Fibrillar type I collagen is the predominant organic component in the mineralized tissues, except tooth enamel, providing a stable template to spatially control the deposition and packing of the mineral crystals. It has become clear that the pattern of collagen post-translational modifications is a critical factor for the formation of functional fibrils that eventually get mineralized. O-glycosylation of collagen is one of such unique modifications occurring at the specific hydroxylysine residues catalyzed sequentially by hydroxylysyl galactosyltransferase (GT) and, then, galactosylhydroxylysyl glucosyltransferase (GGT). Though alterations in collagen glycosylatioon have been implicated in collagen maturation and various bone disorders, the precise mechanisms and the functions of this modification in bone are not well understood. Most recently we have demonstrated that lysyl hydroxylase 3 functions as GGT and, possibly, glycosyltransferase 25 family member 1 (GLT25D1) as GT for bone type I collagen. Based on these and preliminary data, we hypothesized that by manipulating the expression of gene encoding GLT25D1 in osteoblastic cells, under- or overglycosylated type I collagen can be synthesized, and that this system can be used to elucidate the function of glycosylation in collagen maturation and mineralization in bone. To test the hypothesis, the following specific aims are proposed:
Aim 1. To generate type I collagen with varied levels of glycosylation in osteoblastic cells and to define its role in collagen maturation and mineralization in vitro, Aim 2. To determine the effects of collagen glycosylation on collagen maturation and mineralization in an in vivo transplantation system. The proposed study should provide insights into the functions of glycosylation in collagen maturation and mineralization, thus, its involvement in bone formation and pathology, and its potential use for the assessment of bone quality.

Public Health Relevance

The quality of fibrillar type I collagen is an important determinant for bone functions and it is established in part by the post-translational modifications. The goal of this study is to elucidate the mechanism and functions of collagen glycosylation in bone, and the results will advance our understanding of bone mineralization and could provide new insights into the mechanisms of bone disorders.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Sharrock, William J
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University of North Carolina Chapel Hill
Schools of Dentistry
Chapel Hill
United States
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Terajima, Masahiko; Taga, Yuki; Chen, Yulong et al. (2016) Cyclophilin-B Modulates Collagen Cross-linking by Differentially Affecting Lysine Hydroxylation in the Helical and Telopeptidyl Domains of Tendon Type I Collagen. J Biol Chem 291:9501-12
Chen, Yulong; Terajima, Masahiko; Yang, Yanan et al. (2015) Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. J Clin Invest 125:1147-62
Miguez, P A; Terajima, M; Nagaoka, H et al. (2014) Recombinant biglycan promotes bone morphogenetic protein-induced osteogenesis. J Dent Res 93:406-11
Kaku, Masaru; Yamauchi, Mitsuo (2014) Mechano-regulation of collagen biosynthesis in periodontal ligament. J Prosthodont Res 58:193-207
Nagaoka, Hiroko; Nagaoka, Hideaki; Walter, Ricardo et al. (2014) Characterization of genipin-modified dentin collagen. Biomed Res Int 2014:702821
Cabral, Wayne A; Perdivara, Irina; Weis, MaryAnn et al. (2014) Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta. PLoS Genet 10:e1004465
Terajima, Masahiko; Perdivara, Irina; Sricholpech, Marnisa et al. (2014) Glycosylation and cross-linking in bone type I collagen. J Biol Chem 289:22636-47
Nagaoka, Hideaki; Terajima, Masahiko; Yamada, Shizuka et al. (2014) Alfacalcidol enhances collagen quality in ovariectomized rat bones. J Orthop Res 32:1030-6
Perdivara, Irina; Yamauchi, Mitsuo; Tomer, Kenneth B (2013) Molecular Characterization of Collagen Hydroxylysine O-Glycosylation by Mass Spectrometry: Current Status. Aust J Chem 66:760-769
Perepelyuk, Maryna; Terajima, Masahiko; Wang, Andrew Y et al. (2013) Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol 304:G605-14

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