Beneficial Regulation of Matrix Metalloproteinases for Skin Health

Matrix metalloproteinases (MMPs) are essential to the remodeling of the extracellular matrix. While their upregulation facilitates aging and cancer, they are essential to epidermal differentiation and the prevention of wound scars. The pharmaceutical industry is active in identifying products that inhibit MMPs to prevent or treat aging and cancer and products that stimulate MMPs to prevent epidermal hyperproliferative diseases and wound scars.


Introduction
Matrix metalloproteinases (MMPs) are essential to the remodeling of the extracellular matrix. While their upregulation facilitates aging and cancer, they are essential to epidermal differentiation and the prevention of wound scars. The pharmaceutical industry is active in identifying products that inhibit MMPs to prevent or treat aging and cancer and products that stimulate MMPs to prevent epidermal hyperproliferative diseases and wound scars.
Transforming growth factor-β (TGF-β) is a predominant regulator of the expression of MMPs and the ECM [1,2,12]. It is secreted extracellularly in a latent form and activated by proteases to form the mature TGF-β that binds to its receptor complexes to activate Smads and thereby the regulation of various genes, including MMPs, collagen, and elastin [1,2,12]. TGF-β has differential effects in different cell types [1,2,12]. It inhibits MMP-1 and stimulates collagen, MMP-2, and TIMPs in fibroblasts, whereas in keratinocytes it stimulates the expression of MMPs and inhibits cell growth [1, 2, 12].
Lutein is a non-provitamin A carotenoid that inhibits epidermal hyperproliferation, expansion of mutated keratinocytes, and the infiltration of mast cells in response to solar radiation, and thereby photoaging [16]. The mechanism to lutein's antiaging and antiphotoaging effects includes the inhibition of MMP-to-TIMP ratio in dermal fibroblasts and the inhibition of cell loss and membrane damage in ultraviolet radiation-exposed fibroblasts [17].

Skin Cancer and Its Prevention.
Carcinogenesis is characterized by development of tumors from genetic alterations and immunosuppression. The mechanisms also include oxidative stress from reactive oxygen species, inflammation and DNA damage [19]. Malignant tumors metastasize, with MMPs playing a central role [19]. Cancer invasion and metastasis of various cancer types parallelly increased expression of MMPs [19]. MMPs activate growth factors such as TGF-β and VEGF to induce angiogenesis [19]. Furthermore, MMPs contribute to cancer progression by degrading the ECM, basement membrane, and E-cadherin molecules that hold cells together [19][20][21][22]. In our laboratory we have investigated two categories of agents that may prevent or facilitate carcinogenesis through the regulation of expression of MMPs: (a) plant extracts or vitamins and (b) hormones.
The plant extracts or vitamins examined in our laboratory for MMP regulation in cancer cells are P. leucotomos, lutein and ascorbic acid [12,17,23,24]. P. leucotomos inhibits MMP-1 expression transcriptionally, through AP-1 promoter sequence, and stimulates the expression of TIMP-2 in melanoma cells [4]. P. leucotomos in addition inhibits TGF-β, known to stimulate MMPs in cancer cells [12]. In photo-carcinogenesis experiments with rats, lutein inhibits tumor multiplicity, volume, and tumor-free survival time [16]. Furthermore, lutein inhibits MMP-1 and stimulates TIMPs (-1 and -2), to reduce MMP/TIMP ratio and thereby carcinogenesis [17]. Ascorbate has dose dependent differential effects on cancer cell growth versus expression of MMPs/metastasis potential [23,24]. At lower concentrations, ascorbate inhibits cell growth with dramatic increases in the expression of MMPs, which are inhibited by cotreatment with P. leucotomos or gene silencing with MMP siRNA [23,24].

Epidermal Differentiation and Wound Repair.
Hyperproliferative diseases of the skin are associated with reduced MMPs [25]. The expression of MMP-9 is reduced in psoriatic keratinocytes, with hyperproliferative keratinocytes [26]. Hyperproliferative skin diseases are also associated with reduced generation of ceramides (the major lipids of the stratum corneum) or increased ceramidase activity [27][28][29].
Ceramides are intracellular messengers of the sphingomyelin cycle that activate protein kinase C-alpha and stress-activated protein kinases to induce apoptosis and epidermal differentiation [30]. The experiments in our laboratory indicate that ceramide induces MMP-1 expression in keratinocytes through the activator protein-1 (AP-1) sequence and simultaneously inhibits keratinocyte cell viability by apoptosis [25]. The mechanism of MMP-1 gene regulation by ceramide may be through the stimulation of TGF-β, known to inhibit epidermal cell viability [25].
The biologically active concentrations of copper range from 1 to 200 μM in tissue engineering for wound care, without toxicity [35]. The lower copper concentrations (0.3-3 μM) stimulate activity of MMPs whereas the higher Enzyme Research 3 concentrations (1-100 μM) stimulate the expression of MMPs in fibroblasts [31]. Adult wound scars are attributed to increased TGF-β expression and subsequent collagen deposition [33]. However, TGF-β antibodies cause feedback stimulation of TGF-β [32,33]. The feedback stimulation of TGF-β in turn inhibits MMPs and stimulates TIMPs in fibroblasts, with further scarring potential [32,33].

Summary
MMPs are potent proteases that remodel the ECM. It is central to the aging and cancer process. Polypodium leucotomos extract, lutein, and xanthohumol are effective in inhibiting expression and/or activities of MMPs, and thereby aging and cancer. Conversely, MMPs can prevent psoriasis and wound scars. Ceramide stimulates expression of MMP-1 and simultaneously inhibits cell viability. Copper stimulates MMPs, which may be its mechanism to improve wound healing. However, the antibodies to TGF-β cause feedback stimulation of TGF-β, and further scarring potential.