Cell-matrix interaction in the regulation of bone metabolism and its disorder in involutional osteoporosis

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1) Intracellular signaling activated by matrix type I collagen in osteoblastic differentiationWe have previously shown that interaction of type I collagen (COL) with α2β1 integrin is indispensable for the osteoblastic differentiation. Intracellular signaling pathways including focal adhesion kinase (FAK)- Ras-ERK have been shown to be involved in the expression of osteoblastic phenotypes. In this study, we further analyzed signals activated by COL via integrin-independent mechanism. Attachment of cells to COL stimulated tyrosine phosphorylation of discoidin domain receptor-2 (DDR2), that contains tyrosine kinase motif in its intracellular domain. Deletion of kinase region made DDR2 inactive. DDR2 might associate with FAK and phosphatidylinositol 3-kinase (PI3-K) to form a complex of signaling molecules. These signaling pathways may play an important role in the differentiation and function of osteoblasts.2) Essential corss-talk between integrin-FAK-Ras-ERK and BMP-Smad1 in osteoblastic … More differentiationWe have demonstrated that endogenous BMP-2/4 accumulated in extracellular matrices are essential for the osteoblastic differentiation of cells in the osteoblast lineage. In this study, we showed that FAK and its downstream signals were essential for Smad1 signals activated by BMP.Osteoblastic cells constitutively expressing antisense mRNA for FAK did not respond to BMP-2. Although Smad1 was phosphorylated and translocated into nuclei in response to BMP-2, Smad1-dependent transcriptional activity could not be activated in these cells. It was also demonstrated that Ras-MEK-ERK might be involved in this pathway. Therefore, FAK-Ras-ERK signals may be essential for BMP-Smad1 actions in osteoblastic cells. These results further reveal molecular mechanisms whereby cell-matrix interactions is invloved in the osteoblastic differentiation.3) Cell-cell interactions in cancer-induced osteoclastogenesisWe examined molecular mechanisms whereby cancer cells that potentially metastasize to andestruct bone induce osteoclastogenesis in vitro. Direct interactions of breast cancer Balb/c-MC or melanoma B16 cells to bone marrow cells induced RANK ligand expression to stimulate osteoclastogenesis in vitro. Thus, cell-cell interactions between cancer and bone marrow cells may be an important step of bone destruction followed by creating a focus of bone metastasis. Less