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Journal of Biochemistry Advance Access published online on November 27, 2008
Journal of Biochemistry, doi:10.1093/jb/mvn159
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© The authors 2008. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

CCN family 2/connective tissue growth factor modulates BMP signaling as a signal conductor, which action regulates the proliferation and differentiation of chondrocytes.

Azusa Maeda1,2, Takashi Nishida1, Eriko Aoyama3, Satoshi Kubota1, Karen M. Lyons4, Takuo Kuboki2 and Masaharu Takigawa1

1Department of Biochemistry and Molecular Dentistry, 2Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, 3Biodental Research Center, Okayama University Dental School, Okayama, Japan, 4Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, CA, USA

Address correspondence and reprint requests to: Prof. Masaharu Takigawa, D.D.S., Ph.D. Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama 700-8525, Japan, Tel: +81-86-235-6645, Fax: +81-86-235-6649, E-mail: takigawa{at}md.okayama-u.ac.jp

Received September 9, 2008; Accepted November 17, 2008


  Abstract

Both CCN family 2/connective tissue growth factor (CCN2/CTGF) and bone morphogenetic protein (BMP)-2 play an important role in cartilage metabolism. We evaluated whether or not CCN2 would interact with BMP-2, and examined the combination effect of CCN2 with BMP-2 (CCN2-BMP-2) on the proliferation and differentiation of chondrocytes. Immunoprecipitation-Western blotting analysis, solid-phase binding assay, and surface plasmon resonance (SPR) spectroscopy showed that CCN2 directly interacted with BMP-2 with a dissociation constant of 0.77 nM as evaluated by SPR. An in vivo study revealed that CCN2 was co-localized with BMP-2 at the pre-hypertrophic region in the E18.5 mouse growth plate. Interestingly, CCN2-BMP-2 did not affect the BMP-2/CCN2-induced phosphorylation of p38 MAPK but caused less phosphorylation of ERK1/2 in cultured chondrocytes. Consistent with these results, cell proliferation assay showed that CCN2-BMP-2 stimulated cell growth to a lesser degree than by either CCN2 or BMP-2 alone, whereas the expression of chondrocyte marker genes and proteoglycan synthesis, representing the mature chondrocytic phenotype, was increased collaboratively by CCN2-BMP-2 treatment in cultured chondrocytes. These findings suggest that CCN2 may regulate the proliferating and differentiation of chondrocytes by forming a complex with BMP-2 as a novel modulator of BMP signaling.

Key Words: chondrocytes, CCN family 2/connective tissue growth factor (CCN2/CTGF), BMP signaling, BMP-2, endochondral ossification


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