ORCID Profile
0000-0002-4428-2658
Current Organisations
University of Birmingham
,
University of Oxford
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Publisher: MDPI AG
Date: 30-06-2022
DOI: 10.3390/IJMS23137334
Abstract: 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 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a mediator of the anti-inflammatory actions of therapeutic glucocorticoids (GCs) in vivo. In this study we delineate the role of 11β-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-tg11βKO), mesenchymal (including osteoblast) (TNF-tg11βflx/tw2cre) and myeloid (including osteoclast) (TNF-tg11βflx/LysMcre) deletion. Bone parameters were assessed by micro-CT, static histomorphometry and serum metabolism markers. We observed a marked increase in 11β-HSD1 activity in bone in RA relative to osteoarthritis bone, whilst the pro-inflammatory cytokine TNFα upregulated 11β-HSD1 within osteoblasts and osteoclasts. In osteoclasts, 11β-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 11β-HSD1 were resistant to these protective actions, characterised by increased osteoclastic bone resorption. Targeted deletion of 11β-HSD1 within osteoclasts and myeloid derived cells partially reproduced the GC resistant phenotype. These data reveal the critical role of 11β-HSD1 within bone and osteoclasts in mediating the suppression of inflammatory bone loss in response to therapeutic GCs in chronic inflammatory disease.
Publisher: Springer Science and Business Media LLC
Date: 08-2019
Publisher: Frontiers Media SA
Date: 27-08-2021
DOI: 10.3389/FENDO.2021.733611
Abstract: The role of tissue specific metabolism of endogenous glucocorticoids (GCs) in the pathogenesis of human disease has been a field of intense interest over the last 20 years, fuelling clinical trials of metabolism inhibitors in the treatment of an array of metabolic diseases. Localised pre-receptor metabolism of endogenous and therapeutic GCs by the 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes (which interconvert endogenous GCs between their inactive and active forms) are increasingly recognised as being critical in mediating both their positive and negative actions on bone homeostasis. In this review we explore the roles of endogenous and therapeutic GC metabolism by the 11β-HSD enzymes in the context of bone metabolism and bone cell function, and consider future strategies aimed at modulating this system in order to manage and treat various bone diseases.
Publisher: American Physiological Society
Date: 04-2023
DOI: 10.1152/AJPLUNG.00009.2022
Abstract: Muscle atrophy is an extrapulmonary complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The endogenous production and therapeutic application of glucocorticoids (GCs) have been implicated as drivers of muscle loss in AE-COPD. The enzyme 11 β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs and contributes toward GC-induced muscle wasting. To explore the potential of 11βHSD1 inhibition to prevent muscle wasting here, the objective of this study was to ascertain the contribution of endogenous GC activation and lification by 11βHSD1 in skeletal muscle wasting during AE-COPD. Emphysema was induced by intratracheal (IT) instillation of elastase to model COPD in WT and 11βHSD1/KO mice, followed by vehicle or IT-LPS administration to mimic AE. µCT scans were obtained prior and at study endpoint 48 h following IT-LPS, to assess emphysema development and muscle mass changes, respectively. Plasma cytokine and GC profiles were determined by ELISA. In vitro, myonuclear accretion and cellular response to plasma and GCs were determined in C2C12 and human primary myotubes. Muscle wasting was exacerbated in LPS-11βHSD1/KO animals compared with WT controls. RT-qPCR and western blot analysis showed elevated catabolic and suppressed anabolic pathways in muscle of LPS-11βHSD1/KO animals relative to WTs. Plasma corticosterone levels were higher in LPS-11βHSD1/KO animals, whereas C2C12 myotubes treated with LPS-11βHSD1/KO plasma or exogenous GCs displayed reduced myonuclear accretion relative to WT counterparts. This study reveals that 11β-HSD1 inhibition aggravates muscle wasting in a model of AE-COPD, suggesting that therapeutic inhibition of 11β-HSD1 may not be appropriate to prevent muscle wasting in this setting.
Publisher: BMJ
Date: 08-11-2020
DOI: 10.1136/ANNRHEUMDIS-2020-218493
Abstract: The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites of inflammation, its role in peripheral metabolism and action of therapeutic GCs remains poorly understood. We investigated the contribution of 11β-HSD1 to the anti-inflammatory properties of the active GC corticosterone, administered at therapeutic doses in murine models of polyarthritis. Using the tumour necrosis factor-tg and K/BxN serum-induced models of polyarthritis, we examined the anti-inflammatory properties of oral administration of corticosterone in animals with global, myeloid and mesenchymal targeted transgenic deletion of 11β-HSD1. Disease activity and joint inflammation were scored daily. Joint destruction and measures of local and systemic inflammation were determined by histology, micro-CT, quantitative RT-PCR, fluorescence activated cell sorting and ELISA. Global deletion of 11β-HSD1 resulted in a profound GC resistance in animals receiving corticosterone, characterised by persistent synovitis, joint destruction and inflammatory leucocyte infiltration. This was partially reproduced with myeloid, but not mesenchymal 11β-HSD1 deletion, where paracrine GC signalling between cell populations was shown to overcome targeted deletion of 11β-HSD1. We identify an entirely novel component of therapeutic GC action, whereby following their systemic metabolism, they require peripheral reactivation and lification by 11β-HSD1 at sites of inflammation to deliver their anti-inflammatory therapeutic effects. This study provides a novel mechanistic understanding of the anti-inflammatory properties of therapeutic GCs and their targeting to sites of inflammation in polyarthritis.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Claire Martin.