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Departments of Surgery, Ophthalmology, Pathology, Neurology, and Physiology & Cellular Biophysics, College of Physicians & Surgeons, Columbia University, New York, New York 10032
1 Correspondence: Division of Surgical Science, Department of Surgery, College of Physicians & Surgeons, Columbia University, 630 W. 168th St., P&S 17-401, New York, NY 10032, USA. E-mail: ams11{at}columbia.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: transgenic mice • signal transduction • sciatic nerve
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3
4)
. Although RAGE was first described as a receptor for advanced glycation end products (1)
, species that accumulate in hyperglycemia and oxidant stress, other studies demonstrated that S100/calgranulins, amphoterin, and amyloid-ß-peptide also bound RAGE to activate signal transduction and modulate gene expression (2
3
4)
. In chronic diseases such as diabetes, immune/inflammatory foci, tumors, and neurodegenerative disorders, up-regulation of RAGE was associated with sustained cellular perturbation and tissue injury (2
3
4)
. In peripheral nerve tissue, our studies demonstrated that RAGE was present in both axonal elements and in infiltrating mononuclear phagocytes after crush injury to the sciatic nerve (5)
. Pharmacological blockade of RAGE attenuated ligand/RAGE-mediated regeneration after nerve injury in this setting, thereby suggesting that antagonism of RAGE impaired homeostatic properties. We hypothesized that inflammatory and neurite outgrowth-promoting processes are integral to effective repair of adult peripheral nerves subjected to acute crush, and tested the impact of RAGE blockade in sciatic nerve crush injury in wild-type mice. Our studies demonstrated that pharmacological RAGE blockade, using either soluble (s) RAGE, the extracellular ligand binding decoy of RAGE, or blocking F(ab')2 fragments prepared from anti-RAGE, or anti-ligand IgG (anti-S100/calgranulin or anti-amphoterin IgG), suppressed recovery after acute crush to the sciatic nerve in mice, as measured by functional and morphological indices of regeneration (5)
. Although these studies indicated roles for RAGE in modulating the response to acute nerve injury in the peripheral nervous system, they did not elucidate the specific contribution of RAGE-dependent inflammatory or neurite outgrowth-promoting properties to axonal regeneration after acute injury. Thus, the goal of this study was to use cell-specific mutant RAGE mice in which signal transduction in mononuclear phagocytes or peripheral neurons was dysfunctional.
Previous studies in vitro demonstrated that the cytosolic domain of RAGE is critical for ligand/RAGE-triggered modulation of cellular properties in cultured endothelial cells, smooth muscle cells, mononuclear phagocytes, and C6 glioma tumor cells (2
3
, 6)
. Furthermore, when first tested in vivo, transgenic mice expressing cytosolic domain-deleted dominant negative (DN) RAGE in smooth muscle cells (SMC) displayed decreased neointimal expansion consequent to femoral artery injury compared with wild-type mice (7)
. Thus, in both in vitro and in vivo analyses, the RAGE cytosolic domain is critical for RAGE-mediated effector function.
In this study, we generated transgenic mice expressing DN RAGE in either mononuclear phagocytes or peripheral neurons and tested the effect of sciatic nerve crush in both sets of animals, and in transgenic mice expressing DN RAGE in both mononuclear phagocytes and peripheral neurons. Our findings reveal key modulatory roles for RAGE in both mononuclear phagocytes and peripheral neurons consequent to acute injury in the peripheral nervous system.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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9)
. The numbers of mice used for each individual study are indicated in the figure legends.
Generation and characterization of RAGE-modified transgenic mice
Transgenic MSR DN RAGE mice
Transgenic MSR DN RAGE mice were prepared using the macrophage scavenger receptor type A promoter (10)
. Founders were identified by mouse tail biopsy; DNA was prepared and Southern blot performed using human RAGE cDNA as a probe and by PCR. Mice were generated and hemizygous mice backcrossed eight generations into C57BL/6 were used in our studies.
Transgenic thy-1 DN RAGE mice
The transgenic thy-1 DN RAGE mice were prepared using the thy-1 promoter generously provided to us by Dr. Herman van der Putten (11)
to direct expression of human DN RAGE to neurons. Founders were identified by mouse tail biopsy; DNA was prepared and Southern blot performed using human RAGE cDNA as a probe and by PCR. Mice were generated and hemizygous mice backcrossed eight generations into C57BL/6 were used in our studies.
