Ailing Lu, Manuel Antonio Pallero, Weiqi Lei, Huixian Hong, Yang Yang, Mark J. Suto, Joanne E. Murphy-Ullrich
Transforming growth factor (TGF)-β supports multiple myeloma progression and associated osteolytic bone disease. Conversion of latent TGF-β to its biologically active form is a major regulatory node in controlling its activity. Thrombospondin1 (TSP1) binds and activates TGF-β. TSP1 is increased in myeloma; TSP1–TGF-β activation inhibits osteoblast differentiation. We hypothesized that TSP1 regulates TGF-β activity in myeloma and antagonizing TSP1–TGF-β axis may inhibit myeloma progression. Antagonists (LSKL peptide, SRI31277) derived from the LSKL sequence of latent TGF-β that block TSP1–TGF-β activation were used to determine the role of the TSP1–TGF-β pathway in three mouse models of myeloma. TSP1 bound to human myeloma cells and activated latent TGF-β produced by human and mouse myeloma cell lines. Treatment with antagonists delivered via osmotic pump in an intratibial severe combined immunodeficiency CAG myeloma model or in a systemic severe combined immunodeficiency CAG-heparanase model of aggressive myeloma reduced tumor burden, mouse interleukin-6, and osteoclasts, increased osteoblast number, and inhibited bone destruction as measured by microcomputed tomography. Antagonists reduced TGF-β signaling (phospho-Smad2) in bone sections and reduced tumor burden in the immune competent 5TGM1 model of mouse myeloma. SRI31277 was as effective as dexamethasone or bortezomib, and SRI31277 combined with bortezomib showed greater tumor reduction than either agent alone. These studies validate TSP1-regulated TGF-β activation as a therapeutic strategy for targeted inhibition of TGF-β in myeloma.