Mechanism of signal transduction that regulates osteoclast differentiation and its abnormalities in bone distructive diseases

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1. Cloning of RANKL-induced early genes in osteoclast progenitorsHuman leukemia cell line, HL60, expressed RANK upon differentiation induced by TPA and 1, 25-vitamin D. RANKL treatment of thus induced HL60 cells led to further up-regulation of RANK.Meanwhile, we have identified several RANKL target genes with suppression PCR methods by stimulating osteoclast progenitors including primary mouse spleen cells and a mouse preosteoclast cell line, C7, with RANKL for one to four hours. Among such genes are cathepsins and uncharacterized transcription factors. Elucidation of RANKL signaling pathways that induce these target genes would lead to identification of master genes that regulates osteoclast differentiation.2. Mechanism of osteoclast induction by multiple myeloma (MM) cellsWe demonstrated macrophage inflammatory protein (MIP)-1 alpha and beta are abundantly produced by MM cells. These chemokines not only induced RANKL expression by stromal cells via their common receptor CCR5, but also acts in an autocrine/paracrine fashion to activate VLA-4 on MM cells, thereby enhancing cellular interactions with stromal cells which express VCAM-1 on their surface. We also found that MIP-1 enhances binding of MM cells to osteoclasts. Proliferation and survival of MM cells was enhanced by the presence of osteclasts in a manner dependent on direct cell-cell interactions. These effects appeared to involve matrix proteins such as osteopontin abundantly produced by osteoclasts as well as interleukin-6, a known growth factor for MM cells.Taken together, these results suggested that complex cellular interactions in the bone marrow milieu, in which MIP-1 may play a central role, leads to not only efficient activation of osteoclasts but also enhancement of MM proliferation and survival, thereby causing a vicious cycle that leads to profound bone destruction.