Open Access

Fluvastatin improves osteoporosis in fructose-fed insulin resistant model rats through blockade of the classical mevalonate pathway and antioxidant action

  • Authors:
    • Rie Hanayama
    • Hideo Shimizu
    • Hironori Nakagami
    • Mariana Kiomy Osako
    • Hirofumi Makino
    • Yasuo Kunugiza
    • Tetsuya Tomita
    • Ikuyo Tsukamoto
    • Hideki Yoshikawa
    • Hiromi Rakugi
    • Ryuchi Morishita
  • View Affiliations

  • Published online on: May 1, 2009     https://doi.org/10.3892/ijmm_00000167
  • Pages: 581-588
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Abstract

Feeding rats with a high-fructose diet induced insulin resistance, leading to hypertension or metabolic disorders. Although hypertension is known to accelerate osteoporosis, it is not obvious whether insulin resistance would accelerate osteoporosis. In this study, we evaluated whether osteoporosis might accelerate in fructose-fed rats (FFR), and examined the effect of fluvastatin through a blockade of the mevalonate pathway and an antioxidant action. Stimulation of recombinant receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL) expressed by osteoblasts/ stromal cells and macrophage-colony stimulating factor (M-CSF) significantly increased TRAP-positive multinuclear osteoclasts and pit formation, accompanied by an increase in reactive oxygen species as assessed by dichlorodihydrofluorescein (DCF) staining. Interestingly, it was completely abolished by treatment with fluvastatin, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), but not pravastatin. These actions of fluvastatin were partially abolished by co-treatment with geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP). In the estrogen-deficient model by ovariectomy, FFR exhibited a decrease in bone mineral density, activation of osteoclasts, and an increase in urinary deoxypyridinoline. Importantly, the treatment of fluvastatin, but not pravastatin, attenuated FFR-induced osteoporosis. The present study demonstrates that fructose fed to rats induced insulin resistance and accelerated osteoporosis, while fluvastatin, but not pravastatin, significantly attenuated osteoclast differentiation and activation through a blockade of the classical mevalonate pathway and an antioxidant action, leading to prevention of osteoporosis.

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May 2009
Volume 23 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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APA
Hanayama, R., Shimizu, H., Nakagami, H., Osako, M.K., Makino, H., Kunugiza, Y. ... Morishita, R. (2009). Fluvastatin improves osteoporosis in fructose-fed insulin resistant model rats through blockade of the classical mevalonate pathway and antioxidant action. International Journal of Molecular Medicine, 23, 581-588. https://doi.org/10.3892/ijmm_00000167
MLA
Hanayama, R., Shimizu, H., Nakagami, H., Osako, M. K., Makino, H., Kunugiza, Y., Tomita, T., Tsukamoto, I., Yoshikawa, H., Rakugi, H., Morishita, R."Fluvastatin improves osteoporosis in fructose-fed insulin resistant model rats through blockade of the classical mevalonate pathway and antioxidant action". International Journal of Molecular Medicine 23.5 (2009): 581-588.
Chicago
Hanayama, R., Shimizu, H., Nakagami, H., Osako, M. K., Makino, H., Kunugiza, Y., Tomita, T., Tsukamoto, I., Yoshikawa, H., Rakugi, H., Morishita, R."Fluvastatin improves osteoporosis in fructose-fed insulin resistant model rats through blockade of the classical mevalonate pathway and antioxidant action". International Journal of Molecular Medicine 23, no. 5 (2009): 581-588. https://doi.org/10.3892/ijmm_00000167