The Role Of MMPs In Chronic Wound Edema

By Adrianne P.S. Smith, MD, FACEP

What The Literature Reveals
For chronic venous leg ulcers, studies show a 30-fold elevation in MMP activity when compared to acute wounds. MMP-9 activity exceeds MMP-2 activity. In a pressure ulcer model (decubitus ulcers), the levels of MMP-2 and MMP-9 are elevated more than 10-fold and 25-fold respectively. In pressure ulcers, MMP-8 collagenase activity is also elevated. The diabetic foot ulcer model shows a 65-fold increase in MMP-1 collagenase activity, a three-fold increase in MMP-2 proenzyme activity, a six-fold increase in activated MMP-2, a two-fold increase in MMP-8 activity and a 14-fold increase in MMP-9 activity.
The MMP proteolytic activity in acute wounds is not as pronounced. Acute mastectomy wound fluid shows an increased gelatinase activity for MMP-9 and MMP-2. However, these increases were only five to ten-fold. It is also important to note that the inactive zymogen forms tended to persist in acute wound fluid. These results suggest that the pro-inflammatory environment of non-healing ulcers supports high levels of gelatinase activation.
TIMP activity appears to be inversely related to the chronicity of the wound. In the diabetic foot model, TIMP-2 activity is decreased. In the venous ulcer model, TIMP-1 activity is depressed. Likewise, the pressure ulcer model shows lower TIMP activity secondary to complexes of TIMP and activated MMP.
Proteolytic activity normalizes as the wound healing progresses. Studies comparing protease activity in venous leg ulcers showed a reduction in MMP-2 and MMP-9 levels as the wounds healed over a two-week period following treatment with bed rest and leg elevation. Pro-inflammatory cytokines IL-1, IL-6 and TNF-alpha in wound fluid from previously non-healing lower extremity wounds also decrease during healing.
Platelet derived growth factor (PDGF), epidermal growth factor (EGF), basic fibroblast growth factor (FGF-basic) and transforming growth factor-beta (TGF-ß) did not significantly change as wounds healed. These results suggest that the impaired healing response seen in chronic wounds may be more dependent upon inflammatory mediators and MMP activation than upon a deficit in growth factors.
Controlled proteolysis is needed for cell migration, angiogenesis and matrix remodeling. Collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) are expressed in keratinocytes bordering both acute and chronic wounds. Differential collagenase expression suggests various MMPs serve different functions during the wound healing process. The presence of collagenase-1 (MMP-1) in keratinocytes appears to be important for cellular migration whereas collagenase-3 (MMP-13), which present exclusively in fibroblasts embedded deep within the chronic ulcer wound bed, probably functions more in matrix remodelling.
TIMP-1 associated with keratinocytes bordering healing wounds at the basement membrane is not expressed in the epidermis of chronic wounds. TIMP-3 expression is conserved in both acute and chronic wounds, localized in the stromal fibroblast and macrophage-like cells surrounding vessels and sweat glands.
Researchers report no qualitative differences in the expression of MMPs -1, -3, and -10 in the epidermis of chronic wounds when they compared them to normally healing wounds. However, the overall number of stromal cells expressing MMP-1 and MMP-3 are greater in chronic wounds. MMP-10 has not been detected in the dermis of chronic wounds.
These studies outline the need for further research to clarify the connection between cellular expression, concentration and function of the MMPs as balanced with TIMPs. At this time, it is difficult to drawn a causal relationship between wound healing and the presence or absence of a given MMP.

Dr. Smith is the Medical Director of the Wound Care Center at the Texas Diabetes Institute in San Antonio, Texas. She is an Assistant Professor in the Department of Rehabilitative Medicine at the University of Texas Health Science Center, is board-certified in emergency medicine and fellowship-trained in hyperbaric medicine.

Dr. Steinberg (pictured) is an Assistant Professor in the Department of Orthopaedics/Podiatry Service at the University of Texas Health Science Center.


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