Cell culture
Dorsal root ganglia neurons
Dorsal root ganglia (DRG) neurons were isolated from three week old mice (12
, 13)
. Neurite outgrowth studies were performed by seeding DRG neurons on eight-chamber slides (Lab-Tek, Nalge Nunc International, Naperville, IL, USA) coated with poly-L-lysine (50 µg/mL) for 18 h at 37°C. Certain chambers were further coated with RAGE ligand amphoterin (20 µg/mL) (14)
for 6 h at 37°C. Neurons from transgenic thy-1 DN RAGE mice or wild-type littermate dorsal root ganglia were then plated on the slides, and incubated at 37°C, 5% CO2 for 72 h. Two slides (16 chambers) were used in one experiment and the same experiment was repeated for a total of 4 times. Images were acquired by Adobe LE software using a phase contrast microscope that is attached to a camera system. Neurite length of cells not in contact with adjacent cells was measured with Image Pro Plus software (MediaCybernetics, Silver Spring, MD, USA); 25 cells per group were analyzed for longest neurite length in each experiment and the frequency distribution of neurite length in each group was calculated. In other studies, cultured DRG neurons were deprived of fetal bovine serum for 16 h and stimulated with RAGE ligand, amphoterin (14)
(10 µg/mL) or murine serum albumin (MSA) (Sigma-Aldrich, St. Louis, MO, USA) (20 µg/mL) for 30 min. Cells were harvested and Western blot was performed as described below.
Macrophages
Transgenic MSR DN RAGE and wild-type mice received intraperitoneal injections of thioglycollate medium (Sigma-Aldrich) (3% in 1 mL of sterile-filtered (0.22 µm) phosphate buffered saline). Three days later, macrophages were retrieved using 10–20 mL PBS, cytospun. Macrophages were cultured in DMEM containing 10% FBS. In other studies, mononuclear phagocytes were deprived of serum for 16 h and stimulated with RAGE ligands, amphoterin (14)
or S100b (CN Biosciences, Inc. La Jolla, CA, USA), both at 10 µg/mL, or murine serum albumin (MSA) (Sigma-Aldrich) (20 µg/mL) for 30 min. Cells were harvested and Western blot was performed as described below.
Nerve conduction velocity
Twenty-one days after crush injury, mice were anesthetized using ketamine (100 mg/kg) and xylazine (10 mg/kg), both diluted in PBS. The body temperature was kept constant at 37°C. A Nicolet Viking II computerized EMG system was used for stimulation and recording all studies (Nicolet Biomedical, Madison, WI, USA). A square wave stimulus pulse (0.1 ms) at very low amperage (0–20 milliamps, average 4–5 milliamps) was delivered using a bipolar Nicolet Viking stimulator probe (Model S403), through attached subdermal needle electrodes (Nicolet Biomedical Disposable SS-Subdermal Needles). For motor studies, the sciatic nerve and its branches were stimulated at two sites, with recording from the same distal site for both stimulations. For proximal stimulation, the active electrode was placed in the superior dorsomedial upper thigh near midline at the sciatic notch, with the reference electrode 1 to 3 mm distally. For distal stimulation, the active electrode was placed in the vicinity of the medial knee, with the reference lateral. Evoked compound muscle action potentials (CMAPs) were recorded from the gastrocnemius muscle using needle recording electrodes (Medtronic, Inc., Tolochenaz, Switzerland) with the reference electrode in the ankle tendon. Amplitudes were measured in microvolts, and the latency in milliseconds between stimulation and the CMAP onset was determined. Motor conduction velocity was calculated by dividing the distance between electrodes (measured with a fine caliper) by the difference in latency during stimulation at the sciatic notch compared with that obtained during knee stimulation to yield a velocity in meters per second. For sensory nerve conduction, the sural nerve was stimulated orthodromically using needle electrodes placed in the foot, with recording via needle electrodes in the vicinity of the sciatic notch (as described for motor stimulation, above). Prior to recording, current was passed through the recording electrodes and the muscle response observed to insure proper placement of the electrodes proximate to the sciatic nerve. The sensory nerve action potential (SNAP) was recorded. SNAP amplitude was measured and the latency between stimulation and SNAP onset was measured. Sensory nerve conduction velocity was calculated by dividing the distance between the stimulating and recording electrodes (measured with fine caliper) by this latency.
Histology
Transgenic and wild-type mouse unlesioned sciatic nerve segments were immersed in Tissue-Tek (Sakura Finetek USA, Inc., Torrance, CA, USA). Frozen sections, 8 µm thick, were fixed in acetone at –20°C, and incubated with rabbit anti-human RAGE IgG (14)
(25 µg/mL) for 18 h at 4°C, washed with 1xPBS for 5 min 5 times, followed by the addition of peroxidase-conjugated goat anti-rabbit IgG (10 µg/mL) for conventional light microscopy. For semithin section microscopy, mice were anesthetized as above and transcardially perfused with NaCl (0.9%), followed by paraformaldehyde (4%) in phosphate buffer (0.1M, pH 7.4). Sciatic nerve segments from normal unlesioned mice or segments distal to the site of crush (the first 3 mm) from lesioned mice were removed. Nerve segments were fixed in glutaraldehyde (2.5%; EM Science, Ft. Washington, PA, USA), paraformaldehyde (2%) in PBS (0.1M; pH 7.4) at room temperature for 2–4 h and postfixed in osmium tetroxide (1%) for 1–1.5 h. Segments were then serially dehydrated, and embedded in Spurr (EM Science). Semithin sections (0.5 µm) were cut using 2088 ultratome (LKB Produkter AB, Bromma, Sweden). Toluidine blue-stained semithin sections were examined under a Zeiss microscope. Images were captured using a CCD video camera connected to a computer image analysis system (Zeiss, Thornwood, NY, USA). Myelin debris was quantified by pathologists blinded to the experimental protocol (0, no myelin debris; 4, extensive myelin debris). Myelinated fibers from three sections of one mouse in a group of 3–5 mice were counted and fiber density was calculated using Image-Pro Plus software (MediaCybernetics). The numbers of regenerative clusters were determined according to published procedures on sections prepared from 4–10 mice per group (15)
.
Western blot
Antibodies
The antibodies used in these experiments were as follows: polyclonal rabbit anti-human RAGE IgG (14)
(2.5 µg/mL); polyclonal rabbit anti-phospho-/total p44/42 MAP kinase (Thr202/Tyr204) (2 µg/mL), polyclonal rabbit anti-phospho-/total p38 MAP kinase (tyr180/Tyr182) (2 µg/mL), polyclonal rabbit anti-phospho-/totalSTAT3 (Tyr705) (2 µg/mL), and polyclonal rabbit anti-phospho-/total SAPK/JNK (Thr183/Tyr185) (2 µg/mL) were purchased from Cell Signaling (Beverly, MA, USA); monoclonal rat anti-mouse F4/80 IgG (2 µg/mL) was purchased from Accurate Chemical (Westbury, NY, USA) and monoclonal mouse anti-ß-actin IgG (0.54 µg/mL) was purchased from Sigma. In Western blots, as indicated, the following secondary antibodies were used: peroxidase-conjugated goat anti-rabbit IgG (0.3 µg/mL) for RAGE and MAP kinases Western blots; peroxidase-conjugated goat anti-rat IgG (1 µg/mL) for F4/80 Western blot; and peroxidase-conjugated goat anti-mouse IgG (0.5 µg/mL) for ß-actin Western blot.
Preparation of lysates and Western blot
Sciatic nerves were excised, or cultured macrophages and neurons were collected, and extracts were prepared by Duall tissue grinder (Kontes Glass, Vineland, NJ, USA) in lysis buffer (EDTA, 0.01M; EGTA, 0.01M; ß-glycerol-phosphate, 0.01M; sodium vanadate, 0.01M; leupeptin, 10 µg/mL; aprotinin, 10 µg/mL; Tris-Hcl, pH 7.4, 0.2M; and sodium chloride, 1.5M). The homogenates were sonicated and centrifuged to retrieve supernatant. Protein concentration of the supernatant was determined using Bio-Rad protein assay (Bio-Rad, Hercules, CA, USA). Lysate proteins (30 µg) were fractionated on Tris-glycine (6–18%) SDS-PAGE. Contents of the gels were transferred to nitrocellulose membranes and primary and secondary antibodies were used for Western blot, as detailed above. The enhanced chemiluminescence (ECL) detection system (Amersham-Pharmacia Biotech, Piscataway, NJ, USA) was used to visualize the immunoreaction. After the primary reactions, membranes were stripped and reprobed with antibodies for total kinase or ß-actin. Quantitative analysis of the band density was performed using ImageQuant (Molecular Dynamics, Foster City, CA, USA). The blots were repeated three times and representative bands are presented. Mean values are reported after normalization to total kinase or ß-actin immunoreactivity.
