Cargando…
SAT-003 Therapeutic Glucocorticoids Prevent Local and Systemic Bone Loss but Exacerbate Muscle Wasting When Administered in Chronic Inflammation
Glucocorticoids (GCs) are used in the treatment of chronic inflammatory diseases due to their potent anti-inflammatory actions. Their use is limited due to major systemic side effects including osteoporosis and muscle wasting. This is further complicated by pre-existing inflammatory muscle wasting a...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552069/ http://dx.doi.org/10.1210/js.2019-SAT-003 |
_version_ | 1783424517188616192 |
---|---|
author | Fenton, Chloe Webster, Justine Fareed, Syeda Martin, Claire Wehmeyer, Corinna Cooper, Mark Buckley, Chris Lavery, Gareth Langen, Ramon Raza, Karim Hardy, Rowan |
author_facet | Fenton, Chloe Webster, Justine Fareed, Syeda Martin, Claire Wehmeyer, Corinna Cooper, Mark Buckley, Chris Lavery, Gareth Langen, Ramon Raza, Karim Hardy, Rowan |
author_sort | Fenton, Chloe |
collection | PubMed |
description | Glucocorticoids (GCs) are used in the treatment of chronic inflammatory diseases due to their potent anti-inflammatory actions. Their use is limited due to major systemic side effects including osteoporosis and muscle wasting. This is further complicated by pre-existing inflammatory muscle wasting and bone loss, driven by pro-inflammatory pathways that are themselves directly suppressed by GCs. Understanding the interaction between these processes and their net effects on bone and muscle metabolism in vivo is critical in informing our approach to managing these patients. We investigated this in the TNF-tg model of chronic inflammation receiving the GC corticosterone (100 μg/ml) at therapeutic doses in drinking water over 3 weeks. Arthritis severity and clinical parameters were scored, front paws and tibias assessed by μCT analysis and markers of bone metabolism and inflammation determined by serum ELISA. Muscles were weighed and taken for histological analysis. Metabolic and inflammatory gene expression were determined by RT qPCR. Corticosterone potently suppressed clinical scores of inflammation and circulating pro-inflammatory cytokines including IL-6 in TNF-tg mice. A decrease in pro-inflammatory gene expression was seen in bone and muscle. Analysis of trabecular bone volume (BV/TV) and trabecular number (Tb.N) by μCT revealed that TNF-tg mice receiving corticosterone were protected from bone loss relative to controls (BV/TV: TNF-tg 2.19% ± 0.2 vs TNF-tg CORT 4.25% ± 0.2, P≤0.001; Tb.N: TNF-tg 0.0004 1/μm ± 0.00004 vs TNF-tg CORT 0.0008 1/μm ± 0.00003, P≤0.001). Whilst serum markers of bone formation (P1NP) and osteoblast gene expression were significantly suppressed in mice receiving corticosterone, an overwhelming suppression of osteoclast activity determined by serum CTX-1 and osteoclast numbers appeared to mediate the protective actions of GCs in the TNF-tg mouse (CTX-1: TNF-tg 81.6 ng/ml ± 10.7 vs TNF-tg CORT 36 ng/ml ± 2.7, P≤0.01). In contrast, in TNF-tg mice receiving corticosterone muscle wasting was further exacerbated. Muscle weights were significantly reduced in TNF-tg mice receiving corticosterone, with muscle fibre size markedly suppressed (Quad: TNF-tg 0.15 g ± 0.012 vs TNF-tg CORT 0.10 g ± 0.009, P≤0.01; TA: TNF-tg 0.06 g ± 0.005 vs TNF-tg CORT 0.03 g ± 0.004, P≤0.01). This was driven by a marked upregulation of anti-anabolic and catabolic gene expression in TNF-tg mice receiving corticosterone relative to vehicle treated controls (FBXO32; 4.7 fold, p<0.001, TRIM63; 3 fold, p<0.05, REDD1; 4 fold, NS, FoxO1; 3 fold, p<0.01). In the TNF-tg model of chronic inflammation, therapeutic GCs prevented local and systemic bone loss but markedly exacerbated muscle wasting. These results suggest that interventions that preserve muscle mass and function should be prioritised where therapeutic GCs are utilized to treat chronic inflammation. |
format | Online Article Text |
id | pubmed-6552069 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-65520692019-06-13 SAT-003 Therapeutic Glucocorticoids Prevent Local and Systemic Bone Loss but Exacerbate Muscle Wasting When Administered in Chronic Inflammation Fenton, Chloe Webster, Justine Fareed, Syeda Martin, Claire Wehmeyer, Corinna Cooper, Mark Buckley, Chris Lavery, Gareth Langen, Ramon Raza, Karim Hardy, Rowan J Endocr Soc Steroid Hormones and Receptors Glucocorticoids (GCs) are used in the treatment of chronic inflammatory diseases due to their potent anti-inflammatory actions. Their use is limited due to major systemic side effects including osteoporosis and muscle wasting. This is further complicated by pre-existing inflammatory muscle wasting and bone loss, driven by pro-inflammatory pathways that are themselves directly suppressed by GCs. Understanding the interaction between these processes and their net effects on bone