Investigation of inhibitory therapy of osteoclastic bone resorption for cancer-induced osteolysis

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  • SASAKI Akira
    Department of Oral and Maxillofacial Surgery, and Biopathological Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

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  • 破骨細胞性骨吸収を標的とした癌の骨浸潤・骨破壊制御に関する基礎的研究
  • ハコツ サイボウセイコツ キュウシュウ オ ヒョウテキ ト シタ ガン ノ コツ シンジュン コツ ハカイ セイギョ ニ カンスル キソテキ ケンキュウ

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Abstract

Cancer-induced osteolysis such as bone invasion or bone metastasis causes serious morbidity and reduces the survival rate or quality of life of cancer patients. Osteoclastic bone resorption plays an important role in cancer-induced bone diseases. Angiogenesis is an essential process in tumor growth and metastasis formation. Recently, it has been reported that a close relationship exists between osteoclastic bone resorption and angiogenic factors. Therefore, it is expected that potent osteoclastic bone resorption inhibitors or anti-angiogenesis agents would be efficacious for cancer-induced osteolysis.<BR>In the present study, we examined the effects of third-generation bisphosphonate as a bone resorption inhibitor, anti-angiogenesis agent TNP-470, matrix metalloproteinase inhibitor against MMP-2 and -9 (MMI-166), and an antibody against connective tissue growth factor (CTGF) as an angiogenesis inhibitor, on an osteolytic bone metastasis model in nude mice. Moreover, the effects of TNP-470 on a hypercalcemia model of nude mice transplanted with a human oral squamous cell carcinoma secreting PTHrP were examined. Consequently, bisphosphonate markedly inhibited the progression of established osteolytic lesions and prevented the development of new osteolytic lesions. TNP-470, an antibody against CTGF, and MMI-166 also inhibited cancerinduced osteolytic lesions in nude mice. TNP-470 also significantly improved the increase of blood Ca2+ in the hypercalcemia model. TNP-470 suppressed osteoclast formation and bone resorption activity in vitro. Antisense oligonucleotide of CTGF inhibited osteoclast formation, but did not affect the osteoclast activity. This indicates that anti-angiogenesis might suppress the osteoclastic bone resorption. These results suggested that inhibition of osteoclastic bone resorption has a possibility of therapeutic use for the treatment of cancer-induced bone osteolysis.

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