Significance: Matrix metalloproteinases (MMPs) are present in both acute and chronic wounds. They play a pivotal role, with their inhibitors, in regulating extracellular matrix degradation and deposition that is essential for wound reepithelialization. The excess protease activity can lead to a chronic nonhealing wound. The timed expression and activation of MMPs in response to wounding are vital for successful wound healing. MMPs are grouped into eight families and display extensive homology within these families. This homology leads in part to the initial failure of MMP inhibitors in clinical trials and the development of alternative methods for modulating the MMP activity. MMP-knockout mouse models display altered wound healing responses, but these are often subtle phenotypic changes indicating the overlapping MMP substrate specificity and inter-MMP compensation. Recent Advances: Recent research has identified several new MMP modulators, including photodynamic therapy, protease-absorbing dressing, microRNA regulation, signaling molecules, and peptides. Critical Issues: Wound healing requires the controlled activity of MMPs at all stages of the wound healing process. The loss of MMP regulation is a characteristic of chronic wounds and contributes to the failure to heal. Future Directions: Further research into how MMPs are regulated should allow the development of novel treatments for wound healing. SCOPE AND SIGNIFICANCEThis review highlights recent advances in understanding the regulation of matrix metalloproteinases (MMPs) in skin and how this knowledge might be applied in patients to improve wound healing. Selected recent advances include microRNA (MiR) regulation, novel peptides, signal transduction, experimental therapies, and novel dressings. TRANSLATIONAL RELEVANCEWound healing is a complex multicellular process involving fibroblasts, keratinocytes, and endothelial cells as well as inflammatory cells. The healing process follows an orderly sequence of events incorporating four distinct, yet overlapping, phases: hemostasis, the inflammatory phase, the proliferation phase, and the remodeling phase. The phases of wound healing are regulated by cross talk between different groups of molecules, including extracellular matrix (ECM), integrins, growth factors, and MMPs. Migration of cells on ECM, and remodeling and degradation of the ECM by MMPs are key elements of wound repair. CLINICAL RELEVANCEChronic wounds, including pressure sores, venous ulcers, and diabetic ulcers, are a major clinical problem with considerable morbidity and associated financial costs. Excessive MMPs are a feature of chronic wounds. Regulation of MMP levels in wounds could lead to improved wound healing. OVERVIEWThe MMP family is a group of calcium-dependent zinc-containing enzymes that are involved in the degradation of ECM. Family members share structural ( Fig. 1) and sequence similarities, a flexible proline-rich hinge region, and a hemopexinlike C-terminal domain, which functions in recognition of substrates (usually ECM). Excep...

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.

Harlequin ichthyosis (HI) is the most severe and frequently lethal form of recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation have been described, the genetic basis underlying the clinical and cellular phenotypes of HI has yet to be determined. By use of single-nucleotide-polymorphism chip technology and homozygosity mapping, a common region of homozygosity was observed in five patients with HI in the chromosomal region 2q35. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with HI. Since HI epidermis displays abnormal lamellar granule formation, ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. This finding paves the way for early prenatal diagnosis. In addition, functional studies of ABCA12 will lead to a better understanding of epidermal differentiation and barrier formation.

Pachyonychia congenita (PC) is a rare genodermatosis affecting the nails, skin, oral mucosae, larynx, hair, and teeth. Pathogenic mutations in keratins K6a or K16 are associated with the PC-1 phenotype whereas K6b and K17 mutations are associated with the PC-2 phenotype. Analysis of clinical, pathological, and genetic data from the literature and two research registries reveal that >97% of PC cases exhibit fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC-2 patients, although cysts were more commonly seen in PC-1 than previously reported (25%-33%). Previously unreported clinical features of PC include development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%). Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed.

SUM M A R YWe performed genetic and immunohistochemical studies in a sister and brother with autosomal recessive neonatal inflammatory skin and bowel lesions. The girl died suddenly at 12 years of age from parvovirus B19-associated myocarditis; her brother had mild cardiomyopathy. We identified a loss-of-function mutation in ADAM17, which encodes a disintegrin and metalloproteinase 17 (also called tumor necrosis factor α [TNF-α]-converting enzyme, or TACE), as the probable cause of this syndrome. Peripheral-blood mononuclear cells (PBMCs) obtained from the brother at 17 years of age showed high levels of lipopolysaccharide-induced production of interleukin-1β and interleukin-6 but impaired release of TNF-α. Despite repeated skin infections, this young man has led a relatively normal life. (Funded by Barts and the London Charity and the European Commission Seventh Framework Programme.) I nflammatory disorders of the skin and gut, including eczema, psoriasis, and celiac disease, have been linked to changes in barrier function and immune responses, by means of genetic and functional studies. Large casecontrol studies combined with genomewide association studies have identified common genetic risk factors, with low penetrance, for a plethora of human disorders. Such studies have also identified numerous single-nucleotide polymorphisms (SNPs) in genes linked to the regulation of immunity and inflammation affecting epithelial tissues. 1,2High-throughput sequence technology can be used to identify rare but penetrant disease-associated mutations in affected members of families with mendelian conditions. [3][4][5][6] We combined this technology with SNP-homozygosity mapping and targeted sequence capture to identify likely causative genes in a syndrome of neonatal-onset inflammatory skin and bowel disease in two siblings. C A SE R EP OR TTwo of three children born to consanguineous parents (first cousins) of Lebanese origin had the same clinical features involving the skin, hair, and gut. The skin lesions developed on the second day of life, with diarrhea developing in the first week of life. The affected girl died at 12 years of age from fulminant parvovirus B19-associatedThe New England Journal of Medicine Downloaded from nejm.org at MAX DELBRUECK CENTRUM FOR MOLECULAR MED on April 2, 2014. For personal use only. No other uses without permission.

Epidermal wound healing is a complex and highly coordinated process where several different cell types and molecules, such as growth factors and extracellular matrix (ECM) components, play an important role. Among the many proteins that are essential for the restoration of tissue integrity is the metalloproteinase (MMP) family. MMPs can act on ECM and non-ECM components affecting degradation and modulation of the ECM, growth-factor activation and cell-cell and cell-matrix signalling. MMPs are secreted by different cell types such as keratinocytes, fibroblasts and inflammatory cells at different stages and locations during wound healing, thereby regulating this process in a very coordinated and controlled way. In this article, we review the role of MMPs and their inhibitors (TIMPs), as well as the disintegrin and metalloproteinase with the thrombospondin motifs (ADAMs) family, in epithelial wound repair.

We are just beginning to understand some of the cellular mechanisms involved in human keratinocyte migration on extracellular matrix. Extracellular matrix components have differing effects on keratinocyte motility. Signalling through integrin receptors and secretion of collagenase are both components of this process. An understanding of the effect of extracellular matrix on keratinocyte migration has direct relevance to the problem of wound re-epithelialization and will assist in the development of therapeutic efforts to enhance wound healing artificially.

Anonychia and hyponychia congenita (OMIM 206800) are rare autosomal recessive conditions in which the only presenting phenotype is the absence or severe hypoplasia of all fingernails and toenails. After determining linkage to chromosome 20p13, we identified homozygous or compound heterozygous mutations in the gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, in eight affected families. Rspo4 expression was specifically localized to developing mouse nail mesenchyme at embryonic day 15.5, suggesting a crucial role in nail morphogenesis.