ROLE OF RANKL IN OSTEOLYTIC BONE METASTASIS OF MALIGNANT TUMOR

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Breast cancer is frequently associated with osteolytic bone metastasis, where osteoclasts play a major role in bone destruction. Recently, osteoclast differentiation factor (RANKL) has been identified as a prerequisite for the formation and maintenance of osteoclasts from haematopoietic precursors. To elucidate the mechanism of osteoclastogenesis and bone destruction in bone-residing breast cancer, human breast cancer cells (MCF-7) were injected into the forehead of nude mice. The expression of RANKL and PTHrP mRNA, and osteoclastogenesis were analysed by in situ hybridization and TRAP staining. At early stages, spindle-shaped stromal cells and osteoblasts on the bone surface expressed RANKL, then numerous osteoclasts were induced on the periosteal bone surface. Three weeks after the transplantation, cancer cells migrated onto the eroded bone surface, where they survived apoptosis. At all stages, RANKL expression was confined to the stromal/osteoblastic cells, whereas PTHrP was confined to the MCF-7 breast cancer cells. On the other hand, neither induction of osteoclasts nor infiltrative growth of cancer cells was observed in mice transplanted with PTHrP-non producing cancer cells. Moreover, in vitro treatment with PTHrP resulted in increased RANKL mRNA expression and transcription activity in the MC3T3-E1 mouse osteoblastic cell line. Thus PTHrP induces osteoclastic bone resorption through the transactivation of the RANKL gene on stromal/osteoblastic cells, affording a bone microenvironment conducive to the survival of PTHrP-producing cancer cells.We have presented our data at various international as well as domestic meeting, and published scientific papers for academic journals.