Dexamethasone-induced expression of the glucocorticoid response gene lipocalin 2 in chondrocytes

Owen, H.C., Roberts, S.J., Ahmed, S.F. and Farquharson, C. (2008) Dexamethasone-induced expression of the glucocorticoid response gene lipocalin 2 in chondrocytes. American Journal of Physiology: Endocrinology and Metabolism, 294(6), E1023-E1034. (doi: 10.1152/ajpendo.00586.2007)

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Glucocorticoids (GC) are commonly used anti-inflammatory drugs, but long-term use can result in marked growth retardation in children due to their actions on growth plate chondrocytes. To gain an insight into the mechanisms involved in GC-induced growth retardation, we performed Affymetrix microarray analysis of the murine chondrogenic cell line ATDC5, incubated with 10–6 M dexamethasone (Dex) for 24 h. Downregulated genes included secreted frizzled-related protein and IGF-I, and upregulated genes included serum/GC-regulated kinase, connective-tissue growth factor, and lipocalin 2. Lipocalin 2 expression increased 40-fold after 24-h Dex treatment. Expression increased further after 48-h (75-fold) and 96-h (84-fold) Dex treatment, and this response was Dex concentration dependent. Lipocalin 2 was immunolocalized to both proliferating and hypertrophic growth plate zones, and its expression was increased by Dex in primary chondrocytes at 6 h (3-fold, P < 0.05). The lipocalin 2 response was blocked by the GC-receptor antagonist RU-486 and was increased further by the protein synthesis blocker cycloheximide. Proliferation in lipocalin 2-overexpressing cells was less than in control cells (49%, P < 0.05), and overexpression caused an increase in collagen type X expression (4-fold, P < 0.05). The effects of lipocalin 2 overexpression on chondrocyte proliferation (64%, P < 0.05) and collagen type X expression (8-fold, P < 0.05) were further exacerbated with the addition of 10–6 M Dex. This synergistic effect may be explained by a further increase in lipocalin 2 expression with Dex treatment of transfected cells (45%, P < 0.05). These results suggest that lipocalin 2 may mediate Dex effects on chondrocytes and provides a potential novel mechanism for GC-induced growth retardation.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Ahmed, Professor Syed Faisal
Authors: Owen, H.C., Roberts, S.J., Ahmed, S.F., and Farquharson, C.
College/School:College of Medical Veterinary and Life Sciences
Journal Name:American Journal of Physiology: Endocrinology and Metabolism
Journal Abbr.:Am. J. Physiol. Endocrinol. Metab.
Publisher:American Physiological Society
ISSN (Online):1522-1555
Published Online:01 April 2008

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