Abstract
Recent advances provide evidence that the cellular signalling pathway comprising the ligand-receptor duo of thrombospondin-1 (TSP1) and CD47 is involved in mediating a range of diseases affecting renal, vascular, and metabolic function, as well as cancer. In several instances, research has barely progressed past pre-clinical animal models of disease and early phase 1 clinical trials, while for cancers, anti-CD47 therapy has emerged from phase 2 clinical trials in humans as a crucial adjuvant therapeutic agent. This has important implications for interventions that seek to capitalize on targeting this pathway in diseases where TSP1 and/or CD47 play a role. Despite substantial progress made in our understanding of this pathway in malignant and cardiovascular disease, knowledge and translational gaps remain regarding the role of this pathway in kidney and metabolic diseases, limiting identification of putative drug targets and development of effective treatments. This review considers recent advances reported in the field of TSP1-CD47 signalling, focusing on several aspects including enzymatic production, receptor function, interacting partners, localization of signalling, matrix-cellular and cell-to-cell cross talk. The potential impact that these newly described mechanisms have on health, with a particular focus on renal and metabolic disease, is also discussed.
Highlights
Matricellular ProteinsMatricellular proteins consist of a group of diverse proteins which are dynamically expressed and secreted into the extracellular matrix (ECM)
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The thrombospondins are a family of five glycoproteins with functional remodelling properties similar to other matricellular proteins, as they are all capable of mediating extracellular matrix (ECM) organisation, and interact with growth factors and cytokines for cell-to-cell communication
Summary
Matricellular proteins consist of a group of diverse proteins which are dynamically expressed and secreted into the extracellular matrix (ECM). The term ‘matricellular’ was coined to explain the diversity of function attributed to these proteins These proteins do not primarily provide structural integrity to the extracellular microenvironment, but rather perform a regulatory capacity within the ECM by interacting with cell-surface receptors, enzymes, and growth factors. The thrombospondins are a family of five glycoproteins with functional remodelling properties similar to other matricellular proteins, as they are all capable of mediating ECM organisation, and interact with growth factors and cytokines for cell-to-cell communication They display comparable structural features that consist of well-defined binding domains that link to proteoglycans and integrins [4,5]. As the high-affinity receptor for TSP1 and binding at picomolar concentrations, it likely provides the dominant signalling moiety in vivo It is ubiquitously expressed throughout the body, including red blood cells. Under pathological and inflammatory conditions, TSP1 levels in tissue or plasma are elevated to concentrations that assume activation of receptors in addition to CD47
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