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11ß-Hydroxysteroid Dehydrogenase Type 1 within Osteoclasts Mediates the Bone Protective Properties of Therapeutic Corticosteroids in Chronic Inflammation.
Fenton, Chloe G; Crastin, Ana; Martin, Claire S; Suresh, Saicharan; Montagna, Isabella; Hussain, Bismah; Naylor, Amy J; Jones, Simon W; Hansen, Morten S; Gorvin, Caroline M; Price, Maria; Filer, Andrew; Cooper, Mark S; Lavery, Gareth G; Raza, Karim; Hardy, Rowan S.
Afiliación
  • Fenton CG; Institute for Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK.
  • Crastin A; Research into Inflammatory Arthritis Centre Versus Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK.
  • Martin CS; Institute of Clinical Science, University of Birmingham, Birmingham B15 2TT, UK.
  • Suresh S; Institute for Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK.
  • Montagna I; Institute of Clinical Science, University of Birmingham, Birmingham B15 2TT, UK.
  • Hussain B; Institute for Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK.
  • Naylor AJ; Institute of Clinical Science, University of Birmingham, Birmingham B15 2TT, UK.
  • Jones SW; Research into Inflammatory Arthritis Centre Versus Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK.
  • Hansen MS; MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, University of Birmingham, Edgbaston Campus, Birmingham B15 2TT, UK.
  • Gorvin CM; Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark.
  • Price M; Institute for Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK.
  • Filer A; Centre for Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham B15 2TT, UK.
  • Cooper MS; Institute for Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK.
  • Lavery GG; Research into Inflammatory Arthritis Centre Versus Arthritis, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK.
  • Raza K; MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, University of Birmingham, Edgbaston Campus, Birmingham B15 2TT, UK.
  • Hardy RS; ANZAC Research Institute, The University of Sydney, Sydney, NSW 2006, Australia.
Int J Mol Sci ; 23(13)2022 Jun 30.
Article en En | MEDLINE | ID: mdl-35806338
Therapeutic glucocorticoids (GCs) are powerful anti-inflammatory tools in the management of chronic inflammatory diseases such as rheumatoid arthritis (RA). However, their actions on bone in this context are complex. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a mediator of the anti-inflammatory actions of therapeutic glucocorticoids (GCs) in vivo. In this study we delineate the role of 11ß-HSD1 in the effects of GC on bone during inflammatory polyarthritis. Its function was assessed in bone biopsies from patients with RA and osteoarthritis, and in primary osteoblasts and osteoclasts. Bone metabolism was assessed in the TNF-tg model of polyarthritis treated with oral GC (corticosterone), in animals with global (TNF-tg11ßKO), mesenchymal (including osteoblast) (TNF-tg11ßflx/tw2cre) and myeloid (including osteoclast) (TNF-tg11ßflx/LysMcre) deletion. Bone parameters were assessed by micro-CT, static histomorphometry and serum metabolism markers. We observed a marked increase in 11ß-HSD1 activity in bone in RA relative to osteoarthritis bone, whilst the pro-inflammatory cytokine TNFα upregulated 11ß-HSD1 within osteoblasts and osteoclasts. In osteoclasts, 11ß-HSD1 mediated the suppression of bone resorption by GCs. Whilst corticosterone prevented the inflammatory loss of trabecular bone in TNF-tg animals, counterparts with global deletion of 11ß-HSD1 were resistant to these protective actions, characterised by increased osteoclastic bone resorption. Targeted deletion of 11ß-HSD1 within osteoclasts and myeloid derived cells partially reproduced the GC resistant phenotype. These data reveal the critical role of 11ß-HSD1 within bone and osteoclasts in mediating the suppression of inflammatory bone loss in response to therapeutic GCs in chronic inflammatory disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoartritis / Artritis Reumatoide / Resorción Ósea Límite: Animals Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteoartritis / Artritis Reumatoide / Resorción Ósea Límite: Animals Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article Pais de publicación: Suiza