice showed a less severe response to DMM by comparison, with no histological changes seen at any time point. In both sexes the elastic modulus of medial condylar cartilage was decreased in WT mice but not Phlpp1 mice after DMM as measured by AFM. By 6-weeks, cartilage modulus had decreased from 2 MPa to 1 MPa in WT mice. Phlpp1 mice showed no change in modulus at 6-weeks and only a 25% decrease at 12-weeks. The PHLPP inhibitor NSC117079 protected cartilage structure and prevented signs of OA 6-weeks post-injury.
AFM is a sensitive method for detecting early changes in articular cartilage post-injury. Phlpp1 suppression, either through genetic deletion or pharmacological inhibition, protects cartilage degradation in a model of PTOA, validating Phlpp1 as a therapeutic target for PTOA.
Phlpp1 抑制是软骨再生和预防创伤后骨关节炎（PTOA）的潜在治疗策略。为了了解 Phlpp1 缺失如何影响软骨结构，我们使用原子力显微镜（AFM）测量了雄性和雌性小鼠受伤后的软骨弹性模量。
通过内侧半月板不稳定（DMM）在雄性和雌性野生型（WT）和 Phlpp1 小鼠中诱导骨关节炎。在受伤后不同时间点测量活动度，并使用 AFM 和组织学检查膝关节。在另一批 WT 小鼠中，在受伤后 4 周关节内注射 PHLPP 抑制剂 NSC117079。
雄性 WT 小鼠在 DMM 后 12 周而非 6 周时活动减少，且有软骨损伤的组织学迹象。相比之下，雌性小鼠对 DMM 的反应较轻，在任何时间点均未见组织学变化。在两性中，DMM 后 WT 小鼠内侧髁软骨的弹性模量均降低，但 Phlpp1 小鼠则没有。6 周时，WT 小鼠的软骨模量从 2 MPa 降至 1 MPa。Phlpp1 小鼠在 6 周时模量没有变化，仅在 12 周时降低了 25%。PHLPP 抑制剂 NSC117079 保护软骨结构并预防受伤后 6 周的 OA 迹象。
AFM 是一种检测受伤后关节软骨早期变化的敏感方法。Phlpp1 抑制，无论是通过基因缺失还是药物抑制，都能保护 PTOA 模型中的软骨降解，验证了 Phlpp1 是 PTOA 的治疗靶点。
