title: Collagen advanced glycation inhibits its Discoidin Domain Receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts.
abstract: Diabetes increases the risk of bone fracture. Organic and inorganic bone extracellular matrix components determine bone strength. Previous studies indicate that in diabetes, glycation of collagen causes abnormal arrangements of collagen molecules and fragile bones. Diabetic bone fragility is additionally attributed to reduced levels of lysyl oxidase enzyme-dependent collagen cross-links. The mechanism underlying the presence of lower enzymatic collagen cross-links in diabetic bone has not been directly investigated. Here we determine in primary osteoblast cultures the regulation of lysyl oxidase protein by type I collagen and collagen modified by carboxymethylation (CML-collagen), a form of advanced glycation endproducts. Data indicate that non-glycated collagen up-regulates lysyl oxidase levels both in primary non-differentiated and in differentiating mouse and rat osteoblast cultures, while CML-collagen fails to regulate lysyl oxidase in these cells. Collagen binding to Discoidin Domain Receptor-2 (DDR2) mediates lysyl oxidase increases, determined in DDR2 shRNA knockdown studies. DDR2 binding and activation were disrupted by collagen glycation, pointing to a mechanism for the diminished levels of lysyl oxidase and consequently low lysyl oxidase-derived cross-links in diabetic bone. Our studies indicate that collagen-integrin interactions may not play a major role in up-regulating lysyl oxidase. Furthermore, non-collagenous ligands for the receptor for advanced glycation end products (RAGE) failed to alter lysyl oxidase levels. Taken together with published studies a new understanding emerges in which diabetes- and age-dependent inhibition of normal collagen-stimulated DDR2- and integrin-signaling, and independent advanced glycation-stimulated RAGE-signaling, each contributes to different aspects of diabetic osteopenia.
authors.affiliation: Department of Molecular and Cell Biology, Division of Oral Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA. Electronic address: Roozbeh.kh@gmail.com.
authors.forename: Roozbeh
authors.initials: R
authors.lastname: Khosravi
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Sodek
authors.forename: Michael
authors.initials: M
authors.lastname: Faibish
authors.forename: Philip C
authors.initials: PC
authors.lastname: Trackman
mesh_terms: D000818:Animals; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000494:pharmacology*; D000070818:Discoidin Domain Receptors; D015536:Down-Regulation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology*; D008249:Protein-Lysine 6-Oxidase / Q000096:biosynthesis*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D011975:Receptors, Mitogen / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017127:Glycation End Products, Advanced; D016023:Integrins; D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011975:Receptors, Mitogen; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: Advanced glycation endproducts; Diabetes; Discoidin Domain Receptor 2; Lysyl oxidase; Osteoblasts