MMP-28 as a regulator of myelination
© Werner et al; licensee BioMed Central Ltd. 2008
Received: 16 June 2008
Accepted: 09 September 2008
Published: 09 September 2008
Matrix metalloproteinase-28 (MMP-28) is a poorly understood member of the matrix metalloproteinase family. Metalloproteinases are important mediators in the development of the nervous system and can contribute to the maturation of the neural micro-environment.
MMP-28 added to myelinating rat dorsal root ganglion (DRG) co-cultures reduces myelination and two antibodies targeted to MMP-28 (pAb180 and pAb183) are capable of binding MMP-28 and inhibiting its activity in a dose-dependent manner. Addition of 30 nM pAb180 or pAb183 to rat DRG cultures resulted in the 2.6 and 4.8 fold enhancement of myelination respectively while addition of MMP-28 to DRG co-cultures resulted in enhanced MAPK, ErbB2 and ErbB3 phosphorylation. MMP-28 protein expression was increased within demyelinated lesions of mouse experimental autoimmune encephalitis (EAE) and human multiple sclerosis lesions compared to surrounding normal tissue.
MMP-28 is upregulated in conditions of demyelination in vivo, induces signaling in vitro consistent with myelination inhibition and, neutralization of MMP-28 activity can enhance myelination in vitro. These results suggest inhibition of MMP-28 may be beneficial under conditions of dysmyelination.
MMP-28 added to DRG Co-cultures reduces development of myelin
Polyclonal anti-MMP-28 antibodies bind MMP-28
pAb180 and pAb183 inhibit MMP-28 proteolysis
Anti-MMP28 antibodies enhance myelin formation in vitro
Alteration of signaling pathways after MMP-28 inhibition
To begin to understand the mechanism responsible for increased myelination seen in DRG cultures with anti-MMP-28 antibodies, we evaluated the ability of MMP-28 to alter signaling pathways that are known to be important in the development of myelin.
Increased MMP-28 protein in demyelinating lesions
We have shown previously that MMP-28 is expressed in the developing nervous system in a temporally regulated manner . This expression is inversely correlated with the expression of MAG in two models of Xenopus laevis nerve regeneration and in myelinating rat DRG cultures. These data suggested the possibility that MMP-28 may play a role in the development of myelin during normal development and in neural regeneration. Here we show that exogenously added MMP-28 reduces myelination, that activity in vitro can be inhibited by antibodies to MMP-28, and that such inhibition results in enhanced formation of myelin. Specific inhibitors of MMP-28 are not known; therefore, we generated antibodies to two distinct regions of MMP-28 with the goal of developing inhibitory antibodies. The peptides used were unique to MMP-28 and not expected to cross react with other MMPs. In addition, the locations of the epitopes were expected to be near the active site based on the known sequence of MMP-28. Both antibodies were shown to bind and inhibit MMP-28 activity but did not bind or inhibit MMP-2 or MMP-10. MMP-28 is expressed by DRG neurons within the first 14 days after initiation of myelination by ascorbic acid . As MMP-28 expression is downregulated during the period of myelination in vitro as well as in vivo during nerve regeneration, it is possible that MMP-28 activity is antagonistic to myelination. If so, blocking its proteolytic activity may result in enhancement of the myelination program. Addition of either of the two neutralizing anti-MMP-28 antibodies (pAb 180 or pAb 183) to myelinating DRG cultures resulted in an increase in axon associated MAG staining. This strengthens the hypothesis that neuronal MMP-28 expression after the onset of myelination acts as an inhibitor of the development of myelin. It is not known if MMP-28 acts on the matrix of the neural micro-environment or cleaves cell surface molecules involved in signaling. Illman et al.  have shown that MMP-28 is membrane localized, can induce an epithelial-to-mesenchymal transition in lung adenocarcinoma cells and alters signaling mediated through TGF beta. We were therefore interested in the signaling changes that may be mediated by MMP-28 in our cell culture system and chose to evaluate changes in the ErbB activated pathways as signaling downstream of ErbB receptors regulates myelination. Our initial observations suggest that addition of MMP-28 results in rapid phosphorylation of ErbB2 and ErbB3 and enhanced MAPK phosphorylation. Activation of ErbB2 and ErbB3 on glial cells can result in proliferative signals or myelinating signals [22, 23] and does not on its own suggest which pathway might be affected. However, ErbB receptor activity in myelinating glial cells is characterized by reduced phosphorylation of MAPK and enhanced PI3K phosphorylation. The enhanced MAPK phosphorylation following MMP-28 treatment