Tissue inhibitor of metalloproteinases (TIMP) is a group of endogenous enzymes that inhibit the activity of matrix metalloproteinases (MMPs), which is a group of peptidases involved in degradation of the extracellular matrix. . There are four different TIMP identified – TIMP1, TIMP2, TIMP3, TIMP4. TIMP1 is a glycoprotein that can inhibit the activity of the most of the known MMPs. In addition, TIMP1 is able to promote cell proliferation in a wide range of cell types including keratinocyte and dermal fibroblast, and may also have an anti-apoptotic function. Beside as a natural inhibitor of MMPs, TIMP2 has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. TIMP3 is induced in response to mitogenic stimulation and the protein contain a netrin domain and is localized to the extracellular matrix.
The matrix metalloproteinases (MMPs) in the skin play a key role in the maintenance and normal turnover of dermal extracellular matrix. Matrix metalloproteinases (MMPs) are capable of degrading essentially every component of the dermal extracellular matrix including collagen. Excess MMPs activities in the aged skin is associated with the excess degradation and damage of dermal extra cellular matrix (ECM), and with the clinical signs of aging skin. An important natural and internal mechanism for the regulation of the activity of MMPs is via binding to a family of homologous proteins referred to as the tissue inhibitors of metalloproteinases (TIMP-1 to TIMP-4). MMP activity is regulated by the highly specific, endogenous tissue inhibitors of metalloproteinases (TIMPs). MMP and TIMPs can form complexes. Members of TIMPs have been found to exhibit several biochemical and physiological/biological functions including inhibition of active MMPs, proMMP activation, cell growth promotion, matrix binding, inhibition of angiogenesis and the induction of apoptosis.
The regulation of relative amount of and balance of MMP and TIMPs is critical in maintaining skin’s matrix stability and homeostasis in dermal connective tissue. Overexpression of MMP and down regulation of TIMP will result in excess degradation and damage of the extra cellular matrix, particularly the collagen fiber networks, thereby causing wrinkles and skin laxity. Deficiency in MMP level and excess TIMP will also adversely affect the turnover and recycling of the extra cellular matrix. Aged skin is characterized by a strongly increased MMP activity and by a concomitant down regulation of tissue inhibitor of matrix metalloprotease (TIMP) and the resulting dramatic loss and damage of collagen and matrix as well as impaired cell growth and survival. TIMP is decreased with fibroblast senescence, both ex vivo and in vivo, thus contributing to increased catabolic activity within dermis. Although cumulative sun exposure (photo-aging) lead to an immediate and strong increase in MMP activity, the concentrations of the native tissue inhibitors of metalloproteinases (TIMPs) remain unchanged. It is very well established that UV radiation induces MMPs without affecting the amount or activity of TIMPs.
Some anti-aging ingredients were found to be about to regulate the TIMP amount and activity in the skin. DHEA significantly decreased the basal expression of MMP-1 mRNA and protein, but increased the expression of TIMP-1 protein in aged skin. PEPHA®-TIMP is a commercial patented anti-wrinkle ingredient, utilizing the bioengineered TIMP2 protein. The addition of PEPHA®-TIMP attenuates the signs of aging by reducing the degenerative effects of excessive MMP activity. Due to the versatile specificity of TIMP-2 on the most important MMPs regarding skin aging, PEPHA®-TIMP supports the attenuation of the degenerative processes of photo-aging and intrinsic aging based on in vitro and in vivo studies.