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Vol. 15, Issue 12, 5635-5646, December 2004
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* Centre for Rheumatology, Royal Free and University College Medical School, University College London (Royal Free Campus), Hampstead, London NW3 2PF, United Kingdom;
Centre for Cardiovascular Biology and Medicine, King's College London, London SE1 1UL, United Kingdom; and
Departments of Biological Chemistry and Orthopedic Surgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095
Submitted June 15, 2004;
Revised August 5, 2004;
Accepted September 7, 2004
Monitoring Editor: Richard Hynes
In vivo, CCN2 (connective tissue growth factor) promotes angiogenesis, osteogenesis, tissue repair, and fibrosis, through largely unknown mechanisms. In vitro, CCN2 promotes cell adhesion in a variety of systems via integrins and heparin sulfate proteoglycans (HSPGs). However, the physiological relevance of CCN2-mediated cell adhesion is unknown. Here, we find that HSPGs and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cascade are required for adult human dermal fibroblasts to adhere to CCN2. Endogenous CCN2 directly binds fibronectin and the fibronectin receptors integrins 
4 
1 and 5 and syndecan 4. Using Ccn2-/- mouse embryonic fibroblasts, we show that loss of endogenous CCN2 results in impaired spreading on fibronectin, delayed -smooth muscle actin stress fiber formation, and reduced ERK and focal adhesion kinase phosphorylation. These results suggest that a physiological role of CCN2 is to potentiate the ability of fibroblasts to spread on fibronectin, which may be important in modulating fibroblast adhesion to the provisional matrix during tissue development and wound healing. These results are consistent with the notion that a principal function of CCN2 is to modulate receptor/ligand interactions in vivo.
These authors contributed equally to this work.
|| Corresponding author. E-mail address: a.leask{at}rfc.ucl.ac.uk.
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