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Molecular and Cellular Biology, August 2007, p. 5650-5663, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00130-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Stage-Specific Secretion of HMGB1 in Cartilage Regulates Endochondral Ossification{triangledown} ,{dagger}

Noboru Taniguchi,1 Kenji Yoshida,1 Tatsuo Ito,1 Masanao Tsuda,1 Yasunori Mishima,1 Takayuki Furumatsu,1 Lorenza Ronfani,2 Kazuhiro Abeyama,4 Ko-ichi Kawahara,4 Setsuro Komiya,5 Ikuro Maruyama,4 Martin Lotz,1 Marco E. Bianchi,2,3 and Hiroshi Asahara1,6,7*

Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,1 DIBIT, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy,2 San Raffaele University, via Olgettina 58, 20132 Milano, Italy,3 Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan,4 Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan,5 National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan,6 SORST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan7

Received 20 January 2007/ Returned for modification 25 February 2007/ Accepted 19 May 2007

High mobility group box 1 protein (HMGB1) is a chromatin protein that has a dual function as a nuclear factor and as an extracellular factor. Extracellular HMGB1 released by damaged cells acts as a chemoattractant, as well as a proinflammatory cytokine, suggesting that HMGB1 is tightly connected to the process of tissue organization. However, the role of HMGB1 in bone and cartilage that undergo remodeling during embryogenesis, tissue repair, and disease is largely unknown. We show here that the stage-specific secretion of HMGB1 in cartilage regulates endochondral ossification. We analyzed the skeletal development of Hmgb1–/– mice during embryogenesis and found that endochondral ossification is significantly impaired due to the delay of cartilage invasion by osteoclasts, osteoblasts, and blood vessels. Immunohistochemical analysis revealed that HMGB1 protein accumulated in the cytosol of hypertrophic chondrocytes at growth plates, and its extracellular release from the chondrocytes was verified by organ culture. Furthermore, we demonstrated that the chondrocyte-secreted HMGB1 functions as a chemoattractant for osteoclasts and osteoblasts, as well as for endothelial cells, further supporting the conclusion that Hmgb1–/– mice are defective in cell invasion. Collectively, these findings suggest that HMGB1 released from differentiating chondrocytes acts, at least in part, as a regulator of endochondral ossification during osteogenesis.

* Corresponding author. Mailing address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-9026. Fax: (858) 784-2744. E-mail: asahara{at}scripps.edu

{triangledown} Published ahead of print on 4 June 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2007, p. 5650-5663, Vol. 27, No. 16
0270-7306/07/$08.00+0     doi:10.1128/MCB.00130-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Taniguchi, N., Carames, B., Kawakami, Y., Amendt, B. A., Komiya, S., Lotz, M. (2009). Chromatin protein HMGB2 regulates articular cartilage surface maintenance via {beta}-catenin pathway. Proc. Natl. Acad. Sci. USA 106: 16817-16822 [Abstract] [Full Text]  
  • Taniguchi, N., Carames, B., Ronfani, L., Ulmer, U., Komiya, S., Bianchi, M. E., Lotz, M. (2009). Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis. Proc. Natl. Acad. Sci. USA 106: 1181-1186 [Abstract] [Full Text]  
  • Yamoah, K., Brebene, A., Baliram, R., Inagaki, K., Dolios, G., Arabi, A., Majeed, R., Amano, H., Wang, R., Yanagisawa, R., Abe, E. (2008). High-Mobility Group Box Proteins Modulate Tumor Necrosis Factor-{alpha} Expression in Osteoclastogenesis via a Novel Deoxyribonucleic Acid Sequence. Mol. Endocrinol. 22: 1141-1153 [Abstract] [Full Text]  


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