Statistical analysis
The mean ± standard error is reported. Statistical comparisons among groups were determined using one-way ANOVA; where indicated, individual comparisons were performed using Students’ t test. The frequency distribution of neurite lengths between the treatment and genotype groups was analyzed by the chi-square test. Statistical significance was ascribed to the data when P <0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, we prepared transgenic mice expressing human DN RAGE under control of the macrophage scavenger receptor (MSR) -A promoter (10)
. Southern blot and PCR performed on genomic DNA revealed several founders (Fig. 1
a, b, respectively). To determine whether RAGE antigen levels were enhanced in transgenic mouse mononuclear phagocytes, these cells were elicited and retrieved from transgenic and littermate control mice by instillation of thioglycollate into the peritoneal cavity. Western blot of thioglycollate-stimulated mononuclear phagocytes from the peritoneal cavity revealed increased expression of RAGE antigen in transgenic MSR DN-RAGE mice compared with wild-type (WT) littermates, P <0.01 (Fig. 1c
). We subjected transgenic MSR DN-RAGE and littermate mice to sciatic nerve crush.
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On day 3 after crush, numbers of mononuclear phagocytes in the distal segments were significantly diminished in transgenic mice, as demonstrated by Western blot for detection of F4/80, a mononuclear phagocyte marker, P <0.01 (Fig. 1d
), thus supporting the premise that mononuclear phagocyte migration into the nerve segments immediately distal to the site of crush is regulated, at least in part, by RAGE signaling.
Phosphorylation of p44/p42 MAP kinase was significantly reduced in the distal nerve segments at 18 h after crush injury in transgenic vs. littermate mice, P <0.01 (Fig. 1e
), but no difference in phospho-p44/42 MAP kinases was observed between transgenic and littermate mice at baseline. No differences in phospho-p38 or SAPK/JNK MAP kinases or STAT3 were noted at 18 h or 7 days after crush (data not shown). Ex vivo, incubation of thioglycollate-elicited mononuclear phagocytes from transgenic mice to a prototypic S100/calgranulin, S100b, or amphoterin, but not murine serum albumin, revealed reduced phosphorylation of p44/p42 MAP kinases compared with wild-type mononuclear phagocytes, P <0.001 (Fig. 1f
).
Taken together, these studies revealed that mononuclear phagocytes were reduced in transgenic mice expressing DN RAGE in cells of mononuclear phagocyte lineage; in parallel, distal nerve segments revealed decreased phosphorylated p44/p42 MAP kinase.
Transgenic mice expressing dominant negative (DN) RAGE in neurons display decreased neurite outgrowth and phosphorylation of p44/p42 MAP kinase and Stat-3 after sciatic nerve crush
In addition to mononuclear phagocytes, RAGE is also expressed by neuronal elements in the peripheral nervous system, both prior to and after crush injury (5)
. To dissect the potential contribution of neuronal RAGE to regeneration, we generated transgenic mice in which RAGE function was selectively disrupted in neurons. We used a fragment of the thy-1 promoter (11)
to direct expression of the human DN RAGE transgene to neurons to generate multiple founders, as demonstrated by Southern blot and PCR (Fig. 2
a, b). Transverse sections prepared from sciatic nerve demonstrated increased expression of RAGE antigen in transgenic vs. littermate mice (Fig. 2c, d
, respectively).
