Abstract
Due to their potent immunomodulatory anti-inflammatory properties, synthetic glucocorticoids (GCs) are widely utilized in the treatment of chronic inflammatory disease. In this review, we examine our current understanding of how chronic inflammation and commonly used therapeutic GCs interact to regulate bone and muscle metabolism. Whilst both inflammation and therapeutic GCs directly promote systemic osteoporosis and muscle wasting, the mechanisms whereby they achieve this are distinct. Importantly, their interactions in vivo are greatly complicated secondary to the directly opposing actions of GCs on a wide array of pro-inflammatory signalling pathways that underpin catabolic and anti-anabolic metabolism. Several clinical studies have attempted to address the net effects of therapeutic glucocorticoids on inflammatory bone loss and muscle wasting using a range of approaches. These have yielded a wide array of results further complicated by the nature of inflammatory disease, underlying the disease management and regimen of GC therapy. Here, we report the latest findings related to these pathway interactions and explore the latest insights from murine models of disease aimed at modelling these processes and delineating the contribution of pre-receptor steroid metabolism. Understanding these processes remains paramount in the effective management of patients with chronic inflammatory disease.
Highlights
Synthetic glucocorticoids (GCs), such as dexamethasone, prednisolone and hydrocortisone, are widely utilized in the treatment of chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD) and rheumatoid arthritis (RA), with approximately 1% of the adult population in the U.K. and U.S receiving this class of drugs
GCs act via the GC receptor (GR) to suppress the NF-κB and p38-MAPK inflammatory pathways and activator protein 1 (AP-1) pro-inflammatory pathways, which regulate the transcription of various genes relating to inflammation such as tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1β) and -6 [22]
Mootl.eSncit. i2a01l9,b2e0,nxeFfiORtsPEaEnRdRErViIsEkWs of 11β-HSD1 inhibition in chronic inflammat1o2royf 2d2 isease. Both chronic inflammation and therapeutic GCs are potent drivers for systemic bone and muscle wasting resulting from an imbalance between anabolic and catabolic homeostasis
Summary
Synthetic glucocorticoids (GCs), such as dexamethasone, prednisolone and hydrocortisone, are widely utilized in the treatment of chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD) and rheumatoid arthritis (RA), with approximately 1% of the adult population in the U.K. and U.S receiving this class of drugs Their mechanisms of action are diverse, with GCs suppressing a range of pro-inflammatory pathways including p38-mitogen activated protein kinases (p38-MAPK), nuclear factor kappa-light-chain-enhancer (NF-κB) and activator protein (AP-1), in addition to inducing pro-resolving factors such as glucocorticoid induced leucine zipper (GILZ) and annexin-1 [1,2,3]. Despite the potent immune-modulatory anti-inflammatory actions of therapeutic GCs, their clinical application is limited due to severe systemic side effects These occur in up to 70% of patients and can include muscle wasting and GC induced osteoporosis (GIO) [6,7,8,9,10]. We explore how inflammatory drivers and therapeutic GCs interact to regulate bone and muscle metabolism and consider the role of local steroid metabolism in shaping these processes
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