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Impact of sphingosine-1-phosphate in osteolytic bone metastasis

Recent evidence has revealed the direct regulatory activities between TGF-beta/Smad signaling and alterations of sphingosine metabolism including the activation of sphingosine kinase-1 (SphK1) and subsequent production of sphingosine-1-phosphate (S1P). S1P signaling is important in the migratory behavior of monocytic-osteoclast precursor cells to and from the bone surface. TGF-beta-mediated upregulation of sphingosine kinase-1/S1P3 activity drives cellular trans-differentiation to a fibroblastic phenotype. Our hypothesis is that TGF-beta stimulates S1P production via increased sphingosine kinase activity in osteolytic human tumor cells and S1P production/secretion within the bone-tumor microenvironment is a potential key determinant in tumor-induced osteolytic bone destruction. A combined therapy targeting S1P signaling pathways with bisphosphonates(s)/anti-RANKL antibody treatments may be superior in the prevention and/or management of osteolytic bone metastases.