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Inactivation of Pten in Osteo‐Chondroprogenitor Cells Leads to Epiphyseal Growth Plate Abnormalities and Skeletal Overgrowth
Author(s) -
FordHutchinson Alice Fiona,
Ali Zenobia,
Lines Suzen Elizabeth,
Hallgrímsson Benedikt,
Boyd Steven Kyle,
Jirik Frank Robert
Publication year - 2007
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.070420
Subject(s) - pten , pi3k/akt/mtor pathway , biology , protein kinase b , signal transduction , microbiology and biotechnology , endocrinology , cancer research , medicine
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. Introduction: 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. Materials and Methods: Pten gene deletion in osteo‐chondrodroprogenitors was obtained by interbreeding mice with lox P‐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: μCT 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.