Runx2 protein expression utilizes the Runx2 P1 promoter to establish osteoprogenitor cell number for normal bone formation
Authors
Liu, Julie C.Lengner, Christopher Joachim
Gaur, Tripti
Lou, Yang
Hussain, Sadiq
Jones, Marci D.
Borodic, Brent
Colby, Jennifer L.
Steinman, Heather Anne
Van Wijnen, Andre J.
Stein, Janet L.
Jones, Stephen N.
Stein, Gary S.
Lian, Jane B.
UMass Chan Affiliations
Department of Orthopedics and Physical RehabilitationDepartment of Cell Biology
Document Type
Journal ArticlePublication Date
2011-08-26Keywords
AnimalsBone Diseases, Developmental
Bone Diseases, Metabolic
Bone Regeneration
Calcification, Physiologic
Core Binding Factor Alpha 1 Subunit
Gene Expression Regulation
Mice
Mice, Transgenic
Osteoblasts
Osteogenesis
Promoter Regions, Genetic
Stem Cells
Cell Biology
Orthopedics
Metadata
Show full item recordAbstract
The Runt-related transcription factor, Runx2, is essential for osteogenesis and is controlled by both distal (P1) and proximal (P2) promoters. To understand Runx2 function requires determination of the spatiotemporal activity of P1 and P2 to Runx2 protein production. We generated a mouse model in which the P1-derived transcript was replaced with a lacZ reporter allele, resulting in loss of P1-derived protein while simultaneously allowing discrimination between the activities of the two promoters. Loss of P1-driven expression causes developmental defects with cleidocranial dysplasia-like syndromes that persist in the postnatal skeleton. P1 activity is robust in preosteogenic mesenchyme and at the onset of bone formation but decreases as bone matures. Homozygous Runx2-P1(lacZ/lacZ) mice have a normal life span but exhibit severe osteopenia and compromised bone repair in adult mice because of osteoblastic defects and not increased osteoclastic resorption. Gene expression profiles of bone, immunohistochemical studies, and ex vivo differentiation using calvarial osteoblasts and marrow stromal cells identified mechanisms for the skeletal phenotype. The findings indicate that P1 promoter activity is necessary for generating a threshold level of Runx2 protein to commit sufficient osteoprogenitor numbers for normal bone formation. P1 promoter function is not compensated via the P2 promoter. However, the P2 transcript with compensatory mechanisms from bone morphogenetic protein (BMP) and Wnt signaling is adequate for mineralization of the bone tissue that does form. We conclude that selective utilization of the P1 and P2 promoters enables the precise spatiotemporal expression of Runx2 necessary for normal skeletogenesis and the maintenance of bone mass in the adult.Source
J Biol Chem. 2011 Aug 26;286(34):30057-70. Epub 2011 Jun 15. Link to article on publisher's siteDOI
10.1074/jbc.M111.241505Permanent Link to this Item
http://hdl.handle.net/20.500.14038/49581PubMed ID
21676869Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M111.241505