in DRG co-cultures coupled with decreased activation of the p55 subunit of PI3K, the active signaling pathway during myelination, are consistent with MMP-28 activity enhancing the non-myelination pathway downstream of the ErbB receptors. It is not yet clear if MMP-28 activity is directly involved in the generation of these intracellular phosphorylation events but there is evidence for MMP-mediated signaling within the nervous system. Of particular interest, both Neuregulin-1 and the ErbB receptors are known to be processed by MMP proteolysis [9, 13, 25]. As MMP processing of NRG-1 leads to soluble NRG and the myelinating signal is dependent on juxtacrine signaling, it is possible that MMP-28 cleaves NRG-1 in this system and that inhibiting MMP-28 activity results in accumulation of membrane bound NRG-1. In previous studies, we identified increased proteolysis of NCAM and Nogo-A following MMP-28 treated of embryonic rat brains . Alterations in NCAM expression may be involved in the development of myelin [26, 27] and Nogo-A, a component of myelin, regulates multiple aspects of glial and neural cell biology . Cleavage of either protein could potentially result in soluble biologically active fragments or loss of function through degradation. Alternatively, the degradation of MAG by MMP-28 is a possibility. Previously, we showed that in vitro, at much higher doses than used in these experiments, MAG may be a substrate for MMP-28  and it could be that MMP-28 is degrading MAG expressed in the tissues as it develops until the down regulation of MMP-28. The inverse expression of MMP-28 and MAG suggests that MMP-28 regulation is at least temporally coordinated with the myelination program even if it relates only to the post-transcriptional control of MAG. However, the correlation of MAG staining within myelinated and demyelinated regions of both mouse and human nervous tissue with Luxol Blue staining, which stains the lipid component of myelin, suggests that MAG can be used as marker of myelination even in the presence of varying levels of MMP-28. When taken together with data suggesting that signaling related to the myelination program is altered when exogenous MMP-28 is added, these data support the use of MAG reduction to represent a delay or inhibition of myelination. Further work will be required to determine the essential target of MMP-28 action in vivo.
While the experiments performed in vitro demonstrate a role for MMP-28 in regulating PNS myelination, we were curious if a similar role might be involved in the development or maintenance of CNS myelin. We report in this study for the first time that increased MMP-28 expression can be detected within demyelinated lesions of mouse EAE and human MS nervous system tissue. The increase in MMP-28 detected in both cases lends further support to the hypothesis that MMP-28 activity is involved in the regulation of myelin. It can not be determined from these experiments if MMP-28 activity in these tissues is responsible for the demyelination or if it expressed prior to or during any remyelination, however, the timing of the EAE progression in the tissue (21 days after induction) and the increased nuclei (presumably infiltrating immune cells) in both tissues, suggest that these lesions may be actively demyelinating rather than undergoing the process of remyelination. While these experiments represent a small sample size and need to be followed up to determine the specific lesion types that demonstrate this altered expression, the results suggest that MMP-28 may be a relevant target for therapeutic intervention in MS. It is important to note that while there is consistency in MMP-28 expression during development in the CNS and PNS, and between dysmyelination states (PNS renervation, mouse EAE, and MS) the functional implications of altered MMP-28 expression in the CNS may not be the same as in the PNS. Also remaining to be characterized is the role of activation of MMP-28. MMP function is carefully controlled by cleavage of the pro- form to generate the active form of the protein. The sequence of proMMP-28 contains a putative furin recognition sequence but the details of activation for this enzyme in vivo are unknown.
Validation of the functional role of MMP-28 in the CNS remains to be carried out. Although the specific mechanism is unknown, MMP-28 appears to play a role in the development of myelin. We suggest that in the nervous system, signaling pathways such as activation of the ErbB-MAPK cascade can be altered in response to MMP-28-induced proteolysis and that continued expression of this protease results in inhibition of robust myelination. If MMP-28 activity plays a similar role in modulating myelination in vivo, inhibition of this protease may represent a therapeutic mechanism for enhancing remyelination in demyelinating diseases.
