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. 2008 Apr;25(4):419-26.
doi: 10.1111/j.1464-5491.2008.02414.x.

Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing

M Muller  1 , C Trocme, B Lardy, F Morel, S Halimi, P Y Benhamou
Affiliations

Matrix metalloproteinases and diabetic foot ulcers: the ratio of MMP-1 to TIMP-1 is a predictor of wound healing

M Muller et al. Diabet Med. 2008 Apr.

Abstract

Aims: Matrix metalloproteinases (MMPs) play a major role in wound healing: they can degrade all components of the extracellular matrix. In diabetic foot ulcers there is an excess of MMPs and a decrease of the tissue inhibitors of MMPs (TIMPs). This imbalance is probably one cause of impaired healing. However, little is known about changes in MMPs during wound healing.

Methods: Sixteen patients with neuropathic diabetic foot ulcers participated. Wound fluid was collected regularly during the 12-week follow-up period, for measurement of MMP-1, MMP-2, MMP-8, MMP-9 and TIMP-1. Results were analysed by the degree of wound healing: good healers (defined by a reduction of at least 82% in initial wound surface at 4 weeks) and poor healers (reduction of less than 82% in wound surface at 4 weeks).

Results: In good healers, levels of MMP-8 and -9 secreted by inflammatory cells decreased earlier. The initial levels of MMP-1 were similar in good and poor healers (P = 0.1) but rose significantly at week 2 in good healers (P = 0.039). There was a significant correlation between a high ratio of MMP-1/TIMP-1 and good healing (r = 0.65, P = 0.008). Receiver Operator Curve (ROC) analysis showed that an MMP-1/TIMP-1 ratio of 0.39 best predicted wound healing (sensitivity = 71%, specificity = 87.5%).

Conclusions: A high level of MMP-1 seems essential to wound healing, while an excess of MMP-8 and -9 is deleterious, and could be a target for new topical treatments. The MMP-1/TIMP-1 ratio is a predictor of wound healing in diabetic foot ulcers.

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Figures

FIGURE 1
FIGURE 1
Wound area during the 12-week follow-up, expressed as a percentage of the initial area. The values correspond to medians for each group, with 25th and 75th percentiles. The number of patients whose wound is not completely healed is given in parentheses for each visit and each group. By week 8 7/7 patients had healed in the good healer group, whereas by week 12 3/9 patients had not healed in the poor healer group.
FIGURE 2
FIGURE 2
Levels of MMP-8 and MMP-9 for good and poor healers during the 12-week follow-up period (results are expressed as medians with 25th and 75th percentiles).
FIGURE 3
FIGURE 3
Levels of MMP-1 and TIMP-1 for good and poor healers during the 12-week follow-up period (results are expressed as medians with 25th and 75th percentiles).
FIGURE 4
FIGURE 4
The ratio of MMP-1/TIMP-1 is a predictive factor for healing. The ROC analysis gives an area under the curve of 0.821 [confidence interval (CI) 0.6–1.04]. A ratio of 0.39 at week 0 has a sensitivity of 71% and a specificity of 87.5% for detecting a wound area reduction of at least 82% at week 4 (and thus predicting wound healing at week 12).
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