Forkhead box O transcription factors in chondrocytes regulate endochondral bone formation

J Steroid Biochem Mol Biol. 2016 Nov;164:337-343. doi: 10.1016/j.jsbmb.2015.07.015. Epub 2015 Jul 29.

Abstract

The differentiation of embryonic mesenchymal cells into chondrocytes and the subsequent formation of a cartilaginous scaffold that enables the formation of long bones are hallmarks of endochondral ossification. During this process, chondrocytes undergo a remarkable sequence of events involving proliferation, differentiation, hypertrophy and eventually apoptosis. Forkhead Box O (FoxO) transcription factors (TFs) are well-known regulators of such cellular processes. Although FoxO3a was previously shown to be regulated by 1,25-dihydroxyvitamin D3 in osteoblasts, a possible role for this family of TFs in chondrocytes during endochondral ossification remains largely unstudied. By crossing Collagen2-Cre mice with FoxO1lox/lox;FoxO3alox/lox;FoxO4lox/lox mice, we generated mice in which the three main FoxO isoforms were deleted in growth plate chondrocytes (chondrocyte triple knock-out; CTKO). Intriguingly, CTKO neonates showed a distinct elongation of the hypertrophic zone of the growth plate. CTKO mice had increased overall body and tail length at eight weeks of age and suffered from severe skeletal deformities at older ages. CTKO chondrocytes displayed decreased expression of genes involved in redox homeostasis. These observations illustrate the importance of FoxO signaling in chondrocytes during endochondral ossification.

Keywords: Chondrocyte; Forkhead Box O; Growth plate; Hypertrophic; Redox homeostasis.

MeSH terms

  • Animals
  • Bone and Bones / cytology
  • Bone and Bones / metabolism*
  • Cell Cycle Proteins
  • Cell Differentiation
  • Cell Proliferation
  • Chondrocytes / cytology
  • Chondrocytes / metabolism*
  • Collagen Type II / genetics
  • Collagen Type II / metabolism
  • Crosses, Genetic
  • Female
  • Forkhead Box Protein O1 / deficiency
  • Forkhead Box Protein O1 / genetics*
  • Forkhead Box Protein O3 / deficiency
  • Forkhead Box Protein O3 / genetics*
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Integrases / genetics
  • Integrases / metabolism
  • Male
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Transgenic
  • Osteogenesis / genetics*
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Primary Cell Culture
  • Signal Transduction

Substances

  • Cell Cycle Proteins
  • Collagen Type II
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • FoxO4 protein, mouse
  • Foxo1 protein, mouse
  • Oxidoreductases
  • Cre recombinase
  • Integrases