Ulpu Saarialho-Kere

X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein.

Ectodermal dysplasias comprise over 150 syndromes of unknown pathogenesis. X–linked anhidrotic ectodermal dysplasia (EDA) is characterized by abnormal hair, teeth and sweat glands. We now describe the positional cloning of the gene mutated in EDA. Two exons, separated by a 200–kilobase intron, encode a predicted 135–residue transmembrane protein. The gene is disrupted in six patients with X;autosome translocations or submicroscopic deletions; nine patients had point mutations. The gene is expressed in keratinocytes, hair follicles, and sweat glands, and in other adult and fetal tissues. The predicted EDA protein may belong to a novel class with a role in epithelial–mesenchymal signalling.

Matrix metalloproteinases in skin.

Abstract Matrix metalloproteinases (MMPs) are a family of zinc‐dependent endopeptidases collectively capable of degrading essentially all extracellular matrix components. These enzymes can be produced by several different types of cells in skin such as fibroblasts, keratinocytes. macro‐phages, endothelial cells, mast cells, and eosinophils and their activity can be specifically inhibited by TIMPs (tissue inhibitors of metalloproteinases), which bind to active MMPs with 1:1 stoichiometry. In general, MMPs are not constitutively expressed in skin but are induced temporarily in response to exogenous signals such as various cytokines. growth factors, cell‐matrix interactions and altered cell‐cell contacts. At present, more evidence is accumulating thai MMPs play an important role in proteolytic remodeling of extracellular matrix in various physiologic situations, including developmental tissue morphogenesis, tissue repair, and angiogenesis. On the other hand, MMPs play an important pathogenetic role in excessive breakdown of connective tissue components, e.g. in rheumatoid arthritis, oslteoarthritis, chronic ulcers, dermal photoageing, and periodontitis, as well as in tumor cell invasion and metastasis. In this review we discuss the role of MMPs and TIMPs in human skin based on new observations on the regulation of the expression of MMPs, on their substrate specificily, and MMP expression in physiologic and pathologic conditions of skin involving matrix remodeling. Furthermore, therapeutic modalities based on regulating MMP activity will be reviewed.

Matrix metalloproteinases in tumor progression: focus on basal and squamous cell skin cancer

Abstract: Many normal biological processes, such as reproduction, fetal development and wound healing, are critically dependent on controlled degradation of extracellular matrix (ECM) macromolecules. However, excessive degradation of matrix components occurs in pathologic tissue destruction, e.g. in atherosclerosis, rheumatoid arthritis, and cancer. Matrix metalloproteinases (MMPs) are degradative enzymes that play an important role in all aspects of tumor progression by enhancing tumor‐induced angiogenesis and destroying local tissue architecture and basement membranes to allow tumor invasion and metastasis. Efficient breakdown of the ECM surrounding invasive cancer islands involves interplay between tumor cells, stromal cells, and inflammatory cells, all of which express a distinct set of MMPs. Besides the classical role of MMPs in degradation of ECM, MMPs may also indirectly influence the tumor microenvironment through the release of growth factors, cryptic sites or angiogenic factors, or through the generation of matrix fragments that inhibit tumor cell proliferation, migration and angiogenesis. This makes the contribution of MMPs to tumorigenesis much more complex than initially thought. Currently, a number of clinical studies have focused on testing MMP inhibitors as potential antineoplastic agents. In this review we discuss the present role of MMPs in the development and progression of cancer, focusing on non‐melanoma skin cancers basal (BCC) and squamous (SCC) cell carcinoma, and the possible influence of MMPs in their differences.

Trendsin Molecular Medicine: Matrix metalloproteinases and their inhibitors in tumour growth and invasion

Thymic peptides, a heterogenous family of polypeptidic hormones synthesized within the thymus, not only exert important regulatory effects within both the immune and neuroendocrine systems but are also themselves subject to control by hormones derived from the hypothalamic-pituitary-adrenal axis (HPA) and other endocrine glands. Regarding thymic hormonal function, thymulin production is up-regulated by several hormones, including prolactin, growth hormone and thyroid hormones. Other aspects of the physiology of thymic epithelial cells can also be modulated by hormones and neuropeptides, particularly cytokeratin expression, cell growth and production of extracellular matrix proteins, thus characterizing the pleiotrophic action of these molecules on the thymic epithelium. Conversely, thymic-derived peptides also regulate hormone release from the HPA axis and may act directly on target endocrine glands of this axis, modulating gonadal tissues. In addition, it has recently been shown that thymulin can modulate some peripheral nervous sensory functions, including those related to sensitivity to pain. According to the dose given, thymulin induces or reduces hyperalgesia related to both mechanical and thermal nociceptors and thus represents an important interface between the immune, endocrine and nervous systems.

Collagenase-3 (MMP-13) is expressed by hypertrophic chondrocytes, periosteal cells, and osteoblasts during human fetal bone development.

Collagenase‐3 (MMP‐13) is a novel matrix metalloproteinase, the expression of which has so far only been documented in human breast carcinomas and osteoarthritic cartilage. In this study we have examined the expression of MMP‐13 during human fetal development. Northern blot hybridizations revealed abundant expression of MMP‐13 mRNAs in total RNA from fetal cartilage and calvaria at gestational age of 15 weeks. By in situ hybridization MMP‐13 transcripts were detected in chondrocytes of hypertrophic cartilage in vertebrae of the spinal column and in the dorsal end of ribs undergoing ossification, as well as in osteoblasts and periosteal cells below the inner periosteal region of ossified ribs. In contrast, no expression of MMP‐13 could be detected in osteoclasts. Furthermore, expression of MMP‐13 mRNA was detected in osteoblasts and fibroblasts primarily on the inner side of calvarial bone of the skull at 16 weeks of gestation. Expression of MMP‐13 mRNA by primary human fetal chondrocytes in culture was enhanced by transforming growth factor‐β (TGF‐β) and inhibited by bone morphogenetic protein‐2 (BMP‐2). No expression of MMP‐13 mRNA could be noted in other fetal tissues, including the skin, lungs, neural tissue, muscle, and liver. These results suggest that MMP‐13 plays an important role in the extracellular matrix remodeling during fetal bone development both via endochondral and intramembranous ossification. Dev. Dyn. 208:387–395, 1997.

Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas.

SummarySince proteolysis of the dermal collagenous matrix and basement membranes is required for local invasive growth and early metastasis formation of cutaneous melanomas, we have analysed the activities/expression levels of certain metalloproteinases in melanomas and cultured melanoma cells by in situ hybridization and Northern analysis. In addition to collagenases-1 and -3 that have been implicated in invasive growth behaviour of various malignant tumours, we analysed the levels of 72-kDa gelatinase and its activators MT1-MMP and TIMP-2 in cultured melanoma cells. The lesions examined included three cases of lentigo maligna and 28 cases of Clark grade I–V melanomas. The premalignant as well as the grade I tumours were consistently negative for collagenase-1 and -3 and TIMP-1 and -3. The collagenases were predominantly expressed in the cancer cells of Clark grade III and IV tumours. TIMP-1 and -3 were abundantly expressed in the cancer and/or stromal cells of grade III and IV melanomas, while TIMP-2 protein was detected also in melanomas representing lower invasive potential. Northern analysis of seven melanoma cell lines showed that the expression of collagenase-1 and TIMPs-1 and -3 was associated with 72-kDa gelatinase positivity. All melanoma cell lines were positive for MTI-MMP and TIMP-2 mRNAs. Our results suggest that overexpression of collagenases-1 and -3 and TIMPs -1 and -3 is induced during melanoma progression. Expression of TIMPs may reflect host response to tumour invasion in an effort to control MMP activity and preserve extracellular matrix integrity.

Patterns of matrix metalloproteinase and TIMP‐1 expression in chronic and normally healing human cutaneous wounds

Summary The present study was carried out to characterize the patterns of expression of matrix metalloproteinases or their tissue inhibitor (TIMP‐1) in normally healing, acute vs. chronic, skin wounds. In situ hybridization was performed to localize collagenase, stromelysin‐1, stromelysin‐2, matrilysin, urokinase plasminogen activator (uPA) and TIMP‐1 mRNAs in 14 chronic venous ulcers and 10 normally healing wounds, representing different time points after wounding. Surgical wounds, made in piglets harvested at several time points, were studied as controls. Collagenase, stromelysin‐1 and ‐2, as well as uPa, were expressed in keratinocytes in both acute and chronic wounds, while epithelial TIMP‐1 mRNA was not detected in any chronic wound biopsies studied. However, TIMP‐1 was expressed at the epithelial edges of both acute human and pig wounds. Our results suggest that the balance between metalloenzymes and their inhibitor TIMP‐1, is disturbed, in poorly healing wounds.

IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors.

