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Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy.

Simon CM, Rauskolb S, Gunnersen JM, Holtmann B, Drepper C, Dombert B, Braga M, Wiese S, Jablonka S, Pühringer D, Zielasek J, Hoeflich A, Silani V, Wolf E, Kneitz S, Sommer C, Toyka KV, Sendtner M - Acta Neuropathol. (2015)

Bottom Line: IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP.These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration.Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Neurobiology, University of Würzburg, Versbacher-Str. 5, 97078, Würzburg, Germany.

ABSTRACT
Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor (IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.

No MeSH data available.


Related in: MedlinePlus

IGFBP5 protein levels are significantly up-regulated in biopsies of DNP patients. a Western blots of IGFBP5 protein levels in human sural nerve from control (C) individuals (3 samples shown from a total of 5 analyzed), patients (P) with DNP, CIDP, DNP+CIDP (3 samples shown from 4 in total) and other neuropathies (ONP; axonal neuropathy in motor neuron disease (O1, O3), vitamin B12 deficiency (O2). b IGFBP5 protein levels were specifically up-regulated in patients with DNP. Biopsies of patients with DNP showed on average a 5-fold up-regulation compared to CIDP individuals and 50-fold in comparison to healthy controls. Up-regulation in DNP patients with additional CIDP was not significantly higher than in patients with DNP alone. Other neuropathies (ONP) and patients with CIDP showed no significant change in comparison to controls. All values were normalized to CIDP biopsies. QL: quantitative labeling. c IGFBP5 (green) and neurofilament (red) distribution in human sural nerves from a control individual and a patient with DNP. Note that IGFBP5 levels were increased in axons and in the extracellular matrix (ECM) (arrows) in DNP. Scale bar 5 μm
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Fig1: IGFBP5 protein levels are significantly up-regulated in biopsies of DNP patients. a Western blots of IGFBP5 protein levels in human sural nerve from control (C) individuals (3 samples shown from a total of 5 analyzed), patients (P) with DNP, CIDP, DNP+CIDP (3 samples shown from 4 in total) and other neuropathies (ONP; axonal neuropathy in motor neuron disease (O1, O3), vitamin B12 deficiency (O2). b IGFBP5 protein levels were specifically up-regulated in patients with DNP. Biopsies of patients with DNP showed on average a 5-fold up-regulation compared to CIDP individuals and 50-fold in comparison to healthy controls. Up-regulation in DNP patients with additional CIDP was not significantly higher than in patients with DNP alone. Other neuropathies (ONP) and patients with CIDP showed no significant change in comparison to controls. All values were normalized to CIDP biopsies. QL: quantitative labeling. c IGFBP5 (green) and neurofilament (red) distribution in human sural nerves from a control individual and a patient with DNP. Note that IGFBP5 levels were increased in axons and in the extracellular matrix (ECM) (arrows) in DNP. Scale bar 5 μm

Mentions: Previous studies have shown that IGF1 levels are down-regulated in peripheral nerves in diabetic [53] and non-diabetic [16] types of neuropathy. We therefore investigated the expression of IGF family members, their receptors and IGFBPs by microarray expression analysis of sural nerve biopsies from patients with DNP and age-matched control individuals (electronic supplementary Table A1). Microarray expression analysis revealed a decrease of IGF1 mRNA levels and more than sevenfold up-regulation of IGFBP5 expression in DNP. These findings were corroborated by Western blotting using protein extracts from sural nerve biopsies (Fig. 1a). IGFBP5 protein levels were more than 5-fold up-regulated in 6 patients with DNP (P < 0.01, one-way ANOVA) (see electronic supplementary Table 2 for clinical characteristics of these patients) and in 3 patients with combined diabetic neuropathy and chronic inflammatory demyelinating polyradiculoneuropathy (DNP+CIDP; P < 0.001, one-way ANOVA) as compared to CIDP individuals (Fig. 1b, c) and 50-fold in comparison to healthy controls (P < 0.001, one-way ANOVA). Increased IGFBP5 protein levels were only observed in 2 out of 9 CIDP patients, and did not reach statistical significance when compared with controls (P > 0.05, one-way ANOVA). This suggests an association of IGFBP5 overexpression with DNP rather than with the superimposed CIDP in this mixed group. IGFBP5 expression was also low in the 3 patients with non-diabetic neuropathy (P > 0.05, one-way ANOVA) (Fig. 1a, b). This indicates that levels of IGFBP5 are specifically up-regulated in patients with DNP. Enhanced levels of IGFBP5 could also be detected by immunohistochemistry in peripheral nerve sections (Fig. 1c), particularly in axons, as revealed by co-localization with neurofilament H immunoreactivity. IGFBP5 immunoreactivity was also observed in the extracellular matrix surrounding the axons (arrows in Fig. 1c).Fig. 1


Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy.

