ABSTRACT Osteoarthritis (OA) is a chronically painful condition and a leading cause of disability around the world. OA is characterized by articular cartilage deterioration and other joint pathologies including meniscus and ligament damage, synovitis, bone spurs and joint pain. None of the currently approved treatments alter disease progression by slowing articular cartilage degradation or repairing damage to joint tissues. We identified Phlpp phosphatases as modifiable targets for cartilage regeneration and joint pain. Phlpp1 and Phlpp2 are abnormally expressed in human OA cartilage. 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. The overall goals of this project are to define how Phlpp1 and Phlpp2 modulate cartilage quantity and quality (i.e. stiffness) and how Phlpp1/2 inactivation contributes to injury-induced innervation. The specific aims are to: 1) Elucidate the roles of Phlpp1 and Phlpp2 in articular chondrocytes following a joint injury, 2) Determine how Phlpp1 and Phlpp2 affect biomechanical and structural properties of articular cartilage and other joint tissues after injury and throughout aging, and 3) Define activities of Phlpp1/2 in sensory neurons and OA-associated pain behaviors. These studies will provide new information about the relationship between joint damage, joint innervation and pain. Such insights will enable the development of much needed disease- modifying drugs for osteoarthritis.