In the acute phase of atopic dermatitis (AD), T-helper type 2 (Th2) cytokines characterize the inflammatory response in the skin. IL-33 is a new tissue-derived cytokine, which is mainly expressed by cells of barrier tissues, and is known to activate Th2 lymphocytes, mast cells, and eosinophils. IL-33 signals through a receptor complex consisting of IL-33-specific receptor ST2 and a co-receptor IL-1RAcP. As IL-33 is known to promote Th2-type immunity, we examined expression profiles of IL-33 and its receptor components in human AD skin, in the murine model of AD, and in various cell models. We found increased expression of IL-33 and ST2 in AD skin after allergen or staphylococcal enterotoxin B (SEB) exposure, as well as in the skin of 22-week-old filaggrin-deficient mice. In addition, skin fibroblasts, HaCaT keratinocytes, primary macrophages, and HUVEC endothelial cells efficiently produced IL-33 in response to the combined stimulation of tumor necrosis factor-α and IFN-γ, which was further enhanced by a mimetic of double-stranded RNA. Finally, the increased expression of IL-33 and ST2 caused by irritant, allergen, or SEB challenge was suppressed by topical tacrolimus treatment. These results suggest an important role for IL-33-ST2 interaction in AD and highlight the fact that bacterial and viral infections may increase the production of IL-33.

Differential expression of tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4) in normal and aberrant wound healing

Wound healing is characterized by hemostasis, re-epithelialization, granulation tissue formation, and remodeling of the extracellular matrix. Matrix metalloproteinases and their specific inhibitors, TIMPs, contribute to these events. We investigated a total of 47 samples of normally healing wounds, chronic venous ulcers, ulcerative vasculitis, and suction blisters using immunohistochemistry and in situ hybridization, to clarify the role of TIMPs in normal and aberrant wound repair. Expression of TIMP-1 and -3 mRNAs was found in proliferating keratinocytes in 3- to 5-day-old normally healing wounds, whereas no epidermal expression was detected in chronic ulcers. However, TIMP-3 protein was found in the proliferating epidermis in 20 of 24 samples representing both full-thickness acute and chronic wounds. TIMP-1 and TIMP-3 also were abundantly expressed by spindle-shaped, fibroblast-like, and plump, macrophage-like stromal cells, as well as by endothelial cells. In normally healing wounds, TIMP-2 protein localized under the migrating epithelial tip and to the stromal tissue under the eschar more frequently than in chronic ulcers. Occasional staining for TIMP-4 protein was detected in stromal cells of chronic ulcers near blood vessels. Our results indicate that TIMP-1 and TIMP-3 may be involved both in the regeneration of the epidermis by stabilizing the basement membrane zone and in the regulation of stromal remodeling and angiogenesis of the wound bed. Lack of TIMP-2 near the migrating epithelial wound edges might contribute to uncontrolled activity of MMP-2 in chronic ulcers. We conclude also that TIMPs are temporally and spatially tightly regulated and that the imbalance between metalloproteinases and TIMPs-1, -2, and -3 may lead to delayed wound healing.

Differential expression of matrilysin-1 (MMP-7), 92 kD gelatinase (MMP-9), and metalloelastase (MMP-12) in oral verrucous and squamous cell cancer.

Squamous cell carcinoma (SCC) of the oral cavity is a highly invasive tumour of stratified squamous epithelium that spreads through degradation of the basement membrane (BM) and extracellular matrix (ECM). There are currently no reliable tissue or serum markers to predict whether the tumour has metastasized at the time of diagnosis. Verrucous carcinoma (VC) of the oral cavity is a rare low‐grade variant of oral SCC that penetrates into the subepithelial connective tissue. Many matrix metalloproteinases (MMPs), such as MMP‐1, ‐2, ‐7, ‐9, ‐13, and ‐14, as well as integrin receptors have been implicated in cancer invasion. Integrin αvβ6 is induced in SCC and appears to be involved in up‐regulation of MMP‐9 expression by oral keratinocytes and promotion of their migration. The aim of this study was to investigate whether the pattern of MMP expression or that of αvβ6 integrin contributes to the differences in the biological behaviour of oral SCC and VC. The results show that the less aggressive nature of oral VC may be connected to its MMP expression profile. Typically, VCs were devoid of epithelial MMP‐3, ‐7, ‐9, ‐12 and ‐13 expression, compared with SCCs. MMP‐19 was expressed by epithelial keratinocytes in hyperproliferative areas of verrucous hyperplasia, VC, and SCC, but was absent in the invasive cancer cell nests of SCC. MMP‐26 was expressed by hyperproliferative keratinocytes in VC as well as by invasive cancer cells in SCCs. MMP‐10 was expressed widely in the epithelium of all SCC specimens. αvβ6 integrin expression was also detected in some cases of epithelial hyperplasia but was significantly more abundant in cancers at the invasive front. The absence of MMP‐7, ‐9 and ‐12 from epithelial cells may serve as a good prognostic marker of non‐invasive oral carcinoma. Blocking the activity of invasion‐specific MMPs or αvβ6 integrin might offer novel therapeutic modalities in early‐stage oral carcinoma. Copyright