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To determine the effect of deficient RAGE signaling in peripheral neurons, we subjected adult mice to sciatic nerve crush. Levels of phospho-p44/p42 MAP kinases were decreased 18 h after injury in distal segments in transgenic vs. littermate animals, P <0.001 (Fig. 2e
), but no difference in phospho-p44/42 MAP kinases was noted between transgenic and littermate mice at baseline. In parallel, DRG neurons retrieved from transgenic thy-1 DN-RAGE mice displayed significantly decreased phosphorylation of p44/p42 MAP kinases in the presence of RAGE ligand, amphoterin, compared with DRG neurons isolated from wild-type animals, P <0.01 (Fig. 2f
). Levels of phospho-STAT3 were significantly reduced on day 7 in the distal segments of sciatic nerve in transgenic thy-1 DN-RAGE mice compared with littermates, P <0.001 (Fig. 2g
). No differences in phosphorylation of SAP/JNK or p38 MAP kinases in sciatic nerve tissue distal to the site of crush were observed between transgenic vs. wild-type littermates at 18 h or 7 days (data not shown).
We tested the concept that RAGE plays a role in peripheral neurite outgrowth in response to ligands such as amphoterin. DRG neurons were isolated and placed on matrices coated with poly-L-lysine alone (Fig. 2h, j
), or in the presence of poly-L-lysine and amphoterin (Fig. 2i, k
). On poly-L-lysine alone (not a ligand for RAGE), no differences in frequency distribution of neurite length were observed in DRG neurons retrieved from transgenic thy-1 DN RAGE or wild-type mice (Fig. 2h, j
, respectively; Fig. 2l
). However, in the presence of poly-L-lysine and amphoterin, significantly shorter neurite lengths were observed in transgenic thy-1 DN RAGE vs. wild-type mice, P <0.01 (Fig. 2i, k
, respectively; Fig. 2l
).
Transgenic mice expressing DN RAGE in mononuclear phagocytes and peripheral neurons display significantly decreased nerve regeneration after crush
As the mechanisms driving Wallerian degeneration and axonal regeneration are integrated, and introduction of DN RAGE into mononuclear phagocytes and peripheral neurons affected key signaling pathways linked to regeneration, we tested the premise that disruption of RAGE signaling in mononuclear phagocytes and peripheral neurons would suppress regeneration. Thus, we assessed the impact of acute sciatic nerve crush in single transgenic mice, and in double transgenic mice expressing DN RAGE in both mononuclear phagocytes and peripheral neurons. We compared the effect of acute crush in single or double transgenic animals vs. wild-type littermate control mice, or single vs. double transgenic animals.
We assessed the effect of modified RAGE signaling on functional indices of regeneration, by determining motor and sensory nerve conduction velocities. It is important to note that at baseline, no differences in motor or sensory nerve conduction velocities were observed between transgenic mice expressing DN RAGE in mononuclear phagocytes and/or peripheral neurons, as indicated in Fig. 3
a, b (filled-in black bars in each case). First, we compared conduction velocities on day 21 after crush in single transgenic mice vs. respective littermate controls. Compared with wild-type littermate mice, transgenic mice expressing DN RAGE in mononuclear phagocytes displayed an 
40% and 45% decrease in motor and sensory nerve conduction velocities on day 21 after crush, P <0.01 (Fig. 3a, b
, respectively). Compared with wild-type littermate mice, transgenic mice expressing DN RAGE in peripheral neurons displayed an 39% and 37% decrease in motor and sensory nerve conduction velocities on day 21, P <0.01 (Fig. 3a, b
, respectively). To determine whether simultaneous expression of DN RAGE in mononuclear phagocytes and neurons would further exacerbate functional recovery after crush, we performed nerve conduction velocity studies in double transgenic mice. Double transgenic mice displayed an 85% reduction in motor and sensory nerve conduction velocities on day 21 compared with wild-type controls, P <0.01; and an 70% decrease in motor and sensory nerve conduction velocities compared with single transgenic mice expressing DN RAGE in mononuclear phagocytes or peripheral neurons, P <0.05 (Fig. 3a, b
).
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Transverse semithin sections were prepared from transgenic mice expressing DN RAGE in mononuclear phagocytes and/or neurons (Fig. 3d-f
) and from wild-type littermate mice (Fig. 3c
). Quantitative analyses demonstrated that mice expressing DN RAGE in mononuclear phagocytes (single or double transgenic) displayed increased myelin debris compared with wild-type mice, and mice expressing DN RAGE in neurons alone displayed increased myelin debris compared with wild-type mice, P <0.05 (Fig. 3g
). Myelinated fiber density was significantly reduced by 42% in mice carrying the DN RAGE transgene in mononuclear phagocytes or neurons compared with control littermates, P <0.01. Mice expressing DN RAGE in both mononuclear phagocytes and neurons contained 67% fewer myelinated fibers in the sciatic nerve distal segments than wild-type mice, P <0.01; and 43% fewer myelinated fibers than single transgenic animals expressing DN RAGE in either mononuclear phagocytes or peripheral neurons, P <0.05 (Fig. 3h
).
Lastly, we assessed numbers of regenerative clusters in the distal segments on day 21 after crush (15)
. Compared with wild-type littermates, mice expressing DN RAGE in both mononuclear phagocytes and peripheral neurons displayed an 75% decrease in numbers of regenerative clusters, 0.0004±0.0001/µm2 vs. 0.0001±0.00008/µm2, respectively; P = 0.012.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although our findings do not exclude a potential role for RAGE in Schwann cells in Wallerian degeneration after nerve crush, data in single or double transgenic mice suggest that RAGE in mononuclear phagocytes and neurons contributes critically to peripheral nerve repair. Studies have suggested that acute nerve injury triggers dramatic reprogramming of Schwann cells such that Schwann cells assume mononuclear phagocyte-like properties after injury (16
17)
. There is no evidence from our studies that the MSR type A promoter directs expression to Schwann cells, even after crush. Thus, future studies must address the potential impact of RAGE signaling specifically in Schwann cells if promoters become available that do not down-regulate expression in the Schwann cells consequent to acute peripheral nerve injury.
It has been suggested that peripheral nerve injury triggers processes that recapitulate in part developmental mechanisms (18)
. Expression of RAGE and at least one of its ligands, amphoterin, is enhanced in developing central nervous system neurons and falls in the immediate postnatal period (14)
. Although peripheral nerves developed normally in transgenic mice expressing DN RAGE in neurons, as evidenced by normal motor and sensory nerve conduction velocities prior to crush in each genotype, in the adult, disruption of neuronal RAGE suppressed optimal axonal regeneration after crush injury. Indeed, evidence is emerging that signaling pathways linked to development or the (adult) response to neuronal injury do diverge (19)
. Although phosphorylation of STAT3, linked to expression of neuronal growth and adhesion molecules (20
21
22)
, is not a prominent feature in embryonic motor neurons, its activity is strikingly up-regulated in injured adult peripheral neurons (22)
. Our findings demonstrate suppression of phosphorylation of STAT3 in the nerve segment distal to crush injury in transgenic mice if expression of DN RAGE is limited to nerve cells.
In contrast, phosphorylation of p44/p42 MAP kinases was diminished in transgenic mice expressing DN RAGE in either mononuclear phagocytes or peripheral neurons. Phosphorylated p44/p42 kinases play an integral role in mitogenic and migratory properties (23
24
25
26
27)
. In crushed nerve, migration of mononuclear phagocytes, largely from the periphery, and outgrowing neurites contribute to the successful evolution and resolution of integrated degeneration and regeneration programs. These considerations underscore the premise that although roles for mononuclear phagocytes are central in Wallerian degeneration; activity of these cells greatly affects recruitment of regenerative mechanisms triggered by crush (18
, 28
29
30)
. Key roles for RAGE-dependent signaling pathways, including STAT3 and p44/p42 MAP kinases in neurite outgrowth (31)
, are elucidated by our findings in transgenic mice expressing DN RAGE in neurons or mononuclear phagocytes.
Taken together, these findings link RAGE signaling to distinct inflammatory and neuronal reparative mechanisms triggered by acute nerve injury, and demonstrate a new paradigm that highlights innate functions of RAGE-expressing mononuclear phagocytes and peripheral neurons in peripheral neuronal plasticity.
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ACKNOWLEDGMENTS |
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Received for publication March 15, 2004. Accepted for publication August 5, 2004.
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(carboxymethyl)lysine modifications of proteins are ligands for RAGE that activate cell signaling pathways and modulate gene expression. J. Biol. Chem. 274,31740-31749This article has been cited by other articles:
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