“PHLPP Phosphatases and Injury-Induced Osteoarthritis”

We identified Phlpp phosphatases as modifiable targets for cartilage regeneration and joint
pain. Phlpp1 and Phlpp2 are abnormally expressed in human OA cartilage. We have shown that Phlpp1 knockout (KO) mice are protected from cartilage degradation and pain-related behaviors (allodynia and reduced mobility) after surgery that destabilizes the medial meniscus (DMM), but mice where Phlpp1 is conditionally depleted in just aggrecan (Agc)-expressing cells (Phlpp1 CKOAgc) are only protected from cartilage degradation, not reduced mobility. These results indicate an intrinsic role for Phlpp1 in chondrocytes, as well as a role for Phlpp1/2 in other tissues or cells within articulating joints.
Of interest, small molecule inhibitors of Phlpp1 and Phlpp2 further slow cartilage degradation in Phlpp1 CKOAgc mice and increase mobility. Phlpp1/2 inhibitors also stimulate chondrocyte proliferation and matrix production and prevent neurite outgrowth and expression of sensory neuron genes in vitro and in vivo. Together these data indicate that Phlpp1/2 activity in multiple cell types/tissues within articulating joints contributes to OA pathogenesis and that Phlpp2 may contribute to OA phenotypes by compensating for Phlpp1 deficiency in cartilage and/or by regulating joint innervation and pain-related behaviors. In this presentation, I will discuss these finding and present new information on how Phlpp1 and Phlpp2 modulate cartilage quantity and quality (i.e. stiffness) and how Phlpp1/2 inactivation contributes to injury-induced innervation.