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First published online 18 January 2006
doi: 10.1242/dev.02258

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Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation

Sylvain Provot^1,2,*, Hervé Kempf^1,*, L. Charles Murtaugh¹, Ung-il Chung², Dae-Won Kim¹, Jay Chyung¹, Henry M. Kronenberg² and Andrew B. Lassar^1,

¹ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
² Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, 50 Blossom Street, Boston, MA 02114, USA.

Author for correspondence (e-mail: andrew_lassar{at}hms.harvard.edu)

Accepted 6 December 2005

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 downregulated 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 misexpression 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.

Key words: Chondrogenesis, Runx2, Nkx3.2, Bapx1, PTHrP

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