The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression.

Fibrotic diseases, such as systemic sclerosis (SSc), idiopathic pulmonary fibrosis, renal fibrosis and liver cirrhosis are characterized by tissue overgrowth due to excessive extracellular matrix (ECM) deposition. Fibrosis progression is caused by ECM overproduction and the inhibition of ECM degradation due to several events, including inflammation, vascular endothelial dysfunction, and immune abnormalities. Recently, it has been reported that urokinase plasminogen activator (uPA) and its receptor (uPAR), known to be fibrinolytic factors, orchestrate the inflammatory response, vascular homeostasis, and immune homeostasis system.

α2-Antiplasmin as a Potential Therapeutic Target for Systemic Sclerosis.

Systemic sclerosis is a connective tissue disease of unknown origin that is characterized by immune system abnormalities, vascular damage, and extensive fibrosis of the skin and visceral organs. α2-antiplasmin is known to be the main plasmin inhibitor and has various functions such as cell differentiation and cytokine production, as well as the regulation of the maintenance of the immune system, endothelial homeostasis, and extracellular matrix metabolism. The expression of α2-antiplasmin is elevated in dermal fibroblasts from systemic sclerosis patients, and the blockade of α2-antiplasmin suppresses fibrosis progression and vascular dysfunction in systemic sclerosis model mice.

Alternatively activated macrophages are associated with the α2AP production that occurs with the development of dermal fibrosis : The role of alternatively activated macrophages on the development of fibrosis.

Background: Fibrotic diseases are characterized by tissue overgrowth, hardening, and/or scarring because of the excessive production, deposition, and contraction of the extracellular matrix (ECM). However, the detailed mechanisms underlying these disorders remain unclear. It was recently reported that α2-antiplasmin (α2AP) is elevated in fibrotic tissue and that it is associated with the development of fibrosis.

α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses.

Introduction: Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), which is a chronic autoimmune disease. However, the detailed mechanisms underlying this disorder have remained unclear. Alpha2-antiplasmin (α2AP) is known to perform various functions, such as plasmin inhibition and cytokine production, and to be associated with immune and inflammatory responses.

The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, and exacerbates the disease. Fibrinolytic regulators, such as plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and angiostatin, are considered to play an important role in the maintenance of endothelial homeostasis, and are associated with the endothelial dysfunction of SSc.

α2-antiplasmin modulates bone formation by negatively regulating osteoblast differentiation and function.

α2-antiplasmin (α2AP) is known to be a physiological inhibitor of plasmin. Previously, we showed that α2AP displays various functions, such as promotion of extracellular matrix production, cell growth, and cell differentiation that are not promoted by its function as a plasmin inhibitor. We herein investigated the role of α2AP in bone formation by examining calcein incorporation after its injection in α2AP-deficient mice.

uPA-derived peptide, Å6 is involved in the suppression of lipopolysaccaride-promoted inflammatory osteoclastogenesis and the resultant bone loss.

Introduction: Chronic inflammatory diseases such as rheumatoid arthritis and periodontitis frequently cause bone destruction. Inflammation-induced bone loss results from the increase of bone-resorbing osteoclasts. Recently, we demonstrated that urokinase type plasminogen activator (uPA) suppressed lipopolysaccaride (LPS)-inflammatory osteoclastogenesis through the adenosine monophosphate-activated protein kinase (AMPK) pathway, whereas its receptor (uPAR) promoted that through the Akt pathway.

α2AP regulates vascular alteration by inhibiting VEGF signaling in systemic sclerosis: the roles of α2AP in vascular dysfunction in systemic sclerosis.

Background: Systemic sclerosis (SSc) is a connective tissues disease of unknown origin characterized by vascular damage and extensive fibrosis. Recently, we demonstrated that α2-antiplasmin (α2AP) is associated with the development of fibrosis in SSc. We herein investigate the roles of α2AP in vascular dysfunction in SSc.

The blocking of uPAR suppresses lipopolysaccharide-induced inflammatory osteoclastogenesis and the resultant bone loss through attenuation of integrin β3/Akt pathway.

Introduction: Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis, cause the bone destruction by promotion of the differentiation of monocyte/macrophage lineage cells into mature osteoclasts (OCs) with active bone-resorbing character. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated the role of urokinase plasminogen activator receptor (uPAR) in the bone destruction caused by chronic inflammation.

The Antifibrotic Effect of α2AP Neutralization in Systemic Sclerosis Dermal Fibroblasts and Mouse Models of Systemic Sclerosis.

Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by the fibrosis of skin and visceral organs, and peripheral circulatory disturbance. We recently demonstrated that α2-antiplasmin (α2AP), which is the physiological inhibitor of plasmin, is associated with the development of fibrosis. The aim of this study was to clarify the role of α2AP in the pathogenesis of SSc.

uPA Attenuated LPS-induced Inflammatory Osteoclastogenesis through the Plasmin/PAR-1/Ca(2+)/CaMKK/AMPK Axis.

Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis-caused bone destruction, results from an increase of bone-resorbing osteoclasts (OCs) induced by inflammation. However, the detailed mechanisms underlying this disorder remain unclear. We herein investigated that the effect of urokinase-type plasminogen activator (uPA) on inflammatory osteoclastogenesis induced by lipopolysaccharide (LPS), which is a potent stimulator of bone resorption in inflammatory diseases.

Enhancement by Uridine Diphosphate of Macrophage Inflammatory Protein-1 Alpha Production in Microglia Derived from Sandhoff Disease Model Mice.