Simon CM, Rauskolb S, Gunnersen JM, Holtmann B, Drepper C, Dombert B, Braga M, Wiese S, Jablonka S, Pühringer D, Zielasek J, Hoeflich A, Silani V, Wolf E, Kneitz S, Sommer C, Toyka KV, Sendtner M - Acta Neuropathol. (2015)

IGFBP5 protein levels are significantly up-regulated in biopsies of DNP patients. a Western blots of IGFBP5 protein levels in human sural nerve from control (C) individuals (3 samples shown from a total of 5 analyzed), patients (P) with DNP, CIDP, DNP+CIDP (3 samples shown from 4 in total) and other neuropathies (ONP; axonal neuropathy in motor neuron disease (O1, O3), vitamin B12 deficiency (O2). b IGFBP5 protein levels were specifically up-regulated in patients with DNP. Biopsies of patients with DNP showed on average a 5-fold up-regulation compared to CIDP individuals and 50-fold in comparison to healthy controls. Up-regulation in DNP patients with additional CIDP was not significantly higher than in patients with DNP alone. Other neuropathies (ONP) and patients with CIDP showed no significant change in comparison to controls. All values were normalized to CIDP biopsies. QL: quantitative labeling. c IGFBP5 (green) and neurofilament (red) distribution in human sural nerves from a control individual and a patient with DNP. Note that IGFBP5 levels were increased in axons and in the extracellular matrix (ECM) (arrows) in DNP. Scale bar 5 μm
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Related In: Results  -  Collection

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Fig1: IGFBP5 protein levels are significantly up-regulated in biopsies of DNP patients. a Western blots of IGFBP5 protein levels in human sural nerve from control (C) individuals (3 samples shown from a total of 5 analyzed), patients (P) with DNP, CIDP, DNP+CIDP (3 samples shown from 4 in total) and other neuropathies (ONP; axonal neuropathy in motor neuron disease (O1, O3), vitamin B12 deficiency (O2). b IGFBP5 protein levels were specifically up-regulated in patients with DNP. Biopsies of patients with DNP showed on average a 5-fold up-regulation compared to CIDP individuals and 50-fold in comparison to healthy controls. Up-regulation in DNP patients with additional CIDP was not significantly higher than in patients with DNP alone. Other neuropathies (ONP) and patients with CIDP showed no significant change in comparison to controls. All values were normalized to CIDP biopsies. QL: quantitative labeling. c IGFBP5 (green) and neurofilament (red) distribution in human sural nerves from a control individual and a patient with DNP. Note that IGFBP5 levels were increased in axons and in the extracellular matrix (ECM) (arrows) in DNP. Scale bar 5 μm
Mentions: Previous studies have shown that IGF1 levels are down-regulated in peripheral nerves in diabetic [53] and non-diabetic [16] types of neuropathy. We therefore investigated the expression of IGF family members, their receptors and IGFBPs by microarray expression analysis of sural nerve biopsies from patients with DNP and age-matched control individuals (electronic supplementary Table A1). Microarray expression analysis revealed a decrease of IGF1 mRNA levels and more than sevenfold up-regulation of IGFBP5 expression in DNP. These findings were corroborated by Western blotting using protein extracts from sural nerve biopsies (Fig. 1a). IGFBP5 protein levels were more than 5-fold up-regulated in 6 patients with DNP (P < 0.01, one-way ANOVA) (see electronic supplementary Table 2 for clinical characteristics of these patients) and in 3 patients with combined diabetic neuropathy and chronic inflammatory demyelinating polyradiculoneuropathy (DNP+CIDP; P < 0.001, one-way ANOVA) as compared to CIDP individuals (Fig. 1b, c) and 50-fold in comparison to healthy controls (P < 0.001, one-way ANOVA). Increased IGFBP5 protein levels were only observed in 2 out of 9 CIDP patients, and did not reach statistical significance when compared with controls (P > 0.05, one-way ANOVA). This suggests an association of IGFBP5 overexpression with DNP rather than with the superimposed CIDP in this mixed group. IGFBP5 expression was also low in the 3 patients with non-diabetic neuropathy (P > 0.05, one-way ANOVA) (Fig. 1a, b). This indicates that levels of IGFBP5 are specifically up-regulated in patients with DNP. Enhanced levels of IGFBP5 could also be detected by immunohistochemistry in peripheral nerve sections (Fig. 1c), particularly in axons, as revealed by co-localization with neurofilament H immunoreactivity. IGFBP5 immunoreactivity was also observed in the extracellular matrix surrounding the axons (arrows in Fig. 1c).Fig. 1

Bottom Line: IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP.These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration.Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.

View Article: PubMed Central - PubMed

Affiliation: Institute for Clinical Neurobiology, University of Würzburg, Versbacher-Str. 5, 97078, Würzburg, Germany.

ABSTRACT
Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes. The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor (IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.

No MeSH data available.


Related in: MedlinePlus