Role of Interleukin-6 in Uncoupling of Bone In Vivo in a Human Squamous Carcinoma Coproducing Parathyroid Hormone-Related Peptide and Interleukin-6

  • Yumiko Nagai
    Biomedical Research Laboratories, Kureha Chemical Industry, Co., Ltd., Tokyo, Japan
  • Hideyuki Yamato
    Biomedical Research Laboratories, Kureha Chemical Industry, Co., Ltd., Tokyo, Japan
  • Keiko Akaogi
    Biomedical Research Laboratories, Kureha Chemical Industry, Co., Ltd., Tokyo, Japan
  • Kunitaka Hirose
    Biomedical Research Laboratories, Kureha Chemical Industry, Co., Ltd., Tokyo, Japan
  • Yoshito Ueyama
    Central Institute for Experimental Animals, Kanagawa, Japan
  • Kyoji Ikeda
    Department of Geriatric Research, National Institute for Longevity Sciences, Aichi, Japan
  • Toshio Matsumoto
    First Department of Internal Medicine, University of Tokushima School of Medicine, Tokushima, Japan
  • Toshiro Fujita
    Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan
  • Etsuro Ogata
    Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

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<jats:title>Abstract</jats:title> <jats:p>OCC tumor has been established from a human squamous carcinoma associated with humoral hypercalcemia of malignancy (HHM) and shown to overproduce parathyroid hormone-related peptide (PTHrP) and cause aggressive hypercalcemia when implanted into nude rats. In the present study, we have demonstrated by reverse transcription-polymerase chain reaction and Northern blot analysis that OCC tumor also overexpressed interleukin 6 (IL-6) mRNA and that tumor-bearing animals exhibited a marked increase in plasma IL-6 as well as PTHrP concentrations. When a monoclonal antibody against human IL-6 was injected to block the activities of tumor-derived IL-6, bone loss in tumor-bearing animals was significantly prevented. Quantitative bone histomorphometric analysis revealed that treatment with anti–IL-6 antibody caused a substantial decrease in both osteoclast number and eroded surface (as parameters of bone resorption) and also a significant increase in the mineral apposition rate, but little effect on the osteoblastic surface. These results provide in vivo evidence suggesting that in tumors coproducing IL-6 and PTHrP, IL-6 is involved not only in the acceleration of osteoclastic bone resorption but also, at least in part, in the suppression of osteoblastic functions in HHM syndrome.</jats:p>

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