Cbfβ regulates Runx2 function isoform-dependently in postnatal bone development

Runx2 and Cbf beta are essential for skeletal development during the embryonic stage. Runx2 has two isoforms with different N-termini. We examined the functions of the Runx2 isoforms and Cbf beta in postnatal bone development. On luciferase and electrophoretic mobility shift assays, Runx2-I was less active than Runx2-II in the absence of Cbfb, but the two Runx2 isoforms had similar activity levels in the presence of Cbfb. We generated Runx2-I transgenic mice under the control of Colla1 promoter and Runx2-I/Cbfb and Runx2-II/Cbfb double transgenic mice. Runx2-I transgenic mice showed less severe osteopenia and fragility than Runx2-II transgenic mice due to milder inhibition of both osteoblast maturation and transition to osteocytes, even though the former mice showed higher transgene expression. However, Runx2-I/Cbfb and Runx2-II/Cbfb double transgenic mice had enhanced inhibition of osteoblast maturation, resulting in similar severity of osteopenia and fragility, although the latter mice had less osteocytes. These findings indicate that (1) Runx2-II more strongly inhibits osteoblast maturation and transition to osteocytes than Runx2-I;(2) Cbf beta regulates Runx2 function isoform-dependently; and (3) Runx2-I activity is highly dependent on Cbf beta. These findings demonstrate that Runx2 isoforms exert their functions through at least partly different mechanisms and Cbf beta regulates bone development by regulating Runx2 function isoform-dependently. (c) 2006 Elsevier Inc. All rights reserved.