Sandhoff disease (SD) is a lysosomal β-hexosaminidase (Hex) deficiency involving excessive accumulation of undegraded substrates, including GM2 ganglioside, and progressive neurodegeneration. Macrophage inflammatory protein-1α (MIP-1α) is a crucial factor for microglia-mediated neuroinflammation in the onset or progression of SD. However, the transmitter-mediated production of MIP-1α in SD is still poorly understood.

CD62-mediated activation of platelets in cerebral white matter lesions in patients with cognitive decline.

Background: Vascular dementia is related to intracranial arteriosclerosis associated with deep white matter lesions (DWMLs). DWMLs have been linked to thrombogenesis due to sustained platelet activation; therefore, an accurate hematological marker is needed. This study was done to evaluate the usefulness of a new method to examine the function of activated platelets in order to assess DWMLs associated with cognitive decline.

α2AP mediated myofibroblast formation and the development of renal fibrosis in unilateral ureteral obstruction.

Renal fibrosis is the final common pathway of a wide variety of chronic kidney diseases. Myofibroblast formation via the differentiation of from tissue-resident fibroblasts and bone marrow-derived mesenchymal stem cells (MSCs), and epithelial-to-mesenchymal transition (EMT) is known to play a pivotal role in the development of renal fibrosis. However, the detailed mechanisms underlying this disorder remain unclear.

Altered behavior in mice with deletion of the alpha2-antiplasmin gene.

Background: The α2-antiplasmin (α2AP) protein is known to be a principal physiological inhibitor of plasmin, and is expressed in various part of the brain, including the hippocampus, cortex, hypothalamus and cerebellum, thus suggesting a potential role for α2AP in brain functions. However, the involvement of α2AP in brain functions is currently unclear.

Objectives: The goal of this study was to investigate the effects of the deletion of the α2AP gene on the behavior of mice.

Involvement of α2-antiplasmin in dendritic growth of hippocampal neurons.

The α2-Antiplasmin (α2AP) protein is known as a principal physiological inhibitor of plasmin, but we previously demonstrated that it acts as a regulatory factor for cellular functions independent of plasmin. α2AP is highly expressed in the hippocampus, suggesting a potential role for α2AP in hippocampal neuronal functions. However, the role for α2AP was unclear.

Plasminogen/plasmin modulates bone metabolism by regulating the osteoblast and osteoclast function.

The contribution of plasminogen (Plg)/plasmin, which have claimed to be the main fibrinolytic regulators in the bone metabolism, remains unclear. This study evaluated how the absence of Plg affects the function of osteoblast (OB) and osteoclast (OC). There was a larger population of pre-OCs in bone marrow-derived cells from the Plg(-/-) mice than the population of that from the WT mice.

The absence of urokinase-type plasminogen activator receptor plays a role in the insulin-independent glucose metabolism.

The urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol-anchored membrane protein with multiple functions. In the present study, we examined whether the uPAR plays any role in the regulation of glucose metabolism. The experiments were performed using male wild-type (uPAR) and uPAR knockout (uPAR) C57BL/6J mice.

Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue.

Urokinase-type plasminogen activator receptor (uPAR) plays a role in cellular responses which include cellular adhesion, differentiation, proliferation and migration. The aim of this study was to clarify the role of uPAR on the development of adipose tissue. To clarify the role of uPAR on adipogenesis, we examined the effect of uPAR overexpression and uPAR deficiency on the adipocyte differentiation.

alpha2-antiplasmin is associated with the progression of fibrosis.

Systemic sclerosis results in tissue fibrosis due to the activation of fibroblasts and the ensuing overproduction of the extracellular matrix. We previously reported that the absence of alpha2-antiplasmin (alpha2AP) attenuated the process of dermal fibrosis; however, the detailed mechanism of how alpha2AP affects the progression of fibrosis remained unclear. The goal of the present study was to examine the role of alpha2AP in fibrotic change.

The absence of uPAR is associated with the progression of dermal fibrosis.

The fibrinolytic system is considered to play an important role in the degradation of extracellular matrices (ECM). However, the detailed mechanism regarding how this system affects fibrosis remains unclear. Urokinase-type plasminogen activator receptor (uPAR) not only functions as a proteinase receptor but also plays a role in cellular adhesion, differentiation, proliferation, and migration through intracellular signaling.

Alpha2-antiplasmin is involved in the production of transforming growth factor beta1 and fibrosis.

Background: Fibrotic disease occurs in most tissues. Transforming growth factor (TGF)-beta is the major inducer of fibrosis. The fibrinolytic system is considered to play an important role in the degradation of extracellular matrices.

Lack of alpha2-antiplasmin improves cutaneous wound healing via over-released vascular endothelial growth factor-induced angiogenesis in wound lesions.

Background: The fibrinolytic system is supposed to play an important role in the degradation of extracellular matrices for physiological and pathological tissue remodeling; however, the detailed mechanism regarding how this system affects cutaneous wound healing remains to be clarified.

Methods And Results: We performed experimental cutaneous wounding in mice with a deficiency of alpha(2)-antiplasmin (alpha(2)AP), which is a potent and specific plasmin inhibitor. We found that an accelerated wound closure was observed in alpha(2)AP-deficient (alpha(2)AP-/-) mice in comparison with wild type (WT) mice.

Novel ideas of gene therapy for atherosclerosis: modulation of cellular signal transduction of TGF-beta family.

Atherosclerosis is a disease characterized by accumulation of lipids and fibrous elements in the innermost layer of the arterial wall. An asymptomatic atherosclerotic plaque is characterized by a lipid core, composed of modified lipids, macrophages and T cells, which were separated from the lumen vessel by a thick fibrous cap, composed of vascular smooth muscle cell-secreted solid collagen matrix. Recently, it has been reported that expressions of TGF-beta family were up regulated in human atherosclerotic plaques.