title: Forkhead box O transcription factors in chondrocytes regulate endochondral bone formation.
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 D3in 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/loxmice, 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.
authors.affiliation: Clinical and Experimental Endocrinology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Eelen
authors.affiliation: Clinical and Experimental Endocrinology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Verlinden
authors.affiliation: Clinical and Experimental Endocrinology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Maes
authors.affiliation: Clinical and Experimental Endocrinology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Beullens
authors.affiliation: Clinical and Experimental Endocrinology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Gysemans
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York City, NY, USA.
authors.forename: J-H
authors.initials: JH
authors.lastname: Paik
authors.affiliation: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: DePinho
authors.affiliation: Clinical and Experimental Endocrinology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Bouillon
authors.affiliation: Clinical and Experimental Endocrinology, KU Leuven, B-3000 Leuven, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Carmeliet
authors.affiliation: Clinical and Experimental Endocrinology, KU Leuven, B-3000 Leuven, Belgium. Electronic address: mieke.verstuyf@med.kuleuven.be.
authors.forename: A
authors.initials: A
authors.lastname: Verstuyf
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000172:deficiency / Q000235:genetics*; D000071316:Forkhead Box Protein O3 / Q000172:deficiency / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D024043:Collagen Type II; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; C467200:Foxo1 protein, mouse; D010088:Oxidoreductases; C045073:Cre recombinase; D019426:Integrases
keywords: Chondrocyte; Forkhead Box O; Growth plate; Hypertrophic; Redox homeostasis