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NEUROLOGY 2008;71:322-331
© 2008 American Academy of Neurology

The extracellular matrix affects axonal regeneration in peripheral neuropathies

S. C. Previtali, MD, PhD, M. C. Malaguti, MD, N. Riva, MD, M. Scarlato, MD, PhD, P. Dacci, MD, G. Dina, BD, D. Triolo, BD, E. Porrello, BD, I. Lorenzetti, BD, R. Fazio, MD, G. Comi, MD, A. Bolino, PhD and A. Quattrini, MD

From the Department of Neurology and INSPE (S.C.P., M.C.M., N.R., M.S., P.D., R.F., G.C., A.B., A.Q.), Neuropathology Unit (S.C.P., M.C.M., N.R., M.S., P.D., G.D., D.T., E.P., I.L., A.Q.), and Dibit (A.B.), San Raffaele Scientific Institute; and Università "Vita Salute" (G.C.), Milan, Italy.

Address correspondence and reprint requests to Dr. Stefano C. Previtali, Neuropathology Unit, Department of Neurology and INSPE, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy previtali.stefano{at}hsr.it.

Objective: Recent evidence in animal models suggests that components of the extracellular matrix (ECM) play a primary role in peripheral nerve degeneration and regeneration.

Methods: We investigated the expression of several ECM molecules in human sural nerves by immunohistochemistry, Western blot, and reverse transcriptase PCR analysis. To unravel the possible role of these molecules in nerve regeneration, we compared results obtained from nerves with abundant signs of regeneration with those with complete absence of axonal regeneration. The role of some ECM components on neurite extension was further tested in dorsal root ganglion cultures.

Results: We observed that the ECM composition significantly differs in regenerating compared with nonregenerating nerves, independently from their etiologic background. Fibronectin was abundantly expressed in regenerating nerves, whereas vitronectin and fibrin(ogen) prevailed in nonregenerating nerves. Whereas fibronectin is secreted by endoneurial cells, in vivo and vitro studies showed that the source of vitronectin and fibrin(ogen) is the bloodstream.

Conclusions: These data indicate that nerve regeneration is impaired in the presence of breaches in the blood–nerve barrier or impaired extracellular matrix (ECM) degradation that leads to accumulation of plasma vitronectin and fibrin(ogen). The transformation into mature, fibronectin-enriched ECM is necessary for efficient nerve regeneration in humans.

Abbreviations: ANA = antinuclear antibodies; ANCA = antineutrophil cytoplasmic antibodies; Az = azathioprine; B6 def = vitamin B6 deficit; BNB = blood–nerve barrier; Chr Infl Ax Np = chronic inflammatory axonal neuropathy; CK = creatine kinase; CMT2 = Charcot-Marie-Tooth disease type 2; coll = collagen; CS = corticosteroids; Cy = cyclophosphamide; dA = distal arms; degen =degeneration; dL = distal legs; DRG = dorsal root ganglion; ECM = extracellular matrix; ESR = erythrocyte sedimentation rate; FG = fibrin(ogen); FN = fibronectin; GFAP = glial fibrillary acidic protein; HCV mix cryog = hepatitis C virus–associated mixed cryoglobulinemia; Idiopathic Ax Np = idiopathic axonal neuropathy; Ig = immunoglobulin; IVIg = intravenous immunoglobulins; MGUS = monoclonal gammopathy of unknown significance; MN = multineuropathy; mRNA = messenger RNA; Mtx = methotrexate; NA = not applicable; NF = neurofilament; Nonsyst Vasc = nonsystemic vasculitic neuropathy; Np = neuropathy; PAI-1 = plasminogen activator inhibitor; PAN = polyarteritis nodosa; pL = proximal legs; PN = polyneuropathy; PNS = peripheral nervous system; Pt = patient; regen = regeneration; RT-PCR = reverse transcriptase PCR; SDS = sodium dodecyl sulfate; SSA = Sjögren syndrome antigen A; TTR = transthyretin; UCTD = undifferentiated connective tissue disease; VN = vitronectin; Wegener G = Wegener granulomatosis.

Supplemental data at www.neurology.org.

Supported by grants from Telethon Italy (S.C.P. and A.B.), Ricerca Finalizzata-MIUR (S.C.P.), FIRB, Istituto Superiore Sanità (A.Q.), and AFM (A.B.). A.B. is an Associate Telethon Scientist.

Disclosure: The authors report no disclosures.

Received December 3, 2007. Accepted in final form April 22, 2008.






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