Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Locally generated glucocorticoids attenuate bone loss during inflammatory arthritis (#150)

Rowan Hardy 1 , Rumina Begum 1 , Amy Naylor 1 , Atif Saghir 1 , Gareth Lavery 1 , Karim Raza 1 , Mark S Cooper 2
  1. Institute of Inflammation and Aging, University of Birmingham, Birmingham, West Midlands, UK
  2. ANZAC Research Institute, University of Sydney, Concord Hospital, NSW, Australia

Glucocorticoid action at a cellular level is regulated by the 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1) enzyme which converts inactive cortisone to active cortisol (and dehydrocorticosterone to corticosterone in rodents). 11b-HSD1 is expressed in osteoblasts and its activity increases in response to inflammation. The consequences of increased endogenous glucocorticoid activity in bone during inflammation have not been explored. To address this question we examined the impact of deletion of 11b-HSD1 in the TNFa-transgenic (TNF-Tg) mouse model of inflammatory arthritis.

Mice with global deletion of 11b-HSD1 (HSD1KO) or their floxed littermates (WT) were crossed with TNFa transgenic (TNF-Tg) mice to generate TNF-Tg/HSD1KO mice. At 9 weeks of age TNF-Tg/HSD1KO mice had a significantly increased level of arthritis compared to TNF-Tg mice (assessed by joint inflammation and clinical scores). Although TNF-Tg mice demonstrated joint erosions and periarticular bone loss, the extent and degree of bone loss was considerably greater in TNF-Tg/HSD1KO mice (approximately 2 fold p<0.001 depending on site; assessed by histology and microCT). The degree of bone loss in TNF-Tg/HSD1KO mice was also greater than expected for the degree of arthritis. Gene expression analysis of tibial bone demonstrated a significant reduction in markers of osteoblast differentiation (Runx2 and osteoprotegerin reduced by 33% and 81% respectively p<0.05) in TNF-Tg/HSD1KO compared to TNF-Tg. Although mRNA expression of RANK was increased in TNF-Tg mice compared to WT, expression was reduced by 48% in TNF-Tg/HSD1KO compared to TNF-Tg mice (p<0.05).

These results demonstrate that during inflammatory arthritis, local production of glucocorticoids is of critical importance in the prevention of severe bone loss.