Cbf beta regulates Runx2 function isoform-dependently in postnatal bone development.
Runx2 and Cbfbeta 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 Cbfbeta 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 Col1a1 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) Cbfbeta regulates Runx2 function isoform-dependently; and (3) Runx2-I activity is highly dependent on Cbfbeta. These findings demonstrate that Runx2 isoforms exert their functions through at least partly different mechanisms and Cbfbeta regulates bone development by regulating Runx2 function isoform-dependently.
Kanatani
Naoko
N
Department of Developmental and Reconstructive Medicine, Division of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan.
Fujita
Takashi
T
Fukuyama
Ryo
R
Liu
Wenguang
W
Yoshida
Carolina A
CA
Moriishi
Takeshi
T
Yamana
Kei
K
Miyazaki
Toshihiro
T
Toyosawa
Satoru
S
Komori
Toshihisa
T
D000818:Animals; D000831:Animals, Newborn; D001846:Bone Development / Q000502:physiology*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012886:Skull / Q000378:metabolism
C493693:Cbfb protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D050658:Core Binding Factor beta Subunit; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D020033:Protein Isoforms; C493716:Runx2 protein, mouse