title: Deletion of the PH-domain and Leucine-rich Repeat Protein Phosphatase 1 (Phlpp1) Increases Fibroblast Growth Factor (Fgf) 18 Expression and Promotes Chondrocyte Proliferation.
abstract: 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.
authors.affiliation: From the Department of Orthopedic Surgery.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Bradley
authors.affiliation: Mayo Graduate School.
authors.forename: Lomeli R
authors.initials: LR
authors.lastname: Carpio
authors.affiliation: the Department of Pharmacology, University of California, San Diego, La Jolla, California 92093.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
authors.affiliation: From the Department of Orthopedic Surgery, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905 and westendorf.jennifer@mayo.edu.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
mesh_terms: D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009687:Nuclear Proteins; C113569:fibroblast growth factor 18; D005346:Fibroblast Growth Factors; D051057:Proto-Oncogene Proteins c-akt; C519282:PHLPP1 protein, mouse; D010749:Phosphoprotein Phosphatases
keywords: Akt PKB; FOXO; cartilage; fibroblast growth factor (FGF); fibroblast growth factor receptor (FGFR); osteoarthritis