Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro angiogenesis models suggest that new blood vessel formation requires the induction and secretion by endothelial cells of matrix metalloproteinases. These enzymes assist in the controlled proteolytic degradation of the surrounding extracellular matrix during blood vessel formation. The results of in vitro studies cannot be extrapolated directly to the process of in vivo angiogenesis because the type of matrix employed and the repertoire of enzymes secreted by cells in vivo differ dramatically from in vivo conditions. To investigate the in vivo role of matrix metalloproteinases in blood vessel development, we looked for the presence of these proteinases in endothelial cells involved in fetal angiogenesis and in neovascularization of certain invasive skin tumors using immunofluorescent staining. In fetal tissue, interstitial collagenase was present in both early microvessels developing from undifferentiated mesoderm and in microvessels involved in elongation and sprout formation from preexisting blood vessels. In aggressive skin tumors, i.e., morpheaform and recurrent basal cell carcinomas and squamous cell carcinomas, there was a marked increase in the number of collagenase-containing blood vessels, often extending into the tumor nests. Immunofluorescent staining failed to detect stromelysin, matrilysin, or gelatinase A and B (72- and 92-kDa type IV collagenases, respectively) in fetal or tumor blood vessels. These findings are consistent with the hypothesis that proteolytic degradation of the extracellular matrix is required for the formation of new blood vessels. Interstitial collagenase appears to play an important role in this process.
J Invest Dermatol 1995 Sep
PMID:Matrix metalloproteinases in blood vessel development in human fetal skin and in cutaneous tumors. 754 2

Because dermatitis herpetiformis is characterized by neutrophilic inflammation and destructive changes in the basement membrane zone, we studied the in situ expression of interstitial collagenase and stromelysin-1 in 11 lesions. A prominent signal for collagenase mRNA was consistently detected in the basal keratinocytes of rete ridges surrounding the neutrophilic abscesses in 10 of 11 lesions, and the expression was independent of the age of the lesion and the migratory state of the basal keratinocytes. Expression of stromelysin-1 was detected in seven of 11 lesions and co-localized with collagenase. No expression of the 92-kDa gelatinase mRNA or matrilysin protein was found in the vicinity of neutrophilic accumulations or the damaged basement membrane. Urokinase-type plasminogen activator mRNA was found in basal keratinocytes in seven of nine samples. Collagenase, stromelysin-1, and urokinase-type plasminogen activator were not expressed in normal-appearing skin of patients with dermatitis herpetiformis. Our results suggest that in lesions of dermatitis herpetiformis, collagenase and stromelysin-1 may be induced in basal keratinocytes by neutrophil cytokines or by altered cell-matrix interactions through contact of keratinocytes with the matrix due to damaged basement membrane. Stromelysin-1, in particular, may contribute to formation of blisters by degrading basement membrane components.
J Invest Dermatol 1995 Aug
PMID:Enhanced expression of interstitial collagenase, stromelysin-1, and urokinase plasminogen activator in lesions of dermatitis herpetiformis. 763 99

The proteolytic activity of matrix metalloproteinases is involved in normal and disease-related remodeling processes. One member of this family, matrilysin, can degrade a wide spectrum of connective tissue proteins, suggesting that this enzyme is involved in numerous and diverse biologic processes. In fact, recent studies have shown that matrilysin is expressed in developing hair follicles and glands. Using in situ hybridization and immunohistochemistry, we examined the sites of matrilysin expression in normal and diseased adult skin. In normal mature skin, matrilysin mRNA and protein was strongly and consistently expressed in ductal cells and in some secretory cells of all eccrine and apocrine glands and was not found in any other cell type. A similar tissue distribution was also found in numerous benign inflammatory skin lesions, and prominent expression of matrilysin mRNA and protein was also found in glandular disorders such as axillary hidradenitis and sweat gland tumors. These findings indicate that matrilysin is a constitutive product of the epithelium of dermal glands and that its expression may not be related to a disease-specific or remodeling process. Because of its extensive expression in dermal glands, we assessed whether matrilysin might be produced by all exocrine glands. Indeed, we detected matrilysin mRNA and immunoreactive protein in the ductal and glandular epithelium of mammary and parotid glands, pancreas, liver, prostate, and the serous acini of peribronchial glands of the lung. Thus, our findings indicate that matrilysin is constitutively produced by exocrine epithelial cells throughout the body. Because of its broad catalytic activity, we speculate matrilysin may participate in the normal function of exocrine glands by preventing glandular obstruction.
J Invest Dermatol 1995 Aug
PMID:Matrix metalloproteinase matrilysin is constitutively expressed in adult human exocrine epithelium. 763

The purpose of this investigation was to examine the role that keratinocyte growth factor (KGF) plays in the control of matrix-degrading protease activity in epithelial cells. The culture conditions had a significant effect on cellular responses to the growth factor. In histiotypic culture on porous-polycarbonate membranes, porcine periodontal ligament epithelial cells responded to KGF with increased 92-kDa gelatinase (matrix metalloproteinase [MMP]-9) activity. No such response was observed in cells maintained on plastic plates. Epidermal growth factor and platelet-derived growth factor also increased MMP-9 activity in the histiotypic cultures of epithelial cells. Addition of heparin with KGF produced a further increase in MMP-9 activity, with heparin alone having no effect. Precoating of polycarbonate membranes with matrix components showed that fibronectin and an engineered poly-RGD molecule substrate were required for KGF plus heparin to increase MMP-9 activity. Precoating plastic culture plates with the same proteins did not generate the same response. Concomitant with gelatinase activity, KGF also increased urokinase-type plasminogen activator in the epithelial cells. Thus, KGF appears to be an important regulator of protease secretion in epithelial cells.
J Invest Dermatol 1995 Jun
PMID:Keratinocyte growth factor stimulation of gelatinase (matrix metalloproteinase-9) and plasminogen activator in histiotypic epithelial cell culture. 776 70

Matrix-degrading metalloproteinases play a major role in tissue remodeling. Recent studies have shown that enzymes of this class are constitutively expressed primarily by stromal cells and not by epithelium. Here we present immunohistochemical evidence that matrilysin is localized within epidermal cells in developing skin and in tumor cells of cutaneous malignancies. The expression of matrilysin protein in developing fetal skin (6-15 weeks) is localized primarily to the germinative basal cell layer of fetal epidermis and early appendageal buds. The buds continue to express matrilysin during mesenchymal invasion. As development progresses (15-19 weeks) matrilysin is concentrated only in cells at the distal portion of the invading follicular and sweat gland appendageal cords. In adult skin, matrilysin was localized specifically to the outer root sheath of the hair follicles and the secretory cells of the eccrine glands but was absent in the epidermis. Nodulocystic, keratotic, adenoid basal cell carcinomas (BCCs) did not express matrilysin. In contrast, in the more aggressive morpheaform (infiltrative) BCCs and recurrent BCCs, matrilysin was localized at the tumor-stromal interface. In squamous cell carcinomas matrilysin was present in tumor cells at the stromal interface surrounding the tumor nests. The demonstration of matrilysin protein in germinal basal cells during fetal skin development and its presence in tumor cells at the stromal junction suggests that this enzyme may contribute to the proteolytic activity associated with cell-extracellular matrix interactions during appendageal development and tumor invasion.
J Invest Dermatol 1994 Oct
PMID:Matrilysin (PUMP) correlates with dermal invasion during appendageal development and cutaneous neoplasia. 793 Jun 71

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.
Br J Dermatol 1996 Jul
PMID:Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. 877 59

Membrane-type matrix metalloproteinases (MT-MMP) activate the zymogen form of MMP-2/Gelatinase A on cell surfaces and are expressed in invasive tumors. We sought to identify and characterize MT-MMP in a non-malignant cell type that undergoes a physiologic and reversible invasive phenotype during angiogenesis. Human dermal microvascular endothelial cells (HDMEC) were isolated from neonatal tissue and purified by anti-CD31 (PECAM) affinity beads. MT-MMP-1 and -3 transcripts were amplified by reverse transcriptase-polymerase chain reaction and northern blots showed a single 4.5 kB mRNA for MT-MMP-1 that was modulated by angiogenic factors and phorbol ester. Immunoblotting of reduced cellular extracts with different MT-MMP-1 antibodies showed the presence of the 63-65 kDa and 57-60 kDa forms, as well as additional forms at lower molecular weights. HDMEC membranes extracted with Triton X114 were incubated with gelatin-sepharose purified MMP-2 and MMP-9 to show activation of proenzymes. Pre-incubation of HDMEC with anti-MT-MMP-1 antibodies decreased proMMP-2 conversion activity only. The movement of HDMEC and the formation of tubule-like structures in three-dimensional collagen gels was markedly delayed by preincubation with the same anti-MT-MMP-1 antibodies. These results demonstrate the presence of MT-MMP in cutaneous microvascular cells in vitro. Modulation of these cell surface proteinases by angiogenic factors, demonstration of multiple processed forms, and specific attenuation of HDMEC morphogenetic patterns in three-dimensional collagen gels implicate their potential roles in the formation of new blood vessels in the skin.
J Invest Dermatol 1998 Dec
PMID:Membrane-type matrix metalloproteinases in human dermal microvascular endothelial cells: expression and morphogenetic correlation. 985 32

Photodamage is characterized by degradation of collagen and accumulation of abnormal elastin in the superficial dermis and several matrix metalloproteinases have previously been implicated in this process. Using immunohistochemistry and in situ hybridization, we have studied the localization of two elastolytic matrix metalloproteinases, matrilysin (matrix metalloproteinase-7) and human macrophage metalloelastase (matrix metalloproteinase-12) in solar damage. Human macrophage metalloelastase protein was detected in the superficial dermis in areas of elastotic material. Matrix metalloproteinase-7 was seen in the mid-dermis in regions with less damaged elastic fibers and morphologically better preserved collagen as well as in a band-like pattern below basal keratinocytes in eight of 18 solar elastosis. In samples taken from healthy volunteers 3 d after repeated ultraviolet A or ultraviolet B photoprovocation, occasional immunopositive cells for human macrophage metalloelastase (stromal) or matrix metalloproteinase-7 (sweat gland epithelium) were detected. In samples taken 1 d after ultraviolet B exposure, however, basal keratinocytes were matrix metalloproteinase-7 immunopositive, explaining the linear immunostaining below basal keratinocytes noted particularly in ultraviolet B treated 3 d specimens. Upregulation of metalloelastase was also demonstrated in the skin of hairless mice after repeated ultraviolet exposure. In normal skin, no staining for human macrophage metalloelastase or matrix metalloproteinase-7 was observed in association with elastin. The amount of immunoreactivity for the substrates of matrix metalloproteinase-7, versican, and tenascin, was clearly increased in solar elastosis and photoprovocated skin; versican but not tenascin was detected in the same areas as matrix metalloproteinase-7. Our results suggest that both matrix metalloproteinase-7 and -12 may contribute to remodeling of elastotic areas in sun-damaged skin.
J Invest Dermatol 1999 Oct
PMID:Accumulation of matrilysin (MMP-7) and macrophage metalloelastase (MMP-12) in actinic damage. 1050 57

In order to elucidate how chronic inflammation affects the organization of the extracellular matrix in the skin, a prolonged allergic contact dermatitis was induced in a mouse by repeated application to the ear of 2,4-dinitrofluorobenzene every 3 d for 66 d. Subsequently, the spatiotemporal changes of fibronectin, tenascin-C, fibulin-1, and fibulin-2 in the skin were examined. In the acute phase of inflammation (day 3-day 12), the amount of fibronectin and tenascin-C increased markedly and were degraded, whereas the amount of fibulin-2 changed slightly. Abundant deposition of tenascin-C was observed in the connective tissue. Fibulin-1 and fibulin-2 distributed as fine fibrils. In contrast, the amounts of fibronectin and tenascin-C decreased and their degradation was suppressed in the chronic phase (day 15-day 66), but the amount of fibulin-2 increased. Tenascin-C was observed mainly at and underneath the epidermal basement membrane. In the subepidermal region, many fibulin-2-positive microfibrils were distributed. The amount and distribution of fibulin-1 did not change markedly in either phase. MMP-like enzymes of 62 kDa, probably activated MMP-2, were upregulated in the chronic phase, whereas components of 92, 85, or 67 kDa were highly induced in the acute phase. These results suggest that chronic inflammation in allergic contact dermatitis is associated with temporal changes in the expression, deposition, and degradation of inducible extracellular matrix components.
J Invest Dermatol 1999 Dec
PMID:Spatiotemporal changes of fibronectin, tenascin-C, fibulin-1, and fibulin-2 in the skin during the development of chronic contact dermatitis. 1059 29

In skin biology, matrix metalloproteinases (MMPs) have been implicated in inflammatory matrix remodeling, neovascularization, wound healing and malignant transformation. Psoriasis is histologically characterized by keratinocyte hyperproliferation, infiltration of inflammatory cells, neoangiogenesis and production of cytokines, such as TNF-alpha, IL-1beta, TGF-alpha, and IFN-gamma, also capable of regulating MMP transcription. To investigate the role of stromelysins-1 and -2, matrilysin, metalloelastase, collagenases-1 and -3 and 92-kDa gelatinase as well as their inhibitors, TIMPs-1 and -3, in psoriasis, we performed in situ hybridization using 35S-labeled cRNA probes on 29 psoriatic lesions and 9 samples of normal looking skin from psoriatic patients. Metalloelastase mRNA was detected in 21/27 samples in macrophages that had migrated into the epidermis or in the inflammatory infiltrates of the superficial dermis. A quantity of 92-kDa gelatinase was found in macrophages and neutrophils (25/27). Stromelysin-1 mRNA was detected in basal keratinocytes in 4/21 lesions. Intracellular laminin-5 immunosignal in basal keratinocytes of the same samples, suggested that stromelysin-1 might participate in remodeling of the basement membrane zone. No signal for stromelysin-2 or collagenase-3 was found and only sweat glands were positive for matrilysin. TIMP-1 was more abundantly expressed than TIMP-3 in the inflammatory infiltrates and endothelial cells of dermal papillae (22/29). TIMP-3 was expressed perivascularly in 9/16 samples. Our results suggest that overexpression of the investigated MMPs by keratinocytes is not associated with psoriasis. However, macrophages express MMPs in psoriatic skin. Also TIMPs, particularly TIMP-1, were abundantly expressed, suggesting that mere MMP overexpression is unlikely to contribute to psoriatic tissue changes.
Exp Dermatol 2001 Jun
PMID:Metalloelastase (MMP-12) and 92-kDa gelatinase (MMP-9) as well as their inhibitors, TIMP-1 and -3, are expressed in psoriatic lesions. 1138 Jun 13


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