title: Inactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnormalities and skeletal overgrowth.
abstract: To study the role of the Pten tumor suppressor in skeletogenesis, we generated mice lacking this key phosphatidylinositol 3'-kinase pathway regulator in their osteo-chondroprogenitors. A phenotype of growth plate dysfunction and skeletal overgrowth was observed.
  
  
  BACKGROUND
  Skeletogenesis is a complex process relying on a variety of ligands that activate a range of intracellular signal transduction pathways. Although many of these stimuli are known to activate phosphatidylinositol 3'-kinase (PI3K), the function of this pathway during cartilage development remains nebulous. To study the role of PI3K during skeletogenesis, we used mice deficient in a negative regulator of PI3K signaling, the tumor suppressor, Pten.
  
  
  METHODS
  Pten gene deletion in osteo-chondrodroprogenitors was obtained by interbreeding mice with loxP-flanked Pten exons with mice expressing the Cre recombinase under the control of the type II collagen gene promoter (Pten(flox/flox):Col2a1Cre mice). Phenotypic analyses included microcomputed tomography and immunohistochemistry techniques.
  
  
  RESULTS
  MicroCT revealed that Pten(flox/flox):Col2a1Cre mice exhibited both increased skeletal size, particularly of vertebrae, and massive trabeculation accompanied by increased cortical thickness. Primary spongiosa development and perichondrial bone collar formation were prominent in Pten(flox/flox):Col2a1Cre mice, and long bone growth plates were disorganized and showed both matrix overproduction and evidence of accelerated hypertrophic differentiation (indicated by an altered pattern of type X collagen and alkaline phosphatase expression). Consistent with increased PI3K signaling, Pten-deficient chondrocytes showed increased phospho-PKB/Akt and phospho-S6 immunostaining, reflective of increased mTOR and PDK1 activity. Interestingly, no significant change in growth plate proliferation was seen in Pten-deficient mice, and growth plate fusion was found at 6 months.
  
  
  CONCLUSIONS
  By virtue of its ability to modulate a key signal transduction pathway responsible for integrating multiple stimuli, Pten represents an important regulator of both skeletal size and bone architecture.
authors: Department of Biochemistry and Molecular Biology, Alberta Bone and Joint Health Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Alice Fiona
authors: AF
authors: Ford-Hutchinson
authors: Zenobia
authors: Z
authors: Ali
authors: Suzen Elizabeth
authors: SE
authors: Lines
authors: Benedikt
authors: B
authors: Hallgrímsson
authors: Steven Kyle
authors: SK
authors: Boyd
authors: Frank Robert
authors: FR
authors: Jirik
mesh_terms: D000818:Animals; D017209:Apoptosis; D001842:Bone and Bones / Q000002:abnormalities / Q000201:enzymology*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism*; D024043:Collagen Type II / Q000235:genetics; D004789:Enzyme Activation; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D006132:Growth Plate / Q000002:abnormalities / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D024043:Collagen Type II; D051059:PTEN Phosphohydrolase