Insulin-like growth factor binding protein-1 activates integrin-mediated intracellular signaling and migration in oligodendrocytes.

In multiple sclerosis (MS), oligodendrocytes in lesions are lost, leaving damaged tissue virtually devoid of these myelin-producing cells. Our group has recently demonstrated enhanced expression of insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) in oligodendrocytes (CNPase(+)) localized adjacent to MS lesions. In the present study, we demonstrate IGF-1-independent actions of IGFBP-1 on OLN-93 oligodendroglial cells, including activation of kinases ERK1/2, focal adhesion kinase and p21-activated kinase as well as small monomeric GTPases Rac and Ral.

Bone marrow stromal cell interaction reduces syndecan-1 expression and induces kinomic changes in myeloma cells.

CD138 (Syndecan 1) is a heparan sulfate proteoglycan that concentrates heparan sulfate-binding growth factors on the surface of normal and malignant plasma cells (multiple myeloma, MMC). Recent studies have shown the presence of a CD138-negative fraction of MMC within myelomatous bone marrow (BM). We employed kinome array technology to characterize this fraction at a molecular level, using a myeloma cell line model.

Progesterone and dexamethasone differentially regulate the IGF-system in glial cells.

IGF-1 is an important factor for myelin synthesis and hence possesses therapeutic potential in treating demyelinating disease such as multiple sclerosis. However, IGF-1 poorly crosses the blood-brain barrier. In this study, we investigated the effects of the sex steroid progesterone and the glucocorticoid dexamethasone on regulation of the IGF-system in glial cells.

IGF-1 regulates cAMP levels in astrocytes through a beta2-adrenergic receptor-dependant mechanism.

We have recently demonstrated that neonatal astrocytes derived from mice lacking beta-2 adrenergic receptors (beta(2)AR) possess higher proliferation rates, as compared to wild-type cells, an attribute that was shown to involve insulin-like growth factor (IGF) signaling. In the present study, we demonstrate that basal cAMP levels in beta(2)AR knockout astrocytes were significantly lower than in wild type cells. Furthermore, treatment with IGF-1 reduced intracellular cAMP levels in wild type astrocytes, yet had no effects on cAMP levels in beta(2)AR deficient astrocytes.

IGF binding protein alterations on periplaque oligodendrocytes in multiple sclerosis: implications for remyelination.

Why myelin repair greatly fails in multiple sclerosis (MS) is unclear. The insulin-like growth factor (IGF) system plays vital roles in oligodendrocyte development, survival, and myelin synthesis. We used immunohistochemistry to study IGF-I, IGF-I receptors and IGF binding proteins (IGFBPs) 1-6 on oligodendrocytes at the edges of chronic demyelinated plaques and normal appearing white matter of MS, and in cerebral white matter of controls without neurological disease.

Insulin-like growth factor system regulates oligodendroglial cell behavior: therapeutic potential in CNS.

Amongst the many soluble extracellular factors stimulating intracellular signal transduction pathways and driving cellular processes such as proliferation, differentiation and survival, insulin-like growth factors (IGFs) stand out as indispensable factors for proper oligodendrocyte differentiation and accompanying myelin production. Owing to its potent myelinogenic capacity and its neuroprotective properties, IGFs hold therapeutic potential in demyelinating and neurodengenerative diseases. However, the IGF system is comprised of a complex molecular network involving regulatory binding proteins, proteases, cell surface and extracellular matrix components which orchestrate IGF-specific functions.

The insulin-like growth factor system in multiple sclerosis.

Multiple sclerosis (MS) is a chronic disorder of the central nervous system characterized by inflammation, demyelination, and axonal degeneration. Present therapeutic strategies for MS reduce inflammation and its destructive consequences, but are not effective in the progressive phase of the disease. There is a need for neuroprotective and restorative therapies in MS.

Insulin-like growth factor binding protein-2 as a regulator of IGF actions in CNS: implications in multiple sclerosis.

Insulin-like growth factors (IGFs) are indispensable peptide hormones for proper development of the central nervous system (CNS). Because IGF-1 exhibits neuroprotective and myelinogenetic effects, it possesses therapeutic potential in treating neurodegenerative demyelinating diseases such as multiple sclerosis (MS). However, IGF actions are largely dependant on high-affinity regulatory IGF binding proteins (IGFBPs), which are likely to interfere with therapeutic attempts at elevating IGF-1 levels in the CNS.

Enhanced proliferation of astrocytes from beta(2)-adrenergic receptor knockout mice is influenced by the IGF system.

