Matrix metalloproteinase-1 treatment of muscle fibrosis.
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.
Kaar
Joel L
JL
McGowan Institute for Regenerative Medicine, University of Pittsburgh, 100 Technology Drive, Suite #200, Pittsburgh, PA 15219, USA.
Li
Yong
Y
Blair
Harry C
HC
Asche
Gemma
G
Koepsel
Richard R
RR
Huard
Johnny
J
Russell
Alan J
AJ
D000818:Animals; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000008:administration & dosage* / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology*; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
D011994:Recombinant Proteins; D020781:Matrix Metalloproteinase 1