Experimental arthritis inhibits the insulin-like growth factor-I axis and induces muscle wasting through cyclooxygenase-2 activation.
Chronic arthritis induces cachexia associated with an inhibition of the growth hormone (GH)-insulin-like growth factor-I (IGF-I) system and an activation of the E3 ubiquitin-ligating enzymes muscle atrophy F-box (MAFbx) and muscle Ring finger 1 (MuRF1) in the skeletal muscle. The aim of this work was to study the role of cyclooxygenase (COX)-2 in chronic arthritis-induced cachexia. Arthritis was induced in rats by Freund's adjuvant injection, and the effects of two COX inhibitors (indomethacin, a nonspecific inhibitor, and meloxicam, a selective COX-2 inhibitor on pituitary GH and on liver and serum IGF-I levels) were tested. Arthritis decreased body weight gain and GH and liver IGF-I gene expression. In the arthritic rats, both inhibitors, indomethacin and meloxicam, prevented the inhibitory effect of arthritis on body weight gain. Indomethacin and meloxicam administration to arthritic rats increased pituitary GH and liver IGF-I mRNA as well as serum levels of IGF-I. These data suggest that induction of COX-2 during chronic inflammation is involved in the inhibition of the GH-IGF-I axis and in the body weight loss. In the gastrocnemius muscle, arthritis increased the gene expression of tumor necrosis factor (TNF)-alpha, the E3 ubiquitin-ligating enzymes MAFbx and MuRF1, as well as of IGF-I and IGF-binding protein-5 (IGFBP-5). Inhibition of COX-2 by meloxicam administration increased gastrocnemius weight and decreased MAFbx, MuRF1, TNF-alpha, and IGFBP-5 gene expression. In summary, our data indicate that chronic arthritis-induced cachexia and muscle wasting are mediated by the COX-2 pathway resulting in a decreased GH-IGF-I secretion and increased expression of MAFbx and MuRF1 mRNA.
Granado
Miriam
M
Facultad de Medicina, Departamento Fisiología, Universidad Complutense, Madrid, Spain.
Martín
Ana I
AI
Villanúa
Maria Angeles
MA
López-Calderón
Asunción
A
D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications* / Q000378:metabolism*; D002100:Cachexia / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D002908:Chronic Disease; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D013006:Growth Hormone / Q000235:genetics; D007213:Indomethacin / Q000494:pharmacology; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D000077239:Meloxicam; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology*; D010902:Pituitary Gland / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D015430:Weight Gain / Q000187:drug effects
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018975:Insulin-Like Growth Factor Binding Protein 5; D009124:Muscle Proteins; D012333:RNA, Messenger; D013843:Thiazines; D013844:Thiazoles; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D051546:Cyclooxygenase 2; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D000077239:Meloxicam; D007213:Indomethacin