Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation.
Parathyroid hormone-related protein (PTHrP) is essential to maintain a pool of dividing, immature chondrocytes in the growth plate of long bones. In chick and mouse, expression of Nkx3.2/Bapx1 in the growth plate is restricted to the proliferative zone and is down regulated as chondrocyte maturation begins. Nkx3.2/Bapx1 expression is lost in the growth plates of mice engineered to lack PTHrP signaling and, conversely, is maintained by ectopic expression of PTHrP in developing bones. Artificially preventing Nkx3.2/Bapx1 downregulation, by forced expression of either retroviral-encoded PTHrP or Nkx3.2 inhibits chondrocyte maturation. Although wild-type Nkx3.2 blocks chondrocyte maturation by acting as a transcriptional repressor, a ;reverse function' mutant of Nkx3.2 that has been converted into a transcriptional activator conversely accelerates chondrocyte maturation. Nkx3.2 represses expression of the chondrocyte maturation factor Runx2, and Runx2 mis-expression can rescue the Nkx3.2-induced blockade of chondrocyte maturation. Taken together, these results suggest that PTHrP signals block chondrocyte hypertrophy by, in part, maintaining the expression of Nkx3.2/Bapx1, which in turn represses the expression of genes required for chondrocyte maturation.
Provot
Sylvain
S
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Kempf
Hervé
H
Murtaugh
L Charles
LC
Chung
Ung-il
UI
Kim
Dae-Won
DW
Chyung
Jay
J
Kronenberg
Henry M
HM
Lassar
Andrew B
AB
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002642:Chick Embryo; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006132:Growth Plate / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D044162:Parathyroid Hormone-Related Protein / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D050659:Core Binding Factor Alpha 1 Subunit; D018398:Homeodomain Proteins; C107965:Nkx3-2 protein, mouse; D044162:Parathyroid Hormone-Related Protein; D014157:Transcription Factors