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Proteinases and growth factors

Players in the healing process

DURING EVERY PHASE OF THE HEALING PROCESS cytokines, enzymes and growth factors play a major role and allow the different players in the healing process (cells, extracellular matrix) to “communicate” with one another and organise tissue repair. There is therefore a controlled breakdown of the extracellular matrix by proteinases ,which is necessary for cell migration and tissue reconstruction phenomena.

In parallel, various growth factors are synthesised and excreted by the blood and tissue cells to stimulate healing phenomena, such as cell proliferation and the synthesis of matrix components.

Among the various proteinases, matrix metalloproteinases (MMPs) play a major role throughout the healing process. MMPs are produced by different dermal and blood cells to break down all the components of the bruised or damaged extracellular matrix. They are therefore involved at the very initial phase in the elimination of damaged tissue.

The MMP that has been known about for longest is collagenase (MMP-1) but around twenty others have also been identified; these MMPs are responsible for breaking down the damaged extracellular network. Their activity is regulated by specific inhibitors, TIMPs (Tissue Inhibitors of Metalloproteinases).

The biochemical malfunction of chronic wounds and recurring wounds

ANY WOUND can become chronic or recurring if it occurs in an unfavourable context. In this case, biochemical anomalies can be found at each stage of the healing process.

One of the main characteristics of chronic wounds or recurring wounds is an excessive amount of proteinases and a deficiency in growth factors.

Healing phases	Normal healing	Compromised healing
INFLAMMATION	Rapid recruitment and disappearance of inflammatory cells	Excessively prolonged influx of inflammatory cells
GRANULATION	Controlled release of growth factors, MMPs and cytokines, leading to : Re-epithelialisation Angiogenesis Migration of fibroblasts	Uncontrolled release of growth factors, MMPs and cytokines, leading to Cell necrosis Apoptosis
REMODELLING	Formation of the scar	Impossible since no re-epithelialisation

The imbalance in MMPs

THE PRESENCE OF DIFFERENT MMPs at excessively high levels has been systematically found in chronic wounds, particularly MMP-1 (collagenase), associated with low concentrations of its inhibitor, TIMP-1.

Furthermore, in normal wounds, MMP-1 is present exclusively in inactive form, whereas in compromised wounds, the enzyme is in active form. This increase in MMPs has been found in the three major types of chronic wounds or recurring wounds: ulcers, pressure sores and diabetic foot ulcers.

These MMPs will therefore not only cause an excessive and prolonged breakdown of the components of the ECM, hence the dermis, but also growth factors, thereby slowing down the stimulation of healing.

Consequently, one of the current treatment strategies in the management of chronic wounds or recurring wounds is directly aimed at restoring a metabolic balance between MMPs and growth factors

To find out more about the imbalance in MMPs in leg ulcers, pressure ulcers and diabetic foot ulcers:

In contrast with the pattern of balance and control between MMPs and growth factors observed in normal healing, an increased proteinase activity within the wound is a factor that is systematically described in venous leg ulcers, pressure ulcers and diabetic foot ulcers, reflecting persistent inflammation, preventing the process from moving on to the proliferative tissue reconstruction phase.

Types of wounds affected by excess proteinases :

foot ulcers / wounds in diabetic patients :

MMP-1 x 65

Exudate of pressure ulcers / exudate of surgical wounds:

MMP-9 x 25, MMP-2 x10.

These results corroborate those of numerous other experiments demonstrating an elevation in MMP levels (MMP-1, MMP-2, MMP-8 and MMP-9 ) in the exudate produced by chronic or recurring wounds: venous, arterial or mixed ulcers, diabetic foot ulcers, perforating ulcers of the foot, pressure ulcers.

This metabolic profile of a wound with compromised healing appears to be a marker of the course: it persists throughout the period of stagnation of healing, whereas a reduction in MMP activity signals the resumption of the healing process.

As for growth factors, their quantitative determination in compromised wounds demonstrates lower levels than in normal healing. It is currently accepted that in addition to their involvement in protein breakdown of the extracellular network, excessive metalloproteinases also break down growth factors: EGF, TGFß and PDGF

Thus, more generally, the involvement of excessive metalloproteinases in chronic or recurring wounds contributes to the development of delayed healing, via three mechanisms: