TGF‐beta Regulation by the Matricellular Protein Thrombospondin 1

Abstract

Thrombospondin 1 (TSP1) is a matricellular protein that plays multiple roles in disease. Activation of the TGF‐beta latent complex is a major regulatory node for controlling TGF‐beta in homeostasis and disease. TSP1 can regulate the conversion of latent transforming growth factor‐beta (TGF‐beta) to its biologically active form in certain fibrotic diseases and cancers. We have developed peptide and small molecule antagonists that block TSP1 binding to the latent complex and inhibit TSP1‐dependent activation of latent TGF‐beta. These antagonists reduce TGF‐beta activity and extracellular matrix production and fibrosis in multiple rodent models, particularly in fibrotic complications of diabetes. TGF‐beta also plays a role in the osteolytic bone destruction characteristic of the plasma cell cancer, multiple myeloma. In both immune competent syngeneic mouse and human xenograft models, we showed that treatment with the TSP1‐TGF‐beta antagonist reduced disease burden, TGF‐beta activity, and prevented bone destruction via a decrease in osteoclasts and an increase in osteoblasts. Current studies are examining the role of the TSP1‐TGF‐beta pathway in immune dysregulation in multiple myeloma.Support or Funding InformationThe most recent studies (myeloma, drug development) are supported by grants from the Alabama Drug Discovery Alliance and the UAB Comprehensive Cancer Center pilot grant program, the American Society for Hematology Bridge Grant with supporting funds from the UAB Department of Pathology, and NIH grant 1R01CA175012.