The Ihh (Indian Hedgehog) pathway plays an essential role in facilitating chondrocyte hypertrophy and bone formation during skeletal development. Nkx3.2 (NK3 homeobox 2) is initially induced in chondrocyte precursor cells, maintained in early-stage chondrocytes and down-regulated in terminal-stage chondrocytes. Consistent with these expression patterns, Nkx3.2 has been shown to enhance chondrocyte differentiation and cell survival, while inhibiting chondrocyte hypertrophy and apoptosis. Thus, in the present study, we investigated whether Nkx3.2, an early-stage chondrogenic factor, can be regulated by Ihh, a key regulator for chondrocyte hypertrophy. We show that Ihh signalling can induce proteasomal degradation of Nkx3.2. In addition, we found that Ihh can suppress levels of Lrp (low-density-lipoprotein-receptor-related protein) (Wnt co-receptor) and Sfrp (secreted frizzled-related protein) (Wnt antagonist) expression, which, in turn, may selectively enhance Lrp-independent non-canonical Wnt pathways in chondrocytes. In agreement with these findings, Ihh-induced Nkx3.2 degradation requires Wnt5a, which is capable of triggering Nkx3.2 degradation. Finally, we found that Nkx3.2 protein levels in chondrocytes are remarkably elevated in mice defective in Ihh signalling by deletion of either Ihh or smoothened. Thus these results suggest that Ihh/Wnt5a signalling may play a role in negative regulation of Nkx3.2 for appropriate progression of chondrocyte hypertrophy during chondrogenesis.
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Research Article|
April 16 2012
Indian Hedgehog signalling triggers Nkx3.2 protein degradation during chondrocyte maturation
Seung-Won Choi;
Seung-Won Choi
*Department of Biochemistry, Yonsei University College of Life Science and Biotechnology, 262 Seongsanno Seodaemoon-Gu, Seoul, 120-749, Republic of Korea
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Da-Un Jeong;
Da-Un Jeong
*Department of Biochemistry, Yonsei University College of Life Science and Biotechnology, 262 Seongsanno Seodaemoon-Gu, Seoul, 120-749, Republic of Korea
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Jeong-Ah Kim;
Jeong-Ah Kim
*Department of Biochemistry, Yonsei University College of Life Science and Biotechnology, 262 Seongsanno Seodaemoon-Gu, Seoul, 120-749, Republic of Korea
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Boyoung Lee;
Boyoung Lee
*Department of Biochemistry, Yonsei University College of Life Science and Biotechnology, 262 Seongsanno Seodaemoon-Gu, Seoul, 120-749, Republic of Korea
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Kyu Sang Joeng;
Kyu Sang Joeng
†Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, U.S.A.
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Fanxin Long;
Fanxin Long
†Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, U.S.A.
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Dae-Won Kim
Dae-Won Kim
1
*Department of Biochemistry, Yonsei University College of Life Science and Biotechnology, 262 Seongsanno Seodaemoon-Gu, Seoul, 120-749, Republic of Korea
1To whom correspondence should be addressed (email kimdw@yonsei.ac.kr).
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Publisher: Portland Press Ltd
Received:
November 21 2011
Revision Received:
January 25 2012
Accepted:
February 10 2012
Accepted Manuscript online:
April 16 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (3): 789–798.
Article history
Received:
November 21 2011
Revision Received:
January 25 2012
Accepted:
February 10 2012
Accepted Manuscript online:
April 16 2012
Citation
Seung-Won Choi, Da-Un Jeong, Jeong-Ah Kim, Boyoung Lee, Kyu Sang Joeng, Fanxin Long, Dae-Won Kim; Indian Hedgehog signalling triggers Nkx3.2 protein degradation during chondrocyte maturation. Biochem J 1 May 2012; 443 (3): 789–798. doi: https://doi.org/10.1042/BJ20112062
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