Focal adhesion kinase/Src suppresses early chondrogenesis: central role of CCN2.
Adhesive signaling plays a key role in cellular differentiation, including in chondrogenesis. Herein, we probe the contribution to early chondrogenesis of two key modulators of adhesion, namely focal adhesion kinase (FAK)/Src and CCN2 (connective tissue growth factor, CTGF). We use the micromass model of chondrogenesis to show that FAK/Src signaling, which mediates cell/matrix attachment, suppresses early chondrogenesis, including the induction of Ccn2, Agc, and Sox6. The FAK/Src inhibitor PP2 elevates Ccn2, Agc, and Sox6 expression in wild-type mesenchymal cells in micromass culture, but not in cells lacking CCN2. Our results suggest a reduction in FAK/Src signaling is a critical feature permitting chondrogenic differentiation and that CCN2 operates downstream of this loss to promote chondrogenesis.
Pala
Daphne
D
Department of Physiology and Pharmacology and Division of Oral Biology, Canadian Institute of Health Research Group in Skeletal Development and Remodeling, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Kapoor
Mohit
M
Woods
Anita
A
Kennedy
Laura
L
Liu
Shangxi
S
Chen
Shioqiong
S
Bursell
Laura
L
Lyons
Karen M
KM
Carter
David E
DE
Beier
Frank
F
Leask
Andrew
A
D053674:Aggrecans / Q000096:biosynthesis; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002461:Cell Line, Transformed; D020219:Chondrogenesis / Q000502:physiology*; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006609:High Mobility Group Proteins / Q000096:biosynthesis; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D055755:SOXD Transcription Factors; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D053674:Aggrecans; C526318:CCN2 protein, mouse; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse; D014157:Transcription Factors; D055513:Connective Tissue Growth Factor; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases