Cutaneous cryptococcosis in a patient taking fingolimod for multiple sclerosis: Here come the opportunistic infections?

Background: Fingolimod is an oral disease-modifying therapy for relapsing forms of multiple sclerosis, which acts by sequestering lymphocytes within lymph nodes.

Objective: To describe a case of extrapulmonary cryptococcosis in a patient taking fingolimod.

Methods: Case report.

Bioactive nanofibers enable the identification of thrombospondin 2 as a key player in enamel regeneration.

Tissue regeneration and development involves highly synchronized signals both between cells and with the extracellular environment. Biomaterials can be tuned to mimic specific biological signals and control cell response(s). As a result, these materials can be used as tools to elucidate cell signaling pathways and candidate molecules involved with cellular processes.

Lack of thrombospondin-2 reduces fibrosis and increases vascularity around cardiac cell grafts.

Background: Fibrosis around cardiac cell injections represents an obstacle to graft integration in cell-based cardiac repair. Thrombospondin-2 (TSP-2) is a pro-fibrotic, anti-angiogenic matricellular protein and an attractive target for therapeutic knockdown to improve cardiac graft integration and survival.

Methods: We used a TSP-2 knockout (KO) mouse in conjunction with a fetal murine cardiomyocyte grafting model to evaluate the effects of a lack of TSP-2 on fibrosis, vascular density, and graft size in the heart.

Dynamic reciprocity in the wound microenvironment.

Here, we define dynamic reciprocity (DR) as an ongoing, bidirectional interaction among cells and their surrounding microenvironment. In this review, we posit that DR is especially meaningful during wound healing as the DR-driven biochemical, biophysical, and cellular responses to injury play pivotal roles in regulating tissue regenerative responses. Such cell-extracellular matrix interactions not only guide and regulate cellular morphology, but also cellular differentiation, migration, proliferation, and survival during tissue development, including, e.

Metaxin deficiency alters mitochondrial membrane permeability and leads to resistance to TNF-induced cell killing.

Metaxin, a mitochondrial outer membrane protein, is critical for TNF-induced cell death in L929 cells. Its deficiency, caused by retroviral insertion-mediated mutagenesis, renders L929 cells resistance to TNF killing. In this study, we further characterized metaxin deficiency-caused TNF resistance in parallel with Bcl-X(L) overexpression-mediated death resistance.

Thrombospondin-4 regulates vascular inflammation and atherogenesis.

Rationale: Thrombospondin (TSP)-4 is an extracellular protein that has been linked to several cardiovascular pathologies. However, a role for TSP-4 in vascular wall biology remains unknown.

Objective: We have examined the effects of TSP-4 gene (Thbs4) knockout on the development of atherosclerotic lesions in ApoE(-/-) mice.

Expression in SPARC-null mice of collagen type I lacking the globular domain of the α1(I) N-propeptide results in abdominal hernias and loss of dermal collagen.

The sequence encoding the N-propeptide of collagen I is characterized by significant conservation of amino acids across species; however, the function of the N-propeptide remains poorly defined. Studies in vitro have suggested that one activity of this propeptide might be to act as a feedback inhibitor of collagen I synthesis. To determine whether the N-propeptide contributed to decreased collagen content in SPARC-null mice, mice carrying a deletion of exon 2, which encodes the globular domain of the N-propeptide of collagen I, were crossed to SPARC-null animals.

Absence of thrombospondin-2 causes age-related dilated cardiomyopathy.

Background: The progressive shift from a young to an aged heart is characterized by alterations in the cardiac matrix. The present study investigated whether the matricellular protein thrombospondin-2 (TSP-2) may affect cardiac dimensions and function with physiological aging of the heart.

Methods And Results: TSP-2 knockout (KO) and wild-type mice were followed up to an age of 60 weeks.

Thrombospondins function as regulators of angiogenesis.