In the present study, we investigated the IGF system in neonatal astrocytes derived from mice with a targeted disruption of the beta-2 adrenergic receptor (beta(2)AR). beta(2)AR knockout astrocytes demonstrated higher proliferation rates and increased expression of the astrogliotic marker GFAP, as compared with wild-type cells. beta(2)AR deletion also regulated molecules of the IGF system.

Insulin-like growth factor binding proteins: regulation in chronic active plaques in multiple sclerosis and functional analysis of glial cells.

Studies in experimental allergic encephalomyelitis, an animal model of multiple sclerosis (MS), suggest that astrocyte-secreted insulin-like growth factor binding protein-2 (IGFBP-2) helps target IGF-1 to IGF-1 receptor-expressing oligodendrocytes and promote remyelination. We examined the presence of IGFBPs 1-6 in astrocytes in normal post-mortem human brain tissue and lesions of MS by means of immunohistochemistry. Under normal conditions all six IGFBPs were detected.

Intravenous tissue plasminogen activator in patients with stroke increases the bioavailability of insulin-like growth factor-1.

Background And Purpose: Insulin-like growth factor (IGF)-1 has potent neuroprotective properties. We investigated the effects of intravenous administration of tissue plasminogen activator (tPA) on serum levels of IGF-1 and IGF-binding protein (IGFBP)-3 in patients with acute ischemic stroke.

Methods: Serum levels of total IGF-1, free IGF-1, and IGFBP-3 were measured by radioimmunoassay in 10 patients with ischemic stroke treated with intravenous tPA (0.

Simvastatin inhibits interferon-gamma-induced MHC class II up-regulation in cultured astrocytes.

Based on their potent anti-inflammatory properties and a preliminary clinical trial, statins (HMG-CoA reductase inhibitors) are being studied as possible candidates for multiple sclerosis (MS) therapy. The pathogenesis of MS is unclear. One theory suggests that the development of autoimmune lesions in the central nervous system may be due to a failure of endogenous inhibitory control of MHC class II expression on astrocytes, allowing these cells to adapt an interferon (IFN)-gamma-induced antigen presenting phenotype.

5HT4 agonists inhibit interferon-gamma-induced MHC class II and B7 costimulatory molecules expression on cultured astrocytes.

A failure of tight control of MHC class II expression on astrocytes may play a role in the development of autoimmune responses in multiple sclerosis. The 5-HT(4) serotonin receptor agonists cisapride and prucalopride, at concentrations between 10(-10) M and 10(-8) M, reduced interferon-gamma-induced MHC class II immunostaining in cultured astrocytes derived from newborn Wistar rats by approximately 50-60%. The magnitude of MHC class II inhibition by 5-HT(4) agonists was comparable to that of interferon-beta.

Enhanced production and proteolytic degradation of insulin-like growth factor binding protein-2 in proliferating rat astrocytes.

Insulin-like growth factors (IGFs) protect neurons, are important for oligodendrocyte survival and myelin production, and stimulate the proliferation of astrocytes. The effects of IGFs are regulated by a family of IGF binding proteins (IGFBPs). Astrocytes express predominantly IGFBP-2.

Involvement of insulin-like growth factor binding protein-2 in activated microglia as assessed in post mortem human brain.

In vitro studies suggest that insulin-like growth factor (IGF)-I is a mitogen for microglia/macrophages. The actions of IGF-I are mediated by IGF-I receptors and modulated by IGF binding proteins (IGFBPs). The aim of this study was to investigate IGF-I receptors and IGFBPs in human microglia in normal brain white matter and active lesions of multiple sclerosis, which contain activated microglia/macrophages.

Insulin-like growth factor binding protein-1-6 expression in activated microglia.

In the CNS insulin-like growth factor-1 (IGF-1) enhances survival of neurons, promotes myelin synthesis and acts as a mitogen for microglia. The effects of IGF-1 are regulated by a family of 6 IGF binding proteins (IGFBPs). We investigated mRNA expression patterns of IGFBPs in primary rat microglia under basal conditions and after activation with lipopolysaccharide (LPS).

Insulin-like growth factor (IGF)-I binding to a cell membrane associated IGF binding protein-3 acid-labile subunit complex in human anterior pituitary gland.

The binding characteristics of [(125) I]insulin-like growth factor (IGF)-I were studied in human brain and pituitary gland. Competition binding studies with DES(1-3)IGF-I and R(3) -IGF-I, which display high affinity for the IGF-I receptor and low affinity for IGF binding proteins (IGFBPs), were performed to distinguish [(125) I]IGF-I binding to IGF-I receptors and IGFBPs. Specific [(125) I]IGF-I binding in brain regions and the posterior pituitary was completely displaced by DES(1-3)IGF-I and R(3) -IGF-I, indicating binding to IGF-I receptors.