Investigation of mechanism of connective tissue growth factor (CTGF) as a molecular target against cancer-induced bone destruction

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Osteoclastic bone resorption plays an important role on cancer-induced bone disease likes bone metastases or cancer bone invasion. We previously reported that administration of antibody against connective tissue growth factor (CTGF) inhibited osteolytic lesions in nude mice bone metastasis model. It is suggested that inhibition of CTGF has a possibility of therapeutic use for the treatment of the cancer induced bone disease. However, the relationship between osteoclastic bone resorption and CTGF has been still unknown. In the present study, we examined the mechanism of CTGF on osteoclastic bone resorption to know whether we could use CTGF as a molecular target against the cancer-induced bone disease.Immunohistologically, the expression of CTGF protein was observed at bone-marrow stromal cells and osteoclasts, and especially localized at cytoplasm around the nuclei of osteoclasts in murine bone marrow culture system in vitro. CTGF anti-sense oligonucleotide (AS-CTGF) suppressed osteocla … More st formation, but did not inhibit mature osteoclastic bone resorption on dentin slice in vitro. AS-CTGF suppressed the expression of ODF (RANKL) mRNA in bone marrow /stromal cell line ST2, but did not affect the OCIF mRNA expression. Next, we examined the bone metabolism in nude mice subcutaneous implanting CHO cells transfected with CTGF gene. In spite of over-production of CTGF, systemic hypercalcemia was not observed in nude mice. And there is no difference of the tumor growth and body weight loss between the nude mice transfected with the transfectants and non-transfectant.It is well known that many growth factors store in bone matrices. Release of these growth factors like TGF-β by cancer-induced bone resorption probably regulates the biological events in the bone microenvironment. TGF-β dose-dependently increased the expression of CTGF mRNA of not only human breast cancer cells line MDA-231, but also ST2 cell. This indicates that TGF-β might regulate the CTGF expression of local bone resorption sites as paracrine factor. From these results, CTGF may play an important role on the local bone resorption site, and the inhibition of CTGF expression may be useful therapy for local bone destruction induced by cancer. Less