ECTS Abstracts (2015) 1 P445

Plasminogen Activator Inhibitor-1 is Involved in Glucocorticoid-Induced Osteopenia, Diabetes and Muscle Wasting in Mice

Yukinori Tamura1, Naoyuki Kawao1, Masato Yano1, Kiyotaka Okada1, Katsumi Okumoto2, Yasutaka Chiba3, Osamu Matsuo4 & Hiroshi Kaji1


1Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan, 2Life Science Research Institute, Kinki University, Osaka, Japan, 3Clinical Research Center, Kinki University Hospital, Osakasayama, Japan, 4Kinki University Faculty of Medicine, Osakasayama, Japan.


Glucocorticoids (GC) have been widely used for the treatment of inflammatory disease. Despite high efficacy of GC treatment, its clinical use is limited by the numerous adverse effects, including osteoporosis, diabetes and muscle wasting. However, its pathogenesis remains unclear, and the evidence for systemic mediators in GC effects are lacking. Plasminogen activator inhibitor-1 (PAI-1) is adipocytokine, which is induced by GC treatment. Previous studies suggest that elevated circulating PAI-1 level is associated with several metabolic disorders, such as diabetes and osteoporosis. Therefore, in the present study, we examined the role of PAI-1 in GC-induced osteoporosis, glucose/lipid abnormalities and muscle wasting by using PAI-1-deficient mice. GC treatment for 4 weeks markedly increased the levels of circulating PAI-1 and PAI-1 mRNA in white adipose tissues in wild-type mice. Quantitative CT and histological analysis revealed that PAI-1 deficiency blunted GC-induced bone loss and the number of osteoblasts decreased by GC treatment in tibia of mice. Moreover, exogenous PAI-1 treatment induced apoptosis in primary osteoblasts obtained from mouse calvaria in vitro, suggesting that PAI-1 deficiency protects from GC-induced bone loss presumably through a decrease in apoptosis of osteoblasts. PAI-1 deficiency significantly improved insulin resistance but not hyperlipidaemia induced by GC treatment in mice. In vitro study revealed that exogenous PAI-1 treatment inhibits insulin-induced phosphorylation of Akt and glucose uptake in hepatocytes, but not in adipocytes and myotubes, suggesting that PAI-1 is involved in GC-induced insulin resistance by affecting hepatocytes. Moreover, PAI-1 deficiency blunted GC-induced muscle loss in mice. In conclusion, we first demonstrated that PAI-1 is involved in the metabolic adverse effects of GC treatment, such as bone loss, insulin resistance, and muscle wasting in mice. PAI-1 may be a novel therapeutic target for decreasing GC-induced adverse outcomes and also a diagnostic marker of GC-induced osteoporosis, diabetes and muscle wasting.

Disclosure: The authors declared no competing interests.

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