Universität zu Köln

Kuemper, Maike, Zamek, Jan, Steinkamp, Joy ORCID: 0000-0001-9842-3818, Pach, Elke, Mauch, Cornelia and Zigrino, Paola (2022). Role of MMP3 and fibroblast-MMP14 in skin homeostasis and repair. Eur. J. Cell Biol., 101 (4). MUNICH: ELSEVIER GMBH. ISSN 1618-1298

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Abstract

Early lethality of mice with complete deletion of the matrix metalloproteinase MMP14 emphasized the proteases' pleiotropic functions. MMP14 deletion in adult dermal fibroblasts (MMP14Sf-/-) caused collagen type I accu-mulation and upregulation of MMP3 expression. To identify the compensatory role of MMP3, mice were generated with MMP3 deletion in addition to MMP14 loss in fibroblasts. These double deficient mice displayed a fibrotic phenotype in skin and tendons as detected in MMP14Sf-/-mice, but no additional obvious defects were detected. However, challenging the mice with full thickness excision wounds resulted in delayed closure of early wounds in the double deficient mice compared to wildtype and MMP14 single knockout controls. Over time wounds closed and epidermal integrity was restored. Interestingly, on day seven, post-wounding myofibroblast density was lower in the wounds of all knockout than in controls, they were higher on day 14. The delayed resolution of myofibroblasts from the granulation tissue is paralleled by reduced apoptosis of these cells, although proliferation of myofibroblasts is induced in the double deficient mice. Further analysis showed comparable TGF beta 1 and TGF beta R1 expression among all genotypes. In addition, in vitro, fibroblasts lacking MMP3 and MMP14 retained their ability to differentiate into myofibroblasts in response to TGF beta 1 treatment and me-chanical stress. However, in vivo, p-Smad2 was reduced in myofibroblasts at day 5 post-wounding, in double, but most significant in single knockout, indicating their involvement in TGF beta 1 activation. Thus, although MMP3 does not compensate for the lack of fibroblast-MMP14 in tissue homeostasis, simultaneous deletion of both proteases in fibroblasts delays wound closure during skin repair. Notably, single and double deficiency of these proteases modulates myofibroblast formation and resolution in wounds.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kuemper, Maike UNSPECIFIED UNSPECIFIED UNSPECIFIED Zamek, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Steinkamp, Joy UNSPECIFIED orcid.org/0000-0001-9842-3818 UNSPECIFIED Pach, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Mauch, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Zigrino, Paola UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-662504
DOI:	10.1016/j.ejcb.2022.151276
Journal or Publication Title:	Eur. J. Cell Biol.
Volume:	101
Number:	4
Date:	2022
Publisher:	ELSEVIER GMBH
Place of Publication:	MUNICH
ISSN:	1618-1298
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SMOOTH MUSCLE ACTIN; MATRIX-METALLOPROTEINASE; TGF-BETA; CELL-SURFACE; MESENCHYMAL TRANSITION; EXTRACELLULAR-MATRIX; GRANULATION-TISSUE; MT1-MMP; ACTIVATION; COLLAGEN Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66250