Inactivation of Pten in osteo-chondroprogenitor cells leads to epiphyseal growth plate abnormalities and skeletal overgrowth.

Abstract

UNLABELLED:

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 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: Alice Fiona Ford-Hutchinson, Zenobia Ali, Suzen Elizabeth Lines, Benedikt Hallgrímsson, Steven Kyle Boyd, Frank Robert Jirik
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 22 Issue 8 Pg. 1245-59 (Aug 2007) ISSN: 0884-0431 [Print] United States
• PMID: 17456009 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type II
• PTEN Phosphohydrolase

Topics

• Animals
• Apoptosis
• Bone and Bones (abnormalities, enzymology)
• Cell Differentiation
• Chondrocytes (cytology, metabolism)
• Collagen Type II (genetics)
• Enzyme Activation
• Gene Deletion
• Gene Expression Regulation, Enzymologic
• Growth Plate (abnormalities, enzymology)
• Mice
• Mice, Knockout
• Osteoblasts (cytology, enzymology)
• PTEN Phosphohydrolase (deficiency, genetics, metabolism)
• Promoter Regions, Genetic (genetics)