and muscle metabolism in vivo is critical in informing our approach to managing these patients. We investigated this in the TNF-tg model of chronic inflammation receiving the GC corticosterone (100 μg/ml) at therapeutic doses in drinking water over 3 weeks. Arthritis severity and clinical parameters were scored, front paws and tibias assessed by μCT analysis and markers of bone metabolism and inflammation determined by serum ELISA. Muscles were weighed and taken for histological analysis. Metabolic and inflammatory gene expression were determined by RT qPCR. Corticosterone potently suppressed clinical scores of inflammation and circulating pro-inflammatory cytokines including IL-6 in TNF-tg mice. A decrease in pro-inflammatory gene expression was seen in bone and muscle. Analysis of trabecular bone volume (BV/TV) and trabecular number (Tb.N) by μCT revealed that TNF-tg mice receiving corticosterone were protected from bone loss relative to controls (BV/TV: TNF-tg 2.19% ± 0.2 vs TNF-tg CORT 4.25% ± 0.2, P≤0.001; Tb.N: TNF-tg 0.0004 1/μm ± 0.00004 vs TNF-tg CORT 0.0008 1/μm ± 0.00003, P≤0.001). Whilst serum markers of bone formation (P1NP) and osteoblast gene expression were significantly suppressed in mice receiving corticosterone, an overwhelming suppression of osteoclast activity determined by serum CTX-1 and osteoclast numbers appeared to mediate the protective actions of GCs in the TNF-tg mouse (CTX-1: TNF-tg 81.6 ng/ml ± 10.7 vs TNF-tg CORT 36 ng/ml ± 2.7, P≤0.01). In contrast, in TNF-tg mice receiving corticosterone muscle wasting was further exacerbated. Muscle weights were significantly reduced in TNF-tg mice receiving corticosterone, with muscle fibre size markedly suppressed (Quad: TNF-tg 0.15 g ± 0.012 vs TNF-tg CORT 0.10 g ± 0.009, P≤0.01; TA: TNF-tg 0.06 g ± 0.005 vs TNF-tg CORT 0.03 g ± 0.004, P≤0.01). This was driven by a marked upregulation of anti-anabolic and catabolic gene expression in TNF-tg mice receiving corticosterone relative to vehicle treated controls (FBXO32; 4.7 fold, p<0.001, TRIM63; 3 fold, p<0.05, REDD1; 4 fold, NS, FoxO1; 3 fold, p<0.01). In the TNF-tg model of chronic inflammation, therapeutic GCs prevented local and systemic bone loss but markedly exacerbated muscle wasting. These results suggest that interventions that preserve muscle mass and function should be prioritised where therapeutic GCs are utilized to treat chronic inflammation. Endocrine Society 2019-04-30 /pmc/articles/PMC6552069/ http://dx.doi.org/10.1210/js.2019-SAT-003 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Steroid Hormones and Receptors Fenton, Chloe Webster, Justine Fareed, Syeda Martin, Claire Wehmeyer, Corinna Cooper, Mark Buckley, Chris Lavery, Gareth Langen, Ramon Raza, Karim Hardy, Rowan SAT-003 Therapeutic Glucocorticoids Prevent Local and Systemic Bone Loss but Exacerbate Muscle Wasting When Administered in Chronic Inflammation |
title | SAT-003 Therapeutic Glucocorticoids Prevent Local and Systemic Bone Loss but Exacerbate Muscle Wasting When Administered in Chronic Inflammation |
title_full | SAT-003 Therapeutic Glucocorticoids Prevent Local and Systemic Bone Loss but Exacerbate Muscle Wasting When Administered in Chronic Inflammation |
title_fullStr | SAT-003 Therapeutic Glucocorticoids Prevent Local and Systemic Bone Loss but Exacerbate Muscle Wasting When Administered in Chronic Inflammation |
title_full_unstemmed | SAT-003 Therapeutic Glucocorticoids Prevent Local and Systemic Bone Loss but Exacerbate Muscle Wasting When Administered in Chronic Inflammation |
title_short | SAT-003 Therapeutic Glucocorticoids Prevent Local and Systemic Bone Loss but Exacerbate Muscle Wasting When Administered in Chronic Inflammation |
title_sort | sat-003 therapeutic glucocorticoids prevent local and systemic bone loss but exacerbate muscle wasting when administered in chronic inflammation |
topic | Steroid Hormones and Receptors |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552069/ http://dx.doi.org/10.1210/js.2019-SAT-003 |
work_keys_str_mv | AT fentonchloe sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT websterjustine sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT fareedsyeda sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT martinclaire sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT wehmeyercorinna sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT coopermark sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT buckleychris sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT laverygareth sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT langenramon sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT razakarim sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation AT hardyrowan sat003therapeuticglucocorticoidspreventlocalandsystemicbonelossbutexacerbatemusclewastingwhenadministeredinchronicinflammation |