Thrombospondins (TSPs) -1 and -2 were among the first protein inhibitors of angiogenesis to be identified, a property that was subsequently attributed to the interactions of sequences in their type I repeats with endothelial cell-surface receptors. The interactions of TSPs-1 and -2 with cell-surface receptors, proteases, growth factors, and other bioactive molecules, coupled with the absence of direct structural functions that can be attributed to these matrix proteins, qualify them for inclusion in the category of 'matricellular proteins'. The phenotypes of TSP-1, TSP-2, and double TSP-1/2-null mice confirm the roles that these proteins play in the regulation of angiogenesis, and provide clues to some of the other important functions of these multi-domain proteins.

Mice that lack matrix metalloproteinase-9 display delayed wound healing associated with delayed reepithelization and disordered collagen fibrillogenesis.

Matrix metalloproteinase- (MMP-9) is involved in processes that occur during cutaneous wound healing such as inflammation, matrix remodeling, and epithelialization, To investigate its role in healing, full thickness skin wounds were made in the dorsal region of MMP-9-null and control mice and harvested up to 14 days post wounding. Gross examination and histological and immunohistochemical analysis indicated delayed healing in MMP-9-null mice. Specifically, MMP-9-null wounds displayed compromised reepithelialization and reduced clearance of fibrin clots.

Thrombospondin-1 modulates VEGF-A-mediated Akt signaling and capillary survival in the developing retina.

Microvascular development is often perceived to result from a balance of positive and negative factors that impact signaling for proliferation and survival. The survival signaling that results from hypoxia-induced VEGF-A has been well established, but the factors that antagonize this signaling have been poorly studied. As endogenous inhibitors of angiogenesis, thrombospondins (TSPs) are likely candidates to affect survival signaling.

Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9.

Macrophages undergo fusion to form multinucleated giant cells in several pathologic conditions, including the foreign body response (FBR). We detected high levels of matrix metalloproteinase (MMP)-9 during macrophage fusion in vitro and in foreign body giant cells (FBGCs) in vivo. Wild-type (WT) bone marrow-derived macrophages were induced to fuse with IL-4 in the presence of MMP-9 function-blocking antibodies and displayed reduced fusion.

Enhanced angiogenesis and reduced contraction in thrombospondin-2-null wounds is associated with increased levels of matrix metalloproteinases-2 and -9, and soluble VEGF.

Thrombospondin-2 (TSP2) is an inhibitor of angiogenesis with pro-apoptotic and anti-proliferative effects on endothelial cells. Mice deficient in this matricellular protein display improved recovery from ischemia and accelerated wound healing associated with alterations in angiogenesis and extracellular matrix remodeling. In this study, we probed the function of TSP2 by performing a detailed analysis of dermal wounds and wound-derived fibroblasts.

Disruption of the thrombospondin-2 gene alters the lamellar morphology but does not permit vascularization of the adult mouse lumbar disc.

Introduction: The biological basis for the avascular state of the intervertebral disc is not well understood. Previous work has suggested that the presence of thrombospondin-1 (TSP-1), a matricellular protein, in the outer annulus reflects a role for this protein in conferring an avascular status to the disc. In the present study we have examined thrombospondin-2 (TSP-2), a matricellular protein with recognized anti-angiogenic activity in vivo and in vitro.

Thrombospondin-2 modulates extracellular matrix remodeling during physiological angiogenesis.

Thrombospondin 2 (TSP2) can inhibit angiogenesis in vitro by limiting proliferation and inducing apoptosis of endothelial cells (ECs). TSP2 can also modulate the extracellular levels of gelatinases (matrix metalloproteases, MMPs) and potentially influence the remodeling of the extracellular matrix (ECM). Here, we tested the hypothesis that by regulating MMPs, TSP2 could alter EC-ECM interactions.

Skeletal abnormalities in mice lacking extracellular matrix proteins, thrombospondin-1, thrombospondin-3, thrombospondin-5, and type IX collagen.

Thrombospondin-5 (TSP5) is a large extracellular matrix glycoprotein found in musculoskeletal tissues. TSP5 mutations cause two skeletal dysplasias, pseudoachondroplasia and multiple epiphyseal dysplasia; both show a characteristic growth plate phenotype with retention of TSP5, type IX collagen (Col9), and matrillin-3 in the rough endoplasmic reticulum. Whereas most studies focus on defining the disease process, few functional studies have been performed.

