Original Article

Matrix metalloproteinase 3 deletion preserves denervated motor endplates after traumatic nerve injury

  1. Tom Chao MD1,
  2. Derek Frump BS1,
  3. Michael Lin MD, PhD1,
  4. Vincent J. Caiozzo PhD1,
  5. Tahseen Mozaffar MD1,2,
  6. Oswald Steward PhD3,4,5,
  7. Ranjan Gupta MD1,4,*

Article first published online: 31 DEC 2012

DOI: 10.1002/ana.23781

Issue

Annals of Neurology

Annals of Neurology

Volume 73, Issue 2, pages 210–223, February 2013

Additional Information

How to Cite

Chao, T., Frump, D., Lin, M., Caiozzo, V. J., Mozaffar, T., Steward, O. and Gupta, R. (2013), Matrix metalloproteinase 3 deletion preserves denervated motor endplates after traumatic nerve injury. Ann Neurol., 73: 210–223. doi: 10.1002/ana.23781

Author Information

  1. 1

    Department of Orthopaedic Surgery, University of California, Irvine, Irvine, CA

  2. 2

    Department of Neurology, University of California, Irvine, Irvine, CA

  3. 3

    Reeve-Irvine Research Center, University of California, Irvine, Irvine, CA

  4. 4

    Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA

  5. 5

    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA

*Address correspondence to Dr Gupta, Department of Orthopaedic Surgery, University of California, Irvine, 2226 Gillespie Neuroscience Research Facility, Irvine, CA 92697. E-mail: ranjang@uci.edu

Publication History

  1. Issue published online: 22 MAR 2013
  2. Article first published online: 31 DEC 2012
  3. Accepted manuscript online: 1 OCT 2012 06:05AM EST
  4. Manuscript Accepted: 24 SEP 2012
  5. Manuscript Revised: 29 AUG 2012
  6. Manuscript Received: 12 JUN 2012

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Objective

Traumatic peripheral nerve injuries often produce permanent functional deficits despite optimal surgical and medical management. One reason for the impaired target organ reinnervation is degradation of motor endplates during prolonged denervation. Here we investigate the effect of preserving agrin on the stability of denervated endplates. Because matrix metalloproteinase 3 (MMP3) is known to degrade agrin, we examined the changes in endplate structure following traumatic nerve injury in MMP3 knockout mice.

Methods

After creation of a critical size nerve defect to preclude reinnervation, we characterized receptor area, receptor density, and endplate morphology in denervated plantaris muscles in wild-type and MMP3 null mice. The level of agrin and muscle-specific kinase (MuSK) was assessed at denervated endplates. In addition, denervated muscles were subjected to ex vivo stimulation with acetylcholine. Finally, reinnervation potential was compared after long-term denervation.

Results

In wild-type mice, the endplates demonstrated time-dependent decreases in area and receptor density and conversion to an immature receptor phenotype. In striking contrast, all denervation-induced changes were attenuated in MMP3 null mice, with endplates retaining their differentiated form. Agrin and MuSK were preserved in endplates from denervated MMP3 null animals. Furthermore, denervated muscles from MMP3 null mice demonstrated greater endplate efficacy and reinnervation.

Interpretation

These results demonstrate a critical role for MMP3 in motor endplate remodeling, and reveal a potential target for therapeutic intervention to prevent motor endplate degradation following nerve injury. ANN NEUROL 2013;73:210–223

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