CCN2 (Connective Tissue Growth Factor) is essential for extracellular matrix production and integrin signaling in chondrocytes |
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Authors: | Takashi Nishida Harumi Kawaki Ruth M Baxter R Andrea DeYoung Masaharu Takigawa Karen M Lyons |
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Institution: | (1) Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, 2641 MacDonald Research Laboratories, 675 Charles E. Young Dr. South, Los Angeles, CA 90095, USA;(2) Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, 2641 MacDonald Research Laboratories, 675 Charles E. Young Dr. South, Los Angeles, CA 90095, USA;(3) 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 |
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Abstract: | The matricellular protein CCN2 (Connective Tissue Growth Factor; CTGF) is an essential mediator of ECM composition, as revealed through analysis of Ccn2 deficient mice. These die at birth due to complications arising from impaired endochondral ossification. However, the mechanism(s)
by which CCN2 mediates its effects in cartilage are unclear. We investigated these mechanisms using Ccn2
−/−
chondrocytes. Expression of type II collagen and aggrecan were decreased in Ccn2
−/− chondrocytes, confirming a defect in ECM production. Ccn2
−/−
chondrocytes also exhibited impaired DNA synthesis and reduced adhesion to fibronectin. This latter defect is associated
with decreased expression of α5 integrin. Moreover, CCN2 can bind to integrin α5β1 in chondrocytes and can stimulate increased
expression of integrin α5. Consistent with an essential role for CCN2 as a ligand for integrins, immunofluorescence and Western
blot analysis revealed that levels of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK)1/2 phosphorylation
were reduced in Ccn2
−/−
chondrocytes. These findings argue that CCN2 exerts major effects in chondrocytes through its ability to (1) regulate ECM
production and integrin α5 expression, (2) engage integrins and (3) activate integrin-mediated signaling pathways. |
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Keywords: | Connective tissue growth factor/CCN2 Integrin α 5 Extracellular signal-regulated kinase (ERK)1/2 Focal adhesion kinase (FAK) Chondrocyte Fibronectin |
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