Cartilage oligomeric matrix protein is a natural inhibitor of thrombin

Abstract

Key Points• COMP negatively regulates hemostasis and thrombosis.• COMP is a natural inhibitor of thrombin.Thrombin is an effector enzyme for hemostasis and thrombosis; however, endogenous regulators of thrombin remain elusive. Cartilage oligomeric matrix protein (COMP), a matricellular protein also known as thrombospondin-5, is essential for maintaining vascular homeostasis. Here, we asked whether COMP is involved in the process of blood coagulation. COMP deficiency shortened tail-bleeding and clotting time and accelerated ferric-chloride-induced thrombosis in mice. The absence of COMP had no effect on platelet count. In contrast, COMP specifically inhibited thrombin-induced platelet aggregation, activation, and retraction and the thrombin-mediated cleavage of fibrinogen. Furthermore, surface plasmon resonance analysis revealed direct thrombin-COMP binding (K D 5 1.38 6 0.24 mM). In particular, blockage of thrombin exosites with compounds specific for exosite I (hirudin and HD1 aptamer) or exosite II (heparin and HD22 aptamer) impaired the COMP-thrombin interaction, indicating a 2-site binding mechanism. Additionally, epidermal growth factor-like repeats (amino acids 84-261) were identified as a COMP binding site for thrombin. Moreover, COMP was expressed in and secreted by platelets. Using bone marrow transplantation and platelet transfusion to create chimeric mice, platelet-derived but not vessel-wall-derived COMP was demonstrated to inhibit coagulation. Taken together, COMP is an endogenous thrombin inhibitor and negative regulator of hemostasis and thrombosis. (Blood. 2015;126(7):905-914)

Serum Cartilage Oligomeric Matrix Protein in Late-Stage Osteoarthritis: Association with Clinical Features, Renal Function, and Cardiovascular Biomarkers

“…However, high levels of COMP were found to be associated with a lower risk of incident myocardial infarction in a case-control study [41]. This observation might be related to the implication of COMP as a natural inhibitor of thrombin which could explain a respective protective functionality [42]. Interestingly, the significant association of cystatin C with sCOMP was preserved after eGFR adjustment, indicating that this association is at least partly independent of renal function.…”

Thrombospondins Differentially Regulate Proteins Involved in Arterial Remodeling

“…TSP-1, an endogenous protein which is secreted by platelets in response to arterial injury, is the TSP most associated with intimal hyperplasia and arterial remodeling (Adams, 1997). TSP-2 and TSP-5 are molecules that have recently been linked to vascular remodeling and intimal hyperplasia as well; however, little is known regarding the exact role of TSP-2 and TSP-5 in the pathogenesis of intimal hyperplasia (Bodewes et al 2017, Liang et al 2015, Wang et al 2010. The similarity in the chemical structure of TSP-2 to TSP-1 may explain why TSP-1 and TSP-2 may have similar intimal hyperplastic properties (Helkin et al 2015).…”

“…TSP-5, also known as cartilage oligomeric matrix protein (COMP), has some distinctly different functions from TSP-1 and TSP-2, and is potentially protective against the development of intimal hyperplasia (Du et al 2011, Liang et al 2015, Wang et al 2010. TSP-5 is involved in maintaining vascular homeostasis, as TSP-5 is secreted via platelets and specifically inhibits thrombin-induced platelet aggregation and activation (Liang et al 2015). Recent studies show that TSP-5 plays a crucial role in preventing vascular intimal hyperplasia, calcification and remodeling (Du et al 2011, Wang et al 2010.…”

Cartilage oligomeric matrix protein is a novel notch ligand driving embryonic stem cell differentiation towards the smooth muscle lineage

“…Our previous studies and others have identified several proteins that bind to COMP and specifically mediate its effects in various physiological and pathological conditions [49]. In the cardiovascular system, COMP binds to thrombin via EGF repeats [50], BMP-2 via type III repeats [16] and integrin β1 and β3 via the C-terminal domain [18,51] and subsequently fine-tunes hemostasis, vascular calcification, dilated cardiomyopathy and atherosclerosis, respectively. Herein, we further verified that the N-terminal domain of COMP could mimic the inducible effect of COMP in ESC differentiation into VSMCs, which is favorable to the development of new regenerative therapies to repair injured VSMCs in vascular diseases.…”