PMID- 10215629
OWN - NLM
STAT- MEDLINE
DCOM- 19990601
LR  - 20190516
IS  - 0890-9369 (Print)
IS  - 0890-9369 (Linking)
VI  - 13
IP  - 8
DP  - 1999 Apr 15
TI  - A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic
      development.
PG  - 1025-36
AB  - 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
      (DeltaCbfa1) in differentiated osteoblasts only postnatally. DeltaCbfa1 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.
      DeltaCbfa1-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
      DeltaCbfa1-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.
FAU - Ducy, P
AU  - Ducy P
AD  - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 
      Texas 77030, USA.
FAU - Starbuck, M
AU  - Starbuck M
FAU - Priemel, M
AU  - Priemel M
FAU - Shen, J
AU  - Shen J
FAU - Pinero, G
AU  - Pinero G
FAU - Geoffroy, V
AU  - Geoffroy V
FAU - Amling, M
AU  - Amling M
FAU - Karsenty, G
AU  - Karsenty G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
RN  - 0 (Core Binding Factor Alpha 1 Subunit)
RN  - 0 (DNA, Complementary)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Animals, Newborn
MH  - Base Sequence
MH  - Biological Evolution
MH  - Bone Development/*physiology
MH  - Bone Diseases, Metabolic/etiology
MH  - COS Cells
MH  - Cell Differentiation
MH  - Core Binding Factor Alpha 1 Subunit
MH  - DNA, Complementary
MH  - Down-Regulation
MH  - Gene Expression
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Molecular Sequence Data
MH  - *Neoplasm Proteins
MH  - Osteoblasts/cytology/*physiology
MH  - Phenotype
MH  - Transcription Factors/*biosynthesis/genetics
MH  - Transcriptional Activation
PMC - PMC316641
EDAT- 1999/04/24 00:00
MHDA- 1999/04/24 00:01
CRDT- 1999/04/24 00:00
PHST- 1999/04/24 00:00 [pubmed]
PHST- 1999/04/24 00:01 [medline]
PHST- 1999/04/24 00:00 [entrez]
AID - 10.1101/gad.13.8.1025 [doi]
PST - ppublish
SO  - Genes Dev. 1999 Apr 15;13(8):1025-36. doi: 10.1101/gad.13.8.1025.