title: Makings of a brittle bone: Unexpected lessons from a low protein diet study of a mouse OI model.
abstract: Glycine substitutions in type I collagen appear to cause osteogenesis imperfecta (OI) by disrupting folding of the triple helix, the structure of which requires Gly in every third position. It is less clear, however, whether the resulting bone malformations and fragility are caused by effects of intracellular accumulation of misfolded collagen on differentiation and function of osteoblasts, effects of secreted misfolded collagen on the function of bone matrix, or both. Here we describe a study originally conceived for testing how reducing intracellular accumulation of misfolded collagen would affect mice with a Gly610 to Cys substitution in the triple helical region of the α2(I) chain. To stimulate degradation of misfolded collagen by autophagy, we utilized a low protein diet. The diet had beneficial effects on osteoblast differentiation and bone matrix mineralization, but also affected bone modeling and suppressed overall animal growth. Our more important observations, however, were not related to the diet. They revealed how altered osteoblast function and deficient bone formation by each cell caused by the G610C mutation combined with increased osteoblastogenesis might make the bone more brittle, all of which are common OI features. In G610C mice, increased bone formation surface compensated for reduced mineral apposition rate, resulting in normal cortical area and thickness at the cost of altering cortical modeling process, retaining woven bone, and reducing the ability of bone to absorb energy through plastic deformation. Reduced collagen and increased mineral density in extracellular matrix of lamellar bone compounded the problem, further reducing bone toughness. The latter observations might have particularly important implications for understanding OI pathophysiology and designing more effective therapeutic interventions.
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Mertz
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: E
authors.initials: E
authors.lastname: Makareeva
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Mirigian
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: K Y
authors.initials: KY
authors.lastname: Koon
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Perosky
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Kozloff
authors.affiliation: Section on Physical Biochemistry, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: leikins@mail.nih.gov.
authors.forename: S
authors.initials: S
authors.lastname: Leikin
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation; D024042:Collagen Type I / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D018753:Diet, