CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress

• Published in: Journal of cell communication and signaling Vol. 7; no. 3; pp. 219 - 230
• Main Authors: Hall-Glenn, Faith, Aivazi, Armen, Akopyan, Lusi, Ong, Jessica R., Baxter, Ruth R., Benya, Paul D., Goldschmeding, Roel, van Nieuwenhoven, Frans A., Hunziker, Ernst B., Lyons, Karen M.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-08-2013; John Wiley & Sons, Inc
• Subjects: Autophagy; Biomedical and Life Sciences; Biomedicine; Cartilage; CCN2/CTGF; Cell Biology; Cell proliferation; Cell survival; Cellular stress; Cellular stress response; Chondrocytes; Chondrodystrophy; Connective tissue growth factor; Extracellular matrix; Growth plate; Immunofluorescence; Integrins; Lethality; Life Sciences; NF-κB protein; Nuclear factor κB; Phagocytosis; Research Article; Rodents; Survival; Transgenic mice; Cartilage; Cellular stress; CCN2/CTGF; Autophagy; Chondrocytes; Nuclear factor κB
• ISSN: 1873-9601; 1873-961X
• DOI: 10.1007/s12079-013-0201-y

CCN2 (connective tissue growth factor (CTGF/CCN2)) is a matricellular protein that utilizes integrins to regulate cell proliferation, migration and survival. The loss of CCN2 leads to perinatal lethality resulting from a severe chondrodysplasia. Upon closer inspection of
Ccn2
mutant mice, we observed defects in extracellular matrix (ECM) organization and hypothesized that the severe chondrodysplasia caused by loss of CCN2 might be associated with defective chondrocyte survival.
Ccn2
mutant growth plate chondrocytes exhibited enlarged endoplasmic reticula (ER), suggesting cellular stress. Immunofluorescence analysis confirmed elevated stress in
Ccn2
mutants, with reduced stress observed in
Ccn2
overexpressing transgenic mice. In vitro studies revealed that
Ccn2
is a stress responsive gene in chondrocytes. The elevated stress observed in
Ccn2
−/− chondrocytes is direct and mediated in part through integrin α5. The expression of the survival marker NFκB and components of the autophagy pathway were decreased in
Ccn2
mutant growth plates, suggesting that CCN2 may be involved in mediating chondrocyte survival. These data demonstrate that absence of a matricellular protein can result in increased cellular stress and highlight a novel protective role for CCN2 in chondrocyte survival. The severe chondrodysplasia caused by the loss of CCN2 may be due to increased chondrocyte stress and defective activation of autophagy pathways, leading to decreased cellular survival. These effects may be mediated through nuclear factor κB (NFκB) as part of a CCN2/integrin/NFκB signaling cascade.