Inhibition of Phlpp1 preserves the mechanical integrity of articular cartilage in a murine model of post-traumatic osteoarthritis

Abstract

ObjectivePhlpp1 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. MethodsOsteoarthritis 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 intraarticularly injected four weeks after injury. ResultsMale 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 timepoint. 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 2MPa to 1MPa 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. ConclusionsAFM 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.