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Constitutive RelA activation mediated by Nkx3.2 controls chondrocyte viability

Nature Cell Biology volume 9, pages 287–298 (2007)Cite this article

Abstract

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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Figure 1: Nkx3.2 enhances chondrocyte survival.
Figure 2: Nkx3.2 constitutively activates RelA.
Figure 3: Nkx3.2 recruits RelA and IκBα into the nucleus by direct protein interactions.
Figure 4: Nkx3.2 causes proteasome-dependent degradation of IκBα.
Figure 5: Stable interactions with RelA–IκBα are required for Nkx3.2 to activate NF-κB and inhibit chondrocyte apoptosis.
Figure 6: The transcriptional functionality of Nkx3.2 is not required to activate NF-κB or enhance chondrocyte viability.
Figure 7: Stage-specific expression of Nkx3.2 during chondrocyte maturation modulates NF-κB activity and, in turn, regulates chondrocyte viability.

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Acknowledgements

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).

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  1. Minsun Park and Yeryoung Yong: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Yonsei University, SEOUL, 120-749, Republic of Korea

    Minsun Park, Yeryoung Yong, Seung-Won Choi & Dae-Won Kim

  2. Department of Anatomy, Yonsei University College of Medicine, SEOUL, 120-752, Republic of Korea

    Jae Hwan Kim & Jong Eun Lee

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Correspondence to Dae-Won Kim.

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Park, M., Yong, Y., Choi, SW. et al. Constitutive RelA activation mediated by Nkx3.2 controls chondrocyte viability. Nat Cell Biol 9, 287–298 (2007). https://doi.org/10.1038/ncb1538

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