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TGF‐beta Regulation by the Matricellular Protein Thrombospondin 1
Author(s) -
MurphyUllrich Joanne
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.00091
Subject(s) - thrombospondin 1 , matricellular protein , transforming growth factor beta , cancer research , multiple myeloma , transforming growth factor , tgf beta signaling pathway , immune system , extracellular matrix , medicine , endocrinology , immunology , chemistry , microbiology and biotechnology , biology , angiogenesis
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.