Synergistic induction of local glucocorticoid generation by inflammatory cytokines and glucocorticoids: implications for inflammation associated bone loss

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OBJECTIVES: Synovial fibroblasts and osteoblasts generate active glucocorticoids (GCs) via the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme. This activity increases in response to proinflammatory cytokines or GCs. During inflammatory arthritis synovium and bone are exposed to both these factors. We hypothesised that GCs magnify the effects of inflammatory cytokines on local GC production in both synovium and bone. METHODS: We assessed the effects of inflammatory cytokines (IL-1beta/TNFalpha) and GCs, alone or combined, on expression and activity of 11beta-HSD1 in primary synovial fibroblasts, primary human osteoblasts and MG-63 osteosarcoma cells. A range of other target genes and cell types were used to examine the specificity of effects. Functional consequences were assessed using IL-6 ELISA. RESULTS: In synovial fibroblasts and osteoblasts, treatment with cytokines or GCs in isolation induced 11beta-HSD1 expression and activity. However, in combination, 11beta-HSD1 expression, activity and functional consequences were induced synergistically to a level not seen with isolated treatments. This effect was seen in normal skin fibroblasts but not foreskin fibroblasts or adipocytes and was only seen for the 11beta-HSD1 gene. The synergistic induction had functional consequences on IL-6 production. CONCLUSIONS: Combined treatment with inflammatory cytokines and GCs synergistically induces 11beta-HSD1 expression and activity in synovial fibroblasts and osteoblasts, providing a mechanism by which synovium and bone can interact to enhance anti-inflammatory responses by increasing localized GC levels. However, synergistic induction of 11beta-HSD1 might also cause detrimental GC accumulation in bone or surrounding tissues.


Original languageEnglish
Pages (from-to)1185-90
Number of pages6
JournalAnnals of the Rheumatic Diseases
Issue number6
Early online date22 Jun 2009
Publication statusPublished - 1 Jun 2010


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