Although the specific mechanism is unknown, MMP-28 appears to play a role in the development of myelin. We suggest that in the nervous system, signaling pathways such as activation of the ErbB-MAPK cascade can be altered in response to MMP-28-induced proteolysis and that continued expression of this protease results in inhibition of robust myelination. If MMP-28 activity plays a similar role in modulating myelination in vivo, inhibition of this protease may represent a therapeutic mechanism for enhancing remyelination in demyelinating diseases.
Generation of polyclonal antibodies
Rabbit polyclonal antibodies were generated to two distinct peptides of human MMP-28 from regions N-terminal or C-terminal to the active site. These epitopes were chosen as they are near the active site of MMP-28 and expected to be accessible to antibodies based on computer modeled predictions of MMP-28 structure. In addition, they are unique to MMP-28 and not expected to bind to other MMPs. Antibodies were affinity-purified from antisera using the corresponding antigen peptides. Antisera were subsequently further purified using protein G spin columns (GE Healthcare) according to the manufacturer's protocol. These purified antibodies, pAb180 and pAb183, were quantified by absorbance at 260 nM and characterized for their ability to bind and modify activity of MMP-28 protein.
100 ng of purified recombinant human MMP-28, MMP-2, and MMP-10 were loaded onto a 4–12% bis-tris gel and electrophoresed at 125 V for 90 minutes under non-reducing conditions. For detection of rat MMP-28, 14 day myelinating rat DRG co-cultures grown in 24 well plates were lysed directly in the well with 200 ul of lysis buffer (50 mM, 1 mM EDTA, mM PMSF, 300 mM NaCl, 1 mg/ml BSA, 2% NP-40, with sodium orthovanadate, hydrogen peroxide, and Complete protease inhibitors (Roche) added just before use to final concentrations of 10 μM, 0.01%, and 1× respectively). LDS sample buffer (Invitrogen) was added to a final 1× concentration. One tenth of the total protein prepared from one well was analyzed by Western blot. The proteins were transferred to nitrocellulose membrane at 30 volts for 90 minutes. The membranes with recombinant MMPs or rat protein extract were blocked overnight in 5% non-fat dry milk/TBST at 4°C followed by incubation in 0.5% NFDM/TBST with either pAb180 or pAb183 at 50 ng/ml. Blots were washed 3 times in TBST and incubated in 0.5% NFDM/TBST with an anti-rabbit HRP-conjugated secondary antibody (10 ng/ml) for 1 hour. The blots were then washed 6 times for ten minutes in what in TBST. Chemiluminescent detection was carried out using SuperSignal West-Femto (Pierce, Rockford, IL). Radiographic film was exposed to the blots to detect the presence of MMP-28.
MMP-28 protein activity was measured using a fluorescently labeled substrate. The fluorescently labeled and quenched peptide, Omni-MMP (Biomol, Plymouth Meeting, PA), a pan-MMP substrate, was dissolved in DMSO to a concentration of 20 mM. MMP protein was diluted in PBS. MMP-28, 10× protease assay buffer (500 mM HEPES pH 7.0, 100 mM CaCl2, 0.5% Brij-35, 100 μM ZnCl2) and substrate were added to a final concentration of 1× assay buffer, 10 μM substrate in 100 μl final volume. Reactions were carried out in black 96 well plates covered with aluminum foil at 37°C. Fluorescence was measured using a Victor3 plate reader (340 nM excitation, 405 nM emission) for 1 second/well.
DRG cultures were established as described by Svenningsen et. al. (2003). Embryos were isolated at day 17 of gestation from pregnant Long-Evans rats (Harlan) and DRGs removed. Cells were washed in L15 + 10% FBS 3 times and resuspended in Neuralbasal media (Invitrogen) with 100 ng/ml NGF (BD) and 2% B27 supplement (Invitrogen). Cells were grown on plates coated with Matrigel (1:20 L15) for 4 days after plating at which point fresh media was added with 50 μg/ml ascorbic acid (myelination media) to initiate myelination. Identification of cell type was carried out by immunofluorescent detection of antibodies to S-100 (Dako), Neurofilament (Chemicon), O4 (Millipore), and Claudin-11 (Santa Cruz). Percentage of Schwann cells or neurons was determined by counting nuclei and S-100 or Neurofilament positive cells from three random fields. A minimum of 149 cells were counted per field. Determination of myelination was carried out by immunofluorescent detection of MAG (Chemicon), a marker for the early stages of myelination. Experiments were performed in early myelinating cultures (14 days or less under myelination permissive conditions). To determine the extent of early myelination, cultures were stained by immunocytochemistry for MMP-28 (Cederlane), present in axons (Werner et. al. 2007) to detect axon bundles, DAPI to detect associated Schwann cell nuclei and MAG to detect myelin formation as described previously (Werner et. al. 2007) using fluorescently labeled secondary antibodies. Images were captured of MMP-28, DAPI, and MAG staining from three random fields in each well. Identified axon bundles were determined to be MAG positive or MAG negative. Scoring was performed blinded to treatment group. A minimum of 100 axon bundles per well were counted and myelination represented as MAG positive axon bundles compared to total axon bundle number. Three wells per group were counted. MMP-28 protein was expressed and purified as described previously (Werner et al., 2007) and diluted into myelination media. For the 0 nM MMP-28 treatment, a volume of MMP-28 negative elution fraction equal to the volume used for the 20 nM MMP-28 sample was added to the myelination media.
