The metastasis-associated metalloproteinase stromelysin-3 is induced by transforming growth factor-ss in osteoblasts and fibroblasts

Bone matrix serves as a reservoir of growth factors important in growth and tissue remodeling, and transforming growth factor-beta (TGF-beta) is abund ant in bone matrix. Normal processes, such as remodeling, and pathological processes. such as osteolytic metastasis, cause the release of growth facto rs from the matrix, allowing them to influence the behavior of cells within their microenvironment. Breast cancer metastases frequently establish them selves in the bone compartment, often causing localized osteolysis. Stromel ysin-3 is a matrix metalloproteinase associated with tumor metastases. Its expression in host tissues favors the homing and survival of malignant epit helial cells in early tumorigenesis by releasing and/or activating growth f actors sequestered in the extracellular matrix. Osteoblasts express stromel ysin-3, and Northern and Western blot analysis show that its messenger RNA and protein levels are increased by TGF-beta. Nuclear run-off assays demons trate activation of gene transcription, and experiments using transcription inhibitors demonstrate stabilization of stromelysin-3 messenger RNA by TGF -beta. Importantly. TGF beta induces stromelysin-3 in fibroblasts by simila r mechanisms, indicating that it is likely to stimulate stromelysin-3 expre ssion in breast stroma. Stimulation of stromelysin-3 expression by TGF-beta in fibroblasts and osteoblasts could play a role in the metastasis of brea st cancer cells and their homing and survival in bone.