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Molecular and Cellular Biology, August 2009, p. 4201-4219, Vol. 29, No. 15
0270-7306/09/$08.00+0 doi:10.1128/MCB.00056-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
ADAMTS-7, a Direct Target of PTHrP, Adversely Regulates Endochondral Bone Growth by Associating with and Inactivating GEP Growth Factor
,
Xiao-Hui Bai,1,2,
Da-Wei Wang,1,3,
Li Kong,1,
Yan Zhang,1
Yi Luan,1
Tatsuya Kobayashi,4
Henry M. Kronenberg,4
Xiu-Ping Yu,2,5* and
Chuan-ju Liu1,2,6*
Department of Orthopaedic Surgery, New York University School of Medicine, New York, New York 10003,1 Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong 250012, People's Republic of China,2 Department of Vascular Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250012, People's Republic of China,3 Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114,4 Key Laboratory of Experimental Teratology, Chinese Ministry of Education, Jinan, People's Republic of China,5 Department of Cell Biology, New York University School of Medicine, New York, New York 100166
Received 13 January 2009/ Returned for modification 3 March 2009/ Accepted 15 May 2009
ADAMTS-7, a metalloproteinase that belongs to ADAMTS family, is important for the degradation of cartilage extracellular matrix proteins in arthritis. Herein we report that ADAMTS-7 is upregulated during chondrocyte differentiation and demonstrates the temporal and spatial expression pattern during skeletal development. ADAMTS-7 potently inhibits chondrocyte differentiation and endochondral bone formation, and this inhibition depends on its proteolytic activity. The cysteine-rich domain of ADAMTS-7 is required for its interaction with the extracellular matrix, and the C-terminal four-thrombospondin motifs are necessary for its full proteolytic activity and inhibition of chondrocyte differentiation. ADAMTS-7 is an important target of canonical PTHrP signaling, since (i) PTHrP induces ADAMTS-7, (ii) ADAMTS-7 is downregulated in PTHrP null mutant (PTHrP–/–) growth plate chondrocytes, and (iii) blockage of ADAMTS-7 almost abolishes PTHrP-mediated inhibition of chondrocyte hypertrophy and endochondral bone growth. ADAMTS-7 associates with granulin-epithelin precursor (GEP), an autocrine growth factor that has been implicated in tissue regeneration, tumorigenesis, and inflammation. In addition, ADAMTS-7 acts as a new GEP convertase and neutralizes GEP-stimulated endochondral bone formation. Collectively, these findings demonstrate that ADAMTS-7, a direct target of PTHrP signaling, negatively regulates endochondral bone formation by associating with and inactivating GEP chondrogenic growth factor.
* Corresponding author. Mailing address for Xiu-Ping Yu: Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong 250012, People's Republic of China. Phone: 86-531-88382579. Fax: 86-531-88565187. E-mail: yuxp{at}sdu.edu.cn. Mailing address for Chuan-Ju Liu: Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10003. Phone: (212) 598-6103. Fax: (212) 598-6096. E-mail: chuanju.liu{at}med.nyu.edu
Published ahead of print on 1 June 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
These authors contributed equally to the paper.
Molecular and Cellular Biology, August 2009, p. 4201-4219, Vol. 29, No. 15
0270-7306/09/$08.00+0 doi:10.1128/MCB.00056-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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