Matrikines
With respect to skin, the term “matrikines,†proposed by Maquart, is used to describe peptides liberated by partial proteolysis
of ECM macromolecules.12 Some of the fragments generated, possess stimulating and signaling activity in a feedback
loop, initiating the repair process of the tissue matrix, hence their name. These peptide fragments normally participate in the wound healing as natural, non-toxic, locally acting, and highly potent messengers. Matrikines are able to regulate cell activities, modulate cellular proliferation and migration, protein expression and synthesis, protease production, or apoptosis. A number of different matrikines have by now been identified, some with very specialized functions including stimulation of collagen and fibronectin synthesis.
Tripeptide GHK (TP1), a matrikine, simultaneously activates the production of metalloproteinases and anti-proteases that remove
damaged proteins from the ECM macromolecules while activating the synthesis of new proteins for rebuilding the ECM.16-19 TP1 increased MMP-2 (and to a lesser extent MMP-9) levels in conditioned media of cultured fibroblasts demonstrating
increased MMP-2 proteolytic activity. MMP-2, a gelatinase, is important in digesting the gelatin fragments that remain after cleavage of normal collagen by MMP-1 related to sun damage (Figure 2).20 It is thus evident that pre-conditioning is optimal for a 14- 21 day period during which time the MMP-2 levels are still rising and effective in ECM clearance of gelatin fragments.
MMP2 can mobilize vascular endothelial growth factor and release
proteases resulting in ECM modulation and fragmentation absorption (mop-up). Both MMP-2 and -9 degrade denatured collagen (gelatin) and elastin.21,22 TP1 is a potent activator of ECM synthesis and remodeling generated during proteolytic
degradation of proteins in the ECM after tissue injury and tissue turnover.23 To counteract the MMPs, skin expresses natural
inhibitors – tissue inhibitors of matrix metalloproteinases (TIMPs) that slow the process of collagen breakdown. The tripeptide
-1 (TP1) also increased levels of MMP inhibitors TIMP-1
and TIMP-2 in cultures. TIMP-1 preferentially inhibits MMP-9, whereas TIMP-2 is more active on MMP-2.20 Taken together, these results suggest that, by modulating MMPs-2,9 and TIMPs expression and release by fibroblasts, the tripeptide can modulate
a large array of physiological processes, particularly those which require a rapid ECM clearance and turn over, such as cell migration, angiogenesis and tissue remodeling.20
In addition, tripeptide has been shown to upregulate genes associated with the proteasome UPS system, activating the system and thus aiding in removing misfolded proteins.24 The biochemical uniqueness of tripeptide-1 resides both in its very small size, which would permit it to approach membrane receptors more easily than larger proteins, and its unique copper-binding characteristics that allow copper transfer into and from cells, both of which facilitate its entry into the cell.19
Once in the cell, tripeptide has a unique capacity to control inflammation,
a major factor in promoting satisfactory wound healing and scar outcome. It does this by suppressing cellular synthesis or activity of key acute phase cytokines such as tumor necrosis factor-alpha (TNF-α) in wounds and interleukin-1, both of which induce further tissue damage after injuries.19 While stimulating new collagen formation, TP1 also increases levels of lysyl oxidase the beneficial enzymatic cross linker.
In addition, during this regenerative process the alignment of collagen fibers into uniform structures of appropriate length is important. Proteoglycans of the dermis – decorin and dermatopontin,
25 both stimulated by tripeptide – are vital to this process. Elastin production is also stimulated by this tripeptide, particularly fibrillin-1, the component that is most severely
