Prochondrogenic signals induce a competence for Runx2 to activate hypertrophic chondrocyte gene expression.
Whereas Runx2 is necessary for bone formation and cartilage hypertrophy, it is unclear why Runx2 induces markers of chondrocyte hypertrophy only in chondrocytes. We document that chondrocytes either contain a cofactor, which can be induced in somitic cells by prochondrogenic signals, that is necessary for Runx2 to induce chondrocyte hypertrophy or, alternatively, lack a repressor of this maturation program. Sequential Shh and bone morphogenetic protein (BMP) signals or forced expression of either Nkx3.2 or Sox9 (plus BMP signals) induces chondrogenesis in presomitic mesoderm and simultaneously induces a competence for Runx2 to activate the chondrocyte maturation program. The ability of either sequential Shh and BMP signals or retrovirus-encoded Nkx3.2 or Sox9 to induce this competence correlates with their ability to activate chondrogenesis in various embryonic tissues. Consistent with these findings in embryonic tissues, we have found that cotransfected Runx2 and Smad1 are able to induce the expression of a reporter construct driven by the collagen X regulatory sequences in chondrocytes but not in fibroblasts. In contrast, both Runx2 and Smad1 are competent to activate reporters driven by either reiterated Runx or Smad binding sites, respectively, in both cell types. As Sox9 and Nkx3.2 have previously been shown to block chondrocyte maturation in vivo, our findings suggest that these transcription factors can, in addition, either induce the expression or activity of a factor in chondrocytes that is required for Runx2 to activate the chondrocyte maturation program, or alternatively that these transcription factors block the expression or activity of a repressor of this maturation program.
Kempf
Hervé
H
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ionescu
Andreia
A
Udager
Aaron M
AM
Lassar
Andrew B
AB
D000818:Animals; D002642:Chick Embryo; D019902:Chondrocytes / Q000378:metabolism*; D020219:Chondrogenesis / Q000502:physiology*; D050659:Core Binding Factor Alpha 1 Subunit / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D050659:Core Binding Factor Alpha 1 Subunit