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BioMed Research International
Volume 2014, Article ID 437096, 11 pages
Review Article

The CCN Family Proteins: Modulators of Bone Development and Novel Targets in Bone-Associated Tumors

1Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
2Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 40201, Taiwan
3Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan
4Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
5Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan
6Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
7Department of Pharmacology, School of Medicine, China Medical University, Taichung 40402, Taiwan
8Department of Biotechnology, College of Health Science, Asia University, Taichung 41354, Taiwan

Received 12 November 2013; Accepted 19 December 2013; Published 14 January 2014

Academic Editor: Po-Lin Kuo

Copyright © 2014 Po-Chun Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The CCN family of proteins is composed of six extracellular matrix-associated proteins that play crucial roles in skeletal development, wound healing, fibrosis, and cancer. Members of the CCN family share four conserved cysteine-rich modular domains that trigger signal transduction in cell adhesion, migration, proliferation, differentiation, and survival through direct binding to specific integrin receptors and heparan sulfate proteoglycans. In the present review, we discuss the roles of the CCN family proteins in regulating resident cells of the bone microenvironment. In vertebrate development, the CCN family plays a critical role in osteo/chondrogenesis and vasculo/angiogenesis. These effects are regulated through signaling via integrins, bone morphogenetic protein, vascular endothelial growth factor, Wnt, and Notch via direct binding to CCN family proteins. Due to the important roles of CCN family proteins in skeletal development, abnormal expression of CCN proteins is related to the tumorigenesis of primary bone tumors such as osteosarcoma, Ewing sarcoma, and chondrosarcoma. Additionally, emerging studies have suggested that CCN proteins may affect progression of secondary metastatic bone tumors by moderating the bone microenvironment. CCN proteins could therefore serve as potential therapeutic targets for drug development against primary and metastatic bone tumors.