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

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. (2013). CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress. Journal of cell communication and signaling, 7(3), pp. 219-30. Springer 10.1007/s12079-013-0201-y

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Osteoporosis
04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Orthopaedic Surgery

UniBE Contributor:

Hunziker, Ernst Bruno

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1873-9601

Publisher:

Springer

Language:

English

Submitter:

Stephanie Schmutz

Date Deposited:

31 Mar 2014 13:34

Last Modified:

28 Dec 2014 07:20

Publisher DOI:

10.1007/s12079-013-0201-y

PubMed ID:

23666466

BORIS DOI:

10.7892/boris.42804

URI:

https://boris.unibe.ch/id/eprint/42804

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