Matrix metalloproteinase-1 treatment of muscle fibrosis

Kaar, JL and Li, Y and Blair, HC and Asche, G and Koepsel, RR and Huard, J and Russell, AJ (2008) Matrix metalloproteinase-1 treatment of muscle fibrosis. Acta Biomaterialia, 4 (5). 1411 - 1420. ISSN 1742-7061

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Abstract

The onset of scarring after injury may impede the regeneration and functional recovery of skeletal muscle. Matrix metalloproteinase-1 (MMP-1) hydrolyzes type I collagen and thus may improve muscle regeneration by resolving fibrotic tissue. We examined the effect of recombinant human MMP-1 on fibrosis in the lacerated gastrocnemius muscle of NOD/scid mice, allowing treatment potential to be ascertained in isolation from immune response. The efficacy of proMMP-1 and active MMP-1 were compared with or without poly(ethylene glycol) (PEG) modification, which was intended to increase the enzyme's stability. Active MMP-1 was most effective in reducing fibrosis, although treatment with proMMP-1 was also beneficial relative to controls. PEG-modified MMP-1 had minimal activity in vivo, despite retaining activity towards a thioester substrate. Moreover, the modified enzyme was inactivated by trypsin and subtilisin at rates comparable to that of native MMP-1. These results and those of computational structural studies suggest that modification occurs at the C-terminal hemopexin domain of MMP-1, which plays a critical role in collagen turnover. Site-specific modifications that spares catalytic and substrate binding sites while protecting susceptible proteolytic digestion sites may be beneficial. We conclude that active MMP-1 can effectively reduce muscle scarring and that its activity is related to the ability of the enzyme to digest collagen, thereby facilitating remodeling of the injured muscle. © 2008 Acta Materialia Inc.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Kaar, JL Li, Y Blair, HC Asche, G Koepsel, RR Huard, J Russell, AJ
Centers:	Other Centers, Institutes, Offices, or Units > McGowan Institute for Regenerative Medicine
Date:	1 January 2008
Date Type:	Publication
Journal or Publication Title:	Acta Biomaterialia
Volume:	4
Number:	5
Page Range:	1411 - 1420
DOI or Unique Handle:	10.1016/j.actbio.2008.03.010
Schools and Programs:	School of Medicine > Orthopaedic Surgery School of Medicine > Pathology School of Medicine > Surgery Swanson School of Engineering > Chemical Engineering Swanson School of Engineering > Petroleum Engineering
Refereed:	Yes
ISSN:	1742-7061
MeSH Headings:	Animals; Fibrosis--drug therapy; Fibrosis--pathology; Humans; Matrix Metalloproteinase 1--administration & dosage; Matrix Metalloproteinase 1--genetics; Mice; Mice, SCID; Muscle, Skeletal--drug effects; Muscle, Skeletal--pathology; Recombinant Proteins--therapeutic use; Treatment Outcome
PubMed ID:	18440885
Date Deposited:	15 May 2014 20:34
Last Modified:	24 Dec 2021 23:55
URI:	http://d-scholarship.pitt.edu/id/eprint/21592

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