Experimental arthritis inhibits the insulin-like growth factor-I axis and induces muscle wasting through cyclooxygenase-2 activation

Abstract

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)-α, 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-α, 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.

The melanocortin receptor type 3 agonistd-Trp(8)-γMSH decreases inflammation and muscle wasting in arthritic rats

“…However, d ‐Trp(8)‐γMSH, unlike αMSH, was unable to prevent the increased expression of COX‐2 in the hypothalamus of arthritic rats. Taking into account the role of COX‐2 in inflammatory anorexia,34, 35 the lack of effect of d ‐Trp(8)‐γMSH treatment on hypothalamic COX‐2 induction can explain the different effects of both melanocortins on inflammatory anorexia.…”

Eicosapentaenoic acid attenuates arthritis-induced muscle wasting acting on atrogin-1 and on myogenic regulatory factors

“…We recently reported that COX-2 inhibition by meloxicam administration has an important anticachectic effect in arthritic rats (15) by preventing arthritis-induced increase in MuRF1 and atrogin-1 gene expression in the skeletal muscle. However, anti-inflammatory treatment with COX-2 inhibitors has been demonstrated to have several side effects on the cardiovascular system (16).…”

Ptgs2 activation by endotoxin mediates the decrease in Igf1, but not in Igfbp3, gene expression in the liver

“…One possible explanation could be that part of the in vivo meloxicam effect is an indirect effect, exerted outside the liver. In this sense, we have reported that meloxicam prevents the inhibitory effect of chronic arthritis on both pituitary GH and liver Igf1 gene expression (Granado et al 2007). In the present data we did not evaluate pituitary GH, since LPS at the dose of 0 .…”

“…injected with the selective Ptgs2 inhibitor, meloxicam (1 mg/kg, Sigma), while the other half were injected with 250 ml sterile saline. Meloxicam at this dosage decreased serum concentrations of Ptges2 and prevented arthritis-induced decrease in liver Igf1 gene expression (Granado et al 2007).…”

“…We have shown that Ptgs2 inhibition is able to prevent chronic arthritis-induced decrease in serum concentration of Igf1 and its gene expression in the liver (Granado et al 2007). Taking into account that Ptgs2 is expressed in Kupffer cells, and not in hepatocytes, incubated with LPS (Martín-Sanz et al 1998), it is possible that Ptgs2 activation can contribute to the LPS-induced decrease in Igf1 gene expression in the liver.…”