Deletion of the PH-domain and Leucine-rich Repeat Protein Phosphatase 1 (Phlpp1) Increases Fibroblast Growth Factor (Fgf) 18 Expression and Promotes Chondrocyte Proliferation

Background: Phlpp1 is a tumor suppressor that represses Akt2 and other signaling pathways. Results: Chondrocyte proliferation, matrix production, Akt2 phosphorylation, and Fgf18/Erk1/2 signaling were increased in Phlpp1(-/-) mice, but levels of the transcription factor FoxO1 were reduced. Conclusion: Phlpp1 deficiency increases Akt2 activity, which diminishes FoxO1 levels and induces Fgf18 expression to stimulate Erk1/2 activity and chondrocyte proliferation. Significance: Phlpp1 inhibition may promote cartilage regeneration. Endochondral ossification orchestrates formation of the vertebrate skeleton and is often induced during disease and repair processes of the musculoskeletal system. Here we show that the protein phosphatase Phlpp1 regulates endochondral ossification. Phlpp1 null mice exhibit decreased bone mass and notable changes in the growth plate, including increased BrdU incorporation and matrix production. Phosphorylation of known Phlpp1 substrates, Akt2, PKC, and p70 S6 kinase, were enhanced in ex vivo cultured Phlpp1(-/-) chondrocytes. Furthermore, Phlpp1 deficiency diminished FoxO1 levels leading to increased expression of Fgf18, Mek/Erk activity, and chondrocyte metabolic activity. Phlpp inhibitors also increased matrix content, Fgf18 production and Erk1/2 phosphorylation. Chemical inhibition of Fgfr-signaling abrogated elevated Erk1/2 phosphorylation and metabolic activity in Phlpp1-null cultures. These results demonstrate that Phlpp1 controls chondrogenesis via multiple mechanisms and that Phlpp1 inhibition could be a strategy to promote cartilage regeneration and repair.