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Vol. 13, No. 8, pp. 1025-1036, April 15, 1999
1 Department of Molecular and Human Genetics and
2 Program in Developmental Biology, Baylor College of
Medicine, Houston, Texas 77030 USA; 3 Department of Molecular
Genetics, The University of Texas M.D. Anderson Cancer Center, Houston,
Texas 77030 USA; 4 Department of Bone Pathology and
5 Department of Trauma Surgery, University of Hamburg, Hamburg
20246, Germany; 6 Department of Basic Science, The University
of Texas Dental Branch, Houston, Texas 77030 USA
The molecular mechanisms controlling bone extracellular matrix (ECM)
deposition by differentiated osteoblasts in postnatal life, called
hereafter bone formation, are unknown. This contrasts with the growing
knowledge about the genetic control of osteoblast differentiation
during embryonic development. Cbfa1, a transcriptional activator of
osteoblast differentiation during embryonic development, is also
expressed in differentiated osteoblasts postnatally. The perinatal
lethality occurring in Cbfa1-deficient mice has prevented so far the
study of its function after birth. To determine if Cbfa1 plays a role
during bone formation we generated transgenic mice overexpressing Cbfa1
DNA-binding domain (
Cbfa1) in differentiated osteoblasts only
postnatally. Cbfa1 has a higher affinity for DNA than Cbfa1 itself,
has no transcriptional activity on its own, and can act in a
dominant-negative manner in DNA cotransfection assays.
Cbfa1-expressing mice have a normal skeleton at birth but develop an
osteopenic phenotype thereafter. Dynamic histomorphometric studies show
that this phenotype is caused by a major decrease in the bone formation
rate in the face of a normal number of osteoblasts thus indicating that
once osteoblasts are differentiated Cbfa1 regulates their function.
Molecular analyses reveal that the expression of the genes expressed in
osteoblasts and encoding bone ECM proteins is nearly abolished in
transgenic mice, and ex vivo assays demonstrated that
Cbfa1-expressing osteoblasts were less active than wild-type osteoblasts. We also show that Cbfa1 regulates positively the activity
of its own promoter, which has the highest affinity Cbfa1-binding sites
characterized. This study demonstrates that beyond its differentiation function Cbfa1 is the first transcriptional activator of bone formation
identified to date and illustrates that developmentally important genes
control physiological processes postnatally.
[Key Words: Cbfa1; osteoblast function; bone formation; dominant negative; Cbfa1 autoregulation]
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