Thrombospondin-1 Signaling Through the Calreticulin/LDL Receptor Related Protein 1 Axis: Functions and Possible Roles in Glaucoma

Abstract

Thrombospondin-1 (TSP-1) is a matricellular extracellular matrix protein. Matricellular proteins are components of the extracellular matrix (ECM) that regulate key cellular functions and impact ECM organization, but which lack direct primary structural roles in the ECM. TSP-1 expression is upregulated in response to injury, hypoxia, growth factor stimulation, inflammation, glucose, and by reactive oxygen species. Relevant to glaucoma, TSP-1 is also a mechanosensitive molecule upregulated by mechanical stretch. TSP-1 expression is increased in ocular remodeling in glaucoma in both the trabecular meshwork and in the optic nerve head. The exact roles of TSP-1 in glaucoma remain to be defined, however. It plays important roles in cell behavior and in ECM remodeling during wound healing, fibrosis, angiogenesis, and in tumorigenesis and metastasis. At the cellular level, TSP-1 can modulate cell adhesion and migration, protease activity, growth factor activity, anoikis resistance, apoptosis, and collagen secretion and matrix assembly and cross-linking. These multiple functions and macromolecular and receptor interactions have been ascribed to specific domains of the TSP-1 molecule. In this review, we will focus on the cell regulatory activities of the TSP-1 N-terminal domain (NTD) sequence that binds to cell surface calreticulin (Calr) and which regulates cell functions via signaling through Calr complexed with LDL receptor related protein 1 (LRP1). We will describe TSP-1 actions mediated through the Calr/LRP1 complex in regulating focal adhesion disassembly and cytoskeletal reorganization, cell motility, anoikis resistance, and induction of collagen secretion and matrix deposition. Finally, we will consider the relevance of these TSP-1 functions to the pathologic remodeling of the ECM in glaucoma.

Calreticulin accelerates corneal wound closure and mitigates fibrosis: Potential therapeutic applications

“…In contrast to exogenous CALR seemingly anti‐fibrotic effects in tissue regeneration, 6 intracellular ER CALR has been shown to be involved in fibrosis in different organ systems due to its key role in mediating TGF‐β‐induced ECM induction, including atherosclerotic lesions and the foreign body response, with TGF‐β‐mediated signalling requiring ER‐mediated calcium release and NFAT activation. 26 , 27 , 28 , 29 These experiments used CALR null mouse embryo fibroblasts that lacked the TGF‐β‐induced fibrotic response in contrast to the wild type MEFs in which TGF‐β increased levels of collagen 1 and fibronectin. By contrast, topically applied CALR accelerates corneal ophthalmic repair of injury with full wound closure without causing fibrosis at the two lower concentrations used herein.…”

Matricellular proteins: Potential biomarkers in head and neck cancer

“…CCN family proteins are recognized as molecular targets in osteoarthritis and rheumatoid arthritis, exerting their own regulatory functions to control chondrocyte degeneration 39,40 . Moreover, MCPs play a pivotal role not only in orthopedic diseases but also in various other conditions including skin scar regeneration, 41 atherosclerosis, 12 glioblastoma, 42 and glaucoma 43 . Furthermore, extensive evidence confirms the involvement of MCPs in cancer initiation and progression.…”

Immunomodulation of wound healing leading to efferocytosis

“…� Regulates angiogenesis 32 � Promotes proliferation and migration of fibroblasts 33 � Promotes collagen deposition 34 � Accelerates wound closure 35 � Regulates angiogenesis 36 � Immune cell phenotype that promotes regeneration 37 � Promotes cell proliferation 38 � Promotes collagen deposition 39 � Increased proliferation of keratinocytes and fibroblasts 40 � Regulates angiogenesis 41 Bind Eat me signal Phosphatidylserine (PtdSer) Calreticulin (CRT) Thrombospondin 1 (TSP1) Milk fat globule-EGF-factor 8 (MFG-E8) Gas6 Protein S � Participate in hemostasis 42 � Promotes the resolution of inflammation 43 � Ca 2þ homeostasis in vivo 44 � Induces migration of pro-repair cells 45 � Promotes re-epithelialization 46 � Regulates fibroblast secretion and collagen deposition 47 � Regulates cell migration and matrix remodeling 48 � Regulates blood clotting and promotes angiogenesis 49 � Promote the migration and proliferation of fibroblasts 50 � Regulates angiogenesis 51 � None Bridge molecules in the dermis, DCs, macrophages, and T cells predominate. 54 An important step in wound repair is the elimination of cell death induced by the inflammatory environment.…”