Proteinases in cutaneous wound healing

Toriseva, Mervi; Kähäri, Veli‐Matti

doi:10.1007/s00018-008-8388-4

Cited by 174 publications

(165 citation statements)

References 222 publications

(276 reference statements)

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“…8). Although much interest has focused on matrix metalloproteinases (9), the ADAMTSs have now also been found to play a major role in a range of repair and regeneration processes.…”

mentioning

confidence: 99%

Adamts5 Deletion Blocks Murine Dermal Repair through CD44-mediated Aggrecan Accumulation and Modulation of Transforming Growth Factor β1 (TGFβ1) Signaling

Velasco

DiPietro

et al. 2011

Journal of Biological Chemistry

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ADAMTS5 has been implicated in the degradation of cartilage aggrecan in human osteoarthritis. Here, we describe a novel role for the enzyme in the regulation of TGF␤1 signaling in dermal fibroblasts both in vivo and in vitro. Dermal wound healing involves a series of cellular responses that depend on the coordinated temporal and spatial expression of inflammatory cytokines, proteases, growth factors, and extracellular matrix molecules. The early phases of hemostasis, inflammation, and re-epithelialization are followed by granulation tissue formation and finally dermal remodeling (1, 2). The granulation tissue is a loosely organized collagenous matrix that serves as a template for cellular regeneration (3) of the collagen (4) and proteoglycan (5-7) structures of the dermis proper.There has been a long held consensus that proteinases, such as plasmin and matrix metalloproteinases, are major players in dermal repair; however, many questions remain regarding substrate and product identification and to what extent cleavage of particular proteins is destructive or reparative (reviewed in Ref. 8). Although much interest has focused on matrix metalloproteinases (9), the ADAMTSs have now also been found to play a major role in a range of repair and regeneration processes. For example, evidence of a role for ADAMTS activity in dermal repair comes from the finding that human skin contains abundant aggrecanase-generated catabolic fragments of versican V0 and V1 (5) and that both aggrecan and versican are associated with the dermal region of the hair follicle (7). Moreover, to place dermal matrix turnover in a broader context, cleavage of the hyalectans aggrecan, versican, and brevican by one or more aggrecanases (ADAMTS1, -4, -5, -8, -9, and -15) occurs in the remodeling of cartilage (10), aorta (11, 12), spinal cord (13), meniscus (14, 15) intervertebral disc (16), adipose tissue (17), and brain (18). HA 2 in the skin is most abundant in the epidermal layer (6), and it undergoes partial fragmentation in both the dermis and epidermis of human skin explants (19). Its role in skin biology has largely focused on its binding to the cell-surface receptor CD44, an interaction that prevents PDGF-BB receptor activation and human fibroblast migration (20). It also appears to be required for MMP9-mediated activation of TGF␤1 (21). HA has been shown to ligate RHAMM to promote the association of CD44 and p-ERK, an interaction that directly activates cell migration and thereby is required for efficient dermal repair (22,23). HA also regulates the proliferative response of dermal fibroblasts to TGF␤1 (24), and HA12 oligosaccharides stimulate Col3 and TGF␤1 expression (25), a finding that is very relevant to the data described here.TGF␤1 is a key regulator of multiple processes in dermal wound healing (26). In the context of this study, TGF␤1 stimulates col1 and col3 production by fibroblasts and is required for terminal differentiation of myofibroblasts during wound * This work was supported, in whole or in part, by National Institutes o...

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“…8). Although much interest has focused on matrix metalloproteinases (9), the ADAMTSs have now also been found to play a major role in a range of repair and regeneration processes.…”

mentioning

confidence: 99%

Adamts5 Deletion Blocks Murine Dermal Repair through CD44-mediated Aggrecan Accumulation and Modulation of Transforming Growth Factor β1 (TGFβ1) Signaling

Velasco

DiPietro

et al. 2011

Journal of Biological Chemistry

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“…In this respect, members of the MMP family have been studied most extensively due to their implication in all phases of cutaneous wound repair. Technically, detailed expression data for most proteases have been acquired using Northern blots, RNase protection assays and in situ hybridizations in human and mouse skin wounds (Toriseva and Kähäri, 2009). Employing these targeted approaches allowed the temporal and spatial assessment of protease transcripts with high specificity.…”

Section: Defining the Wound Transcriptional Degradomementioning

confidence: 99%

“…Addressing this limitation, some studies monitored the expression of multiple proteases of the same or of different classes within the same experiment (Madlener et al, 1998), whereby either predicted transcriptional linkages between the examined protease genes could be verified or new relations established. In addition, the careful selection of samples in human studies and standardized procedures allows meaningful conclusions when comparing expression data for individually assessed proteases from independent studies (Toriseva and Kähäri, 2009). …”

Section: Defining the Wound Transcriptional Degradomementioning

confidence: 99%

“…To acquire these data, mostly Western blot, immunohistochemistry and immunofluorescence techniques were applied, and in some cases protease proteins were quantified in wound fluids or tissue lysates by ELISA (Toriseva and Kähäri, 2009). While highly sensitive and specific, these single protein approaches have the same limitations as similar techniques for the analysis of individual transcripts.…”

Section: Exploring the Wound Translational Degradomementioning

confidence: 99%

“…Thereby, we will focus on the study of proteases in in vivo and in vitro models of skin repair. For a comprehensive overview of protease biology in wound healing, taking into account additional data from the analysis of proteolytic activity in similar processes, such as inflammation, angiogenesis and carcinogenesis, the reader is referred to two excellent recent reviews by Toriseva and Kähäri (2009) and Moali and Hulmes (2009).…”

Section: Introductionmentioning

confidence: 99%

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Wound degradomics – current status and future perspectives

Hermes

Schlage²,

Keller³

2011

BCHM

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Proteases are pivotal modulators of extracellular matrix components and bioactive proteins at all phases of cutaneous wound healing and thereby essentially contribute to the successful reestablishment of skin integrity upon injury. As a consequence, disturbance of proteolytic activity at the wound site is a major factor in the pathology of chronic wounds. A large body of data acquired in many years of research provide a good understanding of how individual proteases may influence the repair process. The next challenge will be to integrate these findings and to elucidate the complex interactions of proteolytic enzymes, their inhibitors and substrates on a system-wide level. Here, we present novel approaches that might help to achieve this ambitious goal in cutaneous wound healing research.

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