Loss of Osteoblast Runx3 Produces Severe Congenital Osteopenia

Abstract

Congenital osteopenia is a bone demineralization condition that is associated with elevated fracture risk in human infants. Here we show that Runx3, like Runx2, is expressed in precommitted embryonic osteoblasts and that Runx3-deficient mice develop severe congenital osteopenia. Runx3-deficient osteoblast-specific (Runx3^fl/fl/Col1α1-cre), but not chondrocyte-specific (Runx3^fl/fl/Col1α2-cre), mice are osteopenic. This demonstrates that an osteoblastic cell-autonomous function of Runx3 is required for proper osteogenesis. Bone histomorphometry revealed that decreased osteoblast numbers and reduced mineral deposition capacity in Runx3-deficient mice cause this bone formation deficiency. Neonatal bone and cultured primary osteoblast analyses revealed a Runx3-deficiency-associated decrease in the number of active osteoblasts resulting from diminished proliferation and not from enhanced osteoblast apoptosis. These findings are supported by Runx3-null culture transcriptome analyses showing significant decreases in the levels of osteoblastic markers and increases in the levels of Notch signaling components. Thus, while Runx2 is mandatory for the osteoblastic lineage commitment, Runx3 is nonredundantly required for the proliferation of these precommitted cells, to generate adequate numbers of active osteoblasts. Human RUNX3 resides on chromosome 1p36, a region that is associated with osteoporosis. Therefore, RUNX3 might also be involved in human bone mineralization.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01106-14.

ACKNOWLEDGMENTS

This study was supported by a grant from the Israel Science Foundation (ISF) to Y.G.

We thank Tamara Berkuzki and Calanit Ra'anan for their valuable technical assistance; Ron Rotkopf and Kfir Umansky for help in computational analyses; Avraham Keter, Arie Gumberof, and Ofir Higfa for help in animal husbandry; and Eli Zelzer for the Runx2^+/−, Col1α1-cre, Col1α2-cre, and Osx1-cre mouse lines and his helpful suggestions and stimulating discussions throughout this work.