title: Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation.
abstract: Synthesis of cartilage by chondrocytes is an obligatory step for endochondral ossification. Global deletion of the Runx2 gene results in complete failure of the ossification process, but the underlying cellular and molecular mechanisms are not fully known. Here, we elucidated Runx2 regulatory control distinctive to chondrocyte and cartilage tissue by generating Runx2 exon 8 floxed mice. Deletion of Runx2 gene in chondrocytes caused failure of endochondral ossification and lethality at birth. The limbs of Runx2(ΔE8/ΔE8) mice were devoid of mature chondrocytes, vasculature, and marrow. We demonstrate that the C-terminus of Runx2 drives its biological activity. Importantly, nuclear import and DNA binding functions of Runx2 are insufficient for chondrogenesis. Molecular studies revealed that despite normal levels of Sox9 and PTHrP, chondrocyte differentiation and cartilage growth are disrupted in Runx2(ΔE8/ΔE8) mice. Loss of Runx2 in chondrocytes also impaired osteoprotegerin-receptor activator of NF-κB ligand (OPG-RANKL) signaling and chondroclast development. Dwarfism observed in Runx2 mutants was associated with the near absence of proliferative zone in the growth plates. Finally, we show Runx2 directly regulates a unique set of cell cycle genes, Gpr132, Sfn, c-Myb, and Cyclin A1, to control proliferative capacity of chondrocyte. Thus, Runx2 is obligatory for both proliferation and differentiation of chondrocytes.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.forename: Farah Y
authors.initials: FY
authors.lastname: Ghori-Javed
authors.forename: Harunur
authors.initials: H
authors.lastname: Rashid
authors.forename: Mitra D
authors.initials: MD
authors.lastname: Adhami
authors.forename: Rosa
authors.initials: R
authors.lastname: Serra
authors.forename: Soraya E
authors.initials: SE
authors.lastname: Gutierrez
authors.forename: Amjad
authors.initials: A
authors.lastname: Javed
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology*; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D020219:Chondrogenesis / Q000502:physiology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000502:physiology*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013131:Spine / Q000166:cytology / Q000196:embryology*
chemical_list: D018797:Cell Cycle Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D053244:Osteoprotegerin; D053245:RANK Ligand; C493716:Runx2 protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse
keywords: CARTILAGE REMODELING; CHONDROCYTE DIFFERENTIATION; RUNX2; SKELETAL DEVELOPMENT