Thrombospondins use the VLDL receptor and a nonapoptotic pathway to inhibit cell division in microvascular endothelial cells.

TSPs 1 and 2 function as endogenous inhibitors of angiogenesis. Although thrombospondins (TSPs) have been shown to induce apoptosis in HMVECs, we reasoned that a homeostatic mechanism would also be needed to inhibit EC growth without causing cell death, e.g.

SPARC regulates processing of procollagen I and collagen fibrillogenesis in dermal fibroblasts.

A characterization of the factors that control collagen fibril formation is critical for an understanding of tissue organization and the mechanisms that lead to fibrosis. SPARC (secreted protein acidic and rich in cysteine) is a counter-adhesive protein that binds collagens. Herein we show that collagen fibrils in SPARC-null skin from mice 1 month of age were inefficient in fibril aggregation and accumulated in the diameter range of 60-70 nm, a proposed intermediate in collagen fibril growth.

Interactions between CD47 and thrombospondin reduce inflammation.

CD47 on the surface of T cells was shown in vitro to mediate either T cell activation or, in the presence of high amounts of thrombospondin (TSP), T cell apoptosis. We report here that CD47-deficient mice, as well as TSP-1 or TSP-2-deficient mice, sustain oxazolone-induced inflammation for more than four days, whereas wild-type mice reduce the inflammation within 48 h. We observe that prolonged inflammation in CD47-, TSP-1-, or TSP-2-deficient mice is accompanied by a local deficiency of T cell apoptosis.

Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in experimental glomerulonephritis in mice.

The role of thrombospondin 2 (TSP2) was investigated in an anti-glomerular basement membrane (GBM) nephritis model that compared TSP2-null mice with wild-type (WT) controls. TSP2-null mice were analyzed for kidney function, renal cortical matrix expansion, influx of inflammatory cells, proliferation, and apoptosis, as well as for capillary rarefaction after induction of anti-GBM disease. Whereas the renal cortex of normal control WT mice did not show any detectable TSP2 staining above background, TSP2 protein expression was clearly upregulated in anti-GBM disease.

Glycosylation mediates up-regulation of a potent antiangiogenic and proatherogenic protein, thrombospondin-1, by glucose in vascular smooth muscle cells.

Accelerated development of atherosclerotic lesions remains the most frequent and dangerous complication of diabetes, accounting for 80% of deaths among diabetics. However, our understanding of the pathways mediating glucose-induced gene expression in vascular cells remains controversial and incomplete. We have identified an intracellular metabolic pathway activated by high glucose in human aortic smooth muscle cells that mediates up-regulation of thrombospondin-1 (TSP-1).

Thrombospondin-1 inhibits VEGF levels in the ovary directly by binding and internalization via the low density lipoprotein receptor-related protein-1 (LRP-1).

VEGF is a potent pro-angiogenic factor whose effects are opposed by a host of anti-angiogenic proteins, including thrombospondin-1 (TSP-1). We have previously shown that VEGF has important extravascular roles in the ovary and that VEGF and TSP-1 are inversely expressed throughout the ovarian cycle. To date, however, a causal interaction between TSP-1 and VEGF has not been identified.

Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization.

Thrombopoietic cells may differentially promote or inhibit tissue vascularization by releasing both pro- and antiangiogenic factors. However, the molecular determinants controlling the angiogenic phenotype of thrombopoietic cells remain unknown. Here, we show that expression and release of thrombospondins (TSPs) by megakaryocytes and platelets function as a major antiangiogenic switch.

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax.

The association of Bax with mitochondria is an essential step in the implementation of apoptosis. By using a bacterial two-hybrid assay and crosslinking strategies, we have identified TOM22, a component of the translocase of the outer mitochondrial membrane (TOM), as a mitochondrial receptor of Bax. Peptide mapping showed that the interaction of Bax with TOM22 involved the first alpha helix of Bax and possibly two central alpha helices, which are homologous to the pore forming domains of some toxins.