Journal of Biochemistry Advance Access originally published online on November 27, 2008
Journal of Biochemistry 2009 145(2):207-216; doi:10.1093/jb/mvn159
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CCN Family 2/Connective Tissue Growth Factor Modulates BMP Signalling as a Signal Conductor, Which Action Regulates the Proliferation and Differentiation of Chondrocytes
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; and 4Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, CA, USA
*To whom correspondence should be addressed. 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
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Abstract |
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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 signalling.
Key Words: chondrocytes, CCN family 2/connective tissue growth factor (CCN2/CTGF), BMP signalling, BMP-2, endochondral ossification
Abbreviations: E, embryonic day; ECM, extracellular matrix; ERK1/2, extracellular signal-regulated kinase 1/2; HA, influenza virus hemagglutinin; His, histidine; MAPK, mitogen-activated protein kinase; phospho, phosphorylation; rCCN2, recombinant CCN2 protein; WT, wild type
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