Procollagen C-proteinases (PCPs) cleave the C-propetides of procollagens Mil, to yield monomers that form the major fibrous components of ECM. The two PCP enhancer proteins (PCOLCE1 and 2) are not proteinases, yet they somehow enhance PCP activities approximately 10-fold in vitro. The PCOLCE1 C-terminal domain can inhibit matrix metalloproteinases (MMPs) secreted by tumor cells, and provides an anti-angiogenic activity isolated from cartilage. PCOLCE1 may also play a role in growth control, as disruption of the cognate gene results in anchorage-independent growth in cultured fibroblasts. We have generated mice with null alleles for the PCOLCE1 gene Pcolce, to ascertain its in vivo roles. Pcolce-/- mice are viable and fertile, but have profound ECM perturbations in bone and soft tissues, thus identifying PCOLCE1 as a determinant of bone strength and ECM integrity. More recently, we have succeeded in generating mice with null-alleles for the PCOLCE2 gene, Pcolce2, and have found Pcolce2-/- mice to be both viable and fertile. Predominant developmental expression of Pcolce2 in cartilage, plus the skeletal phenotype of Pcolce-/- mice, suggest role(s) for Pcolce2 in endochondral bone formation and in pathogenesis of arthridities. Both Pcolce and Pcolce2 are notable for particularly high expression levels in heart and Pcolce2 is also expressed at high levels in eye. We propose fully characterizing adult and embryo Pcolce-/- and Pcolce2-/- mice and derived cells, to determine the molecular bases and full extents of skeletal and soft tissue abnomalities. Crosses of Pcolce-/- and Pcolce2-/- mice to produce Pcolce/Pcolce2 doubly homozygous null progeny will remove any residual activity due to possible functional redundancy between Pcolce and Pcolce2. Studies of Pcolce-/-, Pcolce2-/- and doubly null mice, embryos and cells will enable clear delineation of PCPE roles in mammalian development, homeostasis and pathology. Based on recent evidience in our lab of physical interactions between PCOLCE1 and BMP1-like PCPs, we also propose studies that promise a paradigmatic shift in our understanding of how PCPs and PCOLCEs function. ? ? ?

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Intercellular Interactions (ICI)
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Wang, Fei
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University of Wisconsin Madison
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Muir, Alison M; Ren, Yinshi; Butz, Delana Hopkins et al. (2014) Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Hum Mol Genet 23:3085-101
Huang, Guorui; Ge, Gaoxiang; Wang, Dingyan et al. (2011) ýý3(V) collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues. J Clin Invest 121:769-83
Kim, Byoungjae; Huang, Guorui; Ho, Wen-Bin et al. (2011) Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3. J Biol Chem 286:29014-25
Muir, Alison; Greenspan, Daniel S (2011) Metalloproteinases in Drosophila to humans that are central players in developmental processes. J Biol Chem 286:41905-11
Branam, Amanda M; Hoffman, Guy G; Pelegri, Francisco et al. (2010) Zebrafish chordin-like and chordin are functionally redundant in regulating patterning of the dorsoventral axis. Dev Biol 341:444-58
Hoffman, Guy G; Branam, Amanda M; Huang, Guorui et al. (2010) Characterization of the six zebrafish clade B fibrillar procollagen genes, with evidence for evolutionarily conserved alternative splicing within the pro-alpha1(V) C-propeptide. Matrix Biol 29:261-75
Huang, Guorui; Zhang, Yue; Kim, Byoungjae et al. (2009) Fibronectin binds and enhances the activity of bone morphogenetic protein 1. J Biol Chem 284:25879-88
Iwata, Takekazu; Philipovskiy, Alexander; Fisher, Amanda J et al. (2008) Anti-type V collagen humoral immunity in lung transplant primary graft dysfunction. J Immunol 181:5738-47