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

Article


Owen, H., Roberts, S., Ahmed, S. 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), pp. E1023-E1034. https://doi.org/10.1152/ajpendo.00586.2007
TypeArticle
TitleDexamethasone-induced expression of the glucocorticoid response gene lipocalin 2 in chondrocytes
AuthorsOwen, H., Roberts, S., Ahmed, S. and Farquharson, C.
Abstract

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.

Keywordsmicroarray; growth retardation
PublisherAmerican Physiological Society
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
ISSN0193-1849
Electronic1522-1555
Publication dates
Print01 Jun 2008
Online04 Jun 2008
Publication process dates
Deposited20 Apr 2016
Accepted28 Mar 2008
Output statusPublished
Digital Object Identifier (DOI)https://doi.org/10.1152/ajpendo.00586.2007
Web of Science identifierWOS:000256469200003
LanguageEnglish
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