Activation of signaling cascades in DRG co-cultures
DRG co-cultures grown in 24 well plates were induced to myelinate for 14 days and then treated with fresh media containing NGF with or without 10 nM MMP-28 (450 ng/ml, 0.5 ml/well). MMP-28 added in the presence of IgG or pAb 180 and pAb 183 was pre-incubated at room temperature for 1 hour prior to addition to cultures. Antibodies added alone to cultures for analysis of myelination were diluted directly in myelination media. Media was aspirated at 0, 1, 5, 10, 15, and 20 minutes after treatment, cells were lysed directly in the wells and subjected to one freeze/thaw cycle at -80°C to disassociate Matrigel. LDS sample buffer (Invitrogen) was added to a final 1× concentration and samples analyzed by Western blot as described earlier. Antibodies were obtained from Cell Signaling Technologies, catalogue numbers as follows: pErbB2 2249S, pErbB3 4784P, pMAPK 4377S, pPI3K 4228P, or LabVision: PCNA Ab-1, PC10. Equal protein loading was confirmed by Coomassie staining of protein in the gel after transfer and Ponceau-S staining of the membrane prior to blocking. For immunoflourescence of phosphoErbB3, cultures were fixed in methanol for 10 minutes followed by three washes in 0.1%Tween 20-PBS (PBST). Nonspecific binding sites were blocked with PBST/5% non-fat dry milk at 37°C for 1 hour followed by incubation with primary antibody (pErbB3, Cell Signaling Technologies No.4784P, acetylated tubulin, Sigma, No. T7451) for 90 minutes at 37°C. Secondary antibodies used were AlexaFluor-488 goat antimouse and Alexa Fluora-555 goat anti-rabbit (Invitrogen). Nuclei are counterstained with DAPI (4',6-diamidino-2-phenylindole, Sigma). To evaluate proliferation in DRG co-cultures, changes in DNA content was measured using the CyQuant NF Cell Proliferation Assay kit (Invitrogen) according to the manufacturers protocol. Briefly, equal number of DRG cells were plated in wells of a 48 well plate and grown under myelination permissive conditions for 14 days at which time, 10 nM MMP-28 or an equal volume of MMP-28 negative column eluate (n = 3 wells per group) was added to the media. After 24 hours, media was removed and 100 μl of 1× dye binding solution was added to the wells and incubated for 60 minutes. Fluorescence was measured on a fluorescent microplate reader (excitation at 485 nm and emission at 535 nm). Proliferation in DRG co-cultures prior to the development of myelin was measured by detection of PCNA by immunofluorescence as described above. Cells were plated at equal number and grown for 2 days at which time 10 MMP-28 or an equal volume of MMP-28 negative column eluate was added for 24 hours. Increases in Schwann cell proliferation have been detected after 24 hours (Lee et al., 1999). Images of three random fields within each well were captured (minimum of 100 cells per field) and total cell number (DAPI stained nuclei) and PCNA positive nuclei were determined.
Determination of myelination in tissues
EAE was established in 6–8 week old C57BL6 mice by immunization to MOG as follows. MOG35-55(Peptide International, Cat. PMG-3660-PI) and heat inactivated M. Tuberculosis (H37 RA, Difco Laboratories, Cat. 231141) were diluted to a final concentration of 1.5 mg/ml and 2.5 mg/ml respectively in CFA (Complete Freund Adjuvant, Difco Laboratories, Cat. 231131) and emulsified by sonication on ice. Mice were immunized in the right flank by subcutaneous injection of 200 μl of MOG emulsion at day 0 and day 7 followed at t = 0 and t = 48 hours with 200 μl of 2.5 μg/ml Pertussis toxin (List Biological Laboratories, Cat. 181) in PBS. Development of EAE clinical signs was monitored daily according to the following scale: 0 = No clinical EAE symptoms, 0.5 = Distal limp or spastic tail, 1 = Limp tail, 1.5 = Limp tail and hind limb weakness, 2 = Unilateral partial hind limb paralysis, 2.5 = Bilateral partial-hind-limb paralysis, 3.0 = Complete bilateral hind-limb paralysis, 3.5 = Complete hind-limb and unilateral partial-forelimb paralysis, 4.0 = Total paralysis of fore and hind-limbs, 5.0 = Moribund or death. After 21 days, the clinical signs score for treated animals was determined to be at 2 or higher. Immunofluorescence staining was performed on 2 sections from spinal cords of three mice with a score of 2 or greater and three normal control spinal cords. For determination of myelination in human MS, frozen 5 μm cerebellar tissue sections from a human MS patient were obtained (Biomax, Ijamsville, MD). Myelination was detected by Luxol fast blue staining or MAG immunohistochemistry. Paraffin sections were deparaffinized through two changes of xylenes followed by a graded series of methanol and a final wash in PBS while frozen sections were thawed to room temperature before processing. Sections were placed in 0.1% Luxol fast blue solution (0.1 g Luxol fast blue (Acros), 0.5 ml acetic acid, in 95% ethanol to 100 ml) for 16 hours at 56°C. The slides are then removed from Luxol fast blue, washed in 95% ethanol, rinsed in distilled, deionized water (ddH2O) and differentiated in 0.05% lithium carbonate (Acros) for 30 seconds. Following differentiation, slides were then rinsed in ddH2O and examined microscopically to verify differentiation of white matter. The slides were then incubated in 0.1% Cresyl echt violet (American Master Tech Scientific) for 40 seconds to counterstain nuclei and gray matter. Excess Cresyl echt violet was rinsed off the slides with ddH2O. The slides were differentiated in 95% ethanol for 5 minutes followed by sequential dehydration in 100% ethanol and Xylenes. The sections were permanently mounted under coverslips using Permount (Sigma). The tissue was analyzed by light microscopy using an upright microscope. To identify changes in protein expression within MS and EAE lesions, immunohistochemistry was performed using standard techniques with antibodies to MMP-28 (Cedarlane) and MAG (Chemicon). Nuclei were counterstained with DAPI. For Western blot analysis of MMP-28 levels in normal or multiple sclerosis patients, frozen brain tissue samples from multiple sclerosis patients were obtained from the Rocky Mountain Multiple Sclerosis Center and normal brain samples were obtained from in house tissue banks (Eli Lilly). Approximately 5 mg of tissue was cut from the frozen samples and lysed in 500 μl 1× LDS buffer (Invitrogen) containing 1× reducing agent (Invitrogen). 5 μl of each sample was loaded onto a 4–12% Bis-Tris gel and electrophoresed under 100 V for 1 hour. The gel was removed and stained with SimplyBlue (Invitrogen) to verify approximately equivalent protein concentrations. Electrophoresis was repeated and proteins were transferred to nitrocellulose. Western blot detection of MMP-28 was carried out as described above using anti-MMP-28 (Cedarlane). Blots were stripped using Restore western blot stripping buffer (Pierce) according to manufacturers instructions and detection of acetylated tubulin (Sigma) was carried out for normalization of protein levels. All animal use protocols were approved by the Eli Lilly Animal Care and Use Committee.
The authors would like to acknowledge Armen Shanafelt, Andrew Glasebrook, and Brian Grinnell for reviewing the manuscript. We also thank Steve Zuckerman for assistance in generating MMP-28 antibodies. EAE tissue was provided by Stuart Bright from studies carried out by Carol Broderick and Joy Saha. Human multiple sclerosis tissue used in Western blot analysis was provided by the Rocky Mountain Multiple Sclerosis Center, Englewood Colorado. Other human tissue specimens were retrieved from the tissue bank of Lilly Research Laboratories. These tissues were obtained from the Cooperative Human Tissue Network using an institutional review board-approved protocol.
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