title: BMP1-like proteinases are essential to the structure and wound healing of skin.
abstract: Closely related extracellular metalloproteinases bone morphogenetic protein 1 (BMP1) and mammalian Tolloid-like 1 (mTLL1) are co-expressed in various tissues and have been suggested to have overlapping roles in the biosynthetic processing of extracellular matrix components. Early lethality of mice null for the BMP1 gene Bmp1 or the mTLL1 gene Tll1 has impaired in vivo studies of these proteinases. To overcome issues of early lethality and functional redundancy we developed the novel BTKOmouse strain, with floxed Bmp1 and Tll1 alleles, for induction of postnatal, simultaneous ablation of the two genes. We previously showed these mice to have a skeletal phenotype that includes elements of osteogenesis imperfecta (OI), osteomalacia, and deficient osteocyte maturation, observations validated by the finding of BMP1 mutations in a subset of human patients with OI-like phenotypes. However, the roles of BMP1-like proteinase in non-skeletal tissues have yet to be explored, despite the supposed importance of putative substrates of these proteinases in such tissues. Here, we employ BTKOmice to investigate potential roles for these proteinases in skin. Loss of BMP1-like proteinase activity is shown to result in markedly thinned and fragile skin with unusually densely packed collagen fibrils and delayed wound healing. We demonstrate deficits in the processing of collagens I and III, decorin, biglycan, and laminin 332 in skin, which indicate mechanisms whereby BMP1-like proteinases affect the biology of this tissue. In contrast, lack of effects on collagen VII processing or deposition indicates this putative substrate to be biosynthetically processed by non-BMP1-like proteinases.
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Muir
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Dawiyat
authors.initials: D
authors.lastname: Massoudi
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Dermatology, VA Medical Center, Palo Alto, CA 94304, USA.
authors.forename: Ngon
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Microimaging Center, Shriners Hospitals for Children, Portland, OR 97239, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA; Research Service, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Davidson
authors.affiliation: Program in Epithelial Biology and Department of Dermatology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Dermatology, VA Medical Center, Palo Alto, CA 94304, USA.
authors.forename: M Peter
authors.initials: MP
authors.lastname: Marinkovich
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. Electronic address: dsgreens@wisc.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Greenspan
mesh_terms: D000818:Animals; D058578:Biglycan / Q000378:metabolism; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D058575:Decorin / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000201:enzymology*; D055786:Gene Knockout Techniques; D008297:Male; D008822:Mice, Transgenic; D062326:Re-Epithelialization; D055394:Tolloid-Like Metalloproteinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C546885:Bgn protein, mouse; D058578:Biglycan; C546879:Dcn protein, mouse; D058575:Decorin; D055394:Tolloid-Like Metalloproteinases; C484477:Tll1 protein, mouse; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1
keywords: Biglycan; Bone morphogenetic protein 1 (BMP1) mammalian tolloid-like 1; Collagen; Decorin; Skin; Wound healing