During endochondral ossification, a process that accounts for the majority of bone formation in vertebrates, hypertrophic chondrocytes display a greater susceptibility to apoptosis when compared to proliferating chondrocytes. However, the molecular mechanisms underlying this phenomenon remain unclear. Nkx3.2, a member of the NK class of homeoproteins, is initially expressed in chondrogenic precursor cells, and later, during cartilage maturation, its expression is restricted to proliferating chondrocytes. Here, we show that the nuclear factor kappa B (NF-κB) pathway is required for chondrocyte viability and that Nkx3.2 supports chondrocyte survival by constitutively activating RelA. Although signal-dependent NF-κB activation has been intensively studied, ligand-independent NF-κB activation is poorly understood. The data presented here support a novel ligand-independent mechanism of NF-κB activation, whereby Nkx3.2 recruits the RelA–IκBα heteromeric complex into the nucleus by direct protein–protein interactions and activates RelA through proteasome-dependent IκBα degradation in the nucleus. Furthermore, we demonstrate that stage-specific NF-κB activation, mediated by Nkx3.2, regulates chondrocyte viability during cartilage maturation.
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This work was supported in part by Korea Research Foundation Grants funded by the Korean Government Basic Research Promotion Fund; KRF-2004-003-C00143, KRF-2005-070-C00091) and by the Science Research Center/Engineering Research Center (SRC/ERC) programme of the Ministry of Science and Technology/Korea Science and Engineering foundation (MOST/KOSEF; R112000078020020).
The authors declare no competing financial interests.
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