title: Loss of Runx2 in committed osteoblasts impairs postnatal skeletogenesis.
abstract: The Runx2 transcription factor is critical for commitment to the osteoblast lineage. However, its role in committed osteoblasts and its functions during postnatal skeletogenesis remain unclear. We established a Runx2-floxed line with insertion of loxP sites around exon 8 of the Runx2 gene. The Runx2 protein lacking the region encoded by exon 8 is imported into the nucleus and binds target DNA but exhibits diminished transcriptional activity. We specifically deleted the Runx2 gene in committed osteoblasts using 2.3-kb col1a-Cre transgenic mice. Surprisingly, the homozygous Runx2 mutant mice were born alive. The Runx2 heterozygous and homozygous null were grossly indistinguishable from wild-type littermates at birth. Runx2 deficiency did not alter proliferative capacity of osteoblasts during embryonic development (E18). Chondrocyte differentiation and cartilage growth in mutants was similar to wild-type mice from birth to 3 months of age. Analysis of the embryonic skeleton revealed poor calcification in homozygous mutants, which was more evident in bones formed by intramembranous ossification. Runx2 mutants showed progressive retardation in postnatal growth and exhibited significantly low bone mass by 1 month of age. Decreased bone formation was associated with decreased gene expression of osteoblast markers and impaired collagen assembly in the extracellular matrix. Consequently, Runx2 mutant bones exhibited decreased stiffness and structural integrity. By 3 months of age, bone acquisition in mutant mice was roughly half that of wild-type littermates. In addition to impaired osteoblast function, mutant mice showed markedly decreased osteoclast number and postnatal bone resorption. Taken together, functional deficiency of Runx2 in osteoblasts does not result in failed embryonic skeletogenesis but disrupts postnatal bone formation.
authors: Department of Oral and Maxillofacial Surgery, Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Mitra D
authors: MD
authors: Adhami
authors: Harunur
authors: H
authors: Rashid
authors: Haiyan
authors: H
authors: Chen
authors: John C
authors: JC
authors: Clarke
authors: Yang
authors: Y
authors: Yang
authors: Amjad
authors: A
authors: Javed
mesh_terms: D000818:Animals; D001846:Bone Development; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D050659:Core Binding Factor Alpha 1 Subunit / Q000172:deficiency*; D005786:Gene Expression Regulation / Q000235:genetics; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse
keywords: ADULT BONE SYNTHESIS; BONE REMODELING; OSTEOBLAST DIFFERENTIATION; OSTEOBLASTS; POSTNATAL SKELETOGENESIS; RUNX2