Stromelysin-2 is a matrix metalloproteinase that degrades in vitro several protein components relevant to wound repair such as collagens III and IV, gelatin, nidogen, laminin-1, proteoglycans, and elastin. Furthermore, it can activate other matrix metalloproteinases, such as collagenase-1 (matrix metalloproteinase-1) and collagenase-2 (matrix metalloproteinase-8), as well as 92 kDa gelatinase. The aim of this study was to determine in a large variety of wounds (normally healing dermal and mucosal wounds, suction blisters, ex vivo cultures, diabetic, decubitus, rheumatic, and venous ulcers) and keratinocyte cultures, which factors contribute to stromelysin-2 expression and how it is induced in relation to other matrix metalloproteinases. Our results show that stromelysin-2 mRNA and protein are upregulated later (at 3 d) than matrix metalloproteinase-1 in normally healing wounds and ex vivo explants, in which stromelysin-2 is invariably expressed by keratinocytes migrating over dermal matrix. The number of keratinocytes expressing stromelysin-2 was greatest in chronic inflamed diabetic and venous ulcers compared with rheumatoid and decubitus ulcers, six of which had no signal. In keratinocyte cultures, tumor necrosis factor-alpha, epidermal growth factor, and transforming growth factor-beta1 induced stromelysin-2 expression as measured by quantitative reverse transcriptase-polymerase chain reaction, whereas different matrices did not upregulate the mRNA. Immunostaining demonstrated stromal transforming growth factor-beta1 in contact with the stromelysin-2-positive keratinocytes. Our results suggest that stromelysin-2 expression is important for the normal repair process and is upregulated by cytokines rather than cell-matrix interactions. Stromelysin-2 is most likely to participate in the remodeling of the newly formed basement membrane, and is not overexpressed in retarded wound healing.

NOTE.-Phosphomannomutase and protein were measured as described elsewhere (Van Schaftingen and Jaeken 1995; Jaeken et al. 1997a). Phosphomannose isomerase was assayed at 30ЊC in a reaction mixture (1 ml) containing 50 mM Hepes, pH 7.1, 5 mM MgCl 2 , 25 mM KCl, 1 mM dithiothreitol, 0.6 mM NAD ϩ , 0.5 mM mannose 6phosphate, 2.5 U/ml glucose 6-phosphate dehydrogenase from Leuconostoc mesenteroides, and 10 mg/ml phosphoglucose isomerase with 10 ml of an extract containing 5-20 mg protein/ml. Control and PMM deficient measures are mean values ‫ע‬ SD. Where two data are given, the values were obtained on two different subcultures.

In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.

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Mutations in ectodysplasin, the protein product of the EDA or ED1 gene, cause X-linked anhidrotic ectodermal dysplasia. From sixteen families we have identified thirteen mutations, of which nine were novel: a deletion of the entire exon 1, altered splicing site in intron 7 (IVS-2A-->G) and in intron 9 (IVS9+8 C-->G), deletion of 8 bp (1967-1974 nt), four missense mutations (G255C, G255D, W274G, C332Y) and nonsense mutation W274X. Previously identified and the novel mutations form four clusters: 1) at the junction of the transmembrane and extracellular domains, 2) at a putative protease recognition site, possibly affecting cleavage of ectodysplasin, 3) at the trimerizing collagen-like domain, and 4) at regions of high homology to tumor necrosis factor domains. Truncating and splice site mutations occur within the proximal two-thirds of the protein. Our data suggest the functional importance of specific ectodysplasin domains. Hum Mutat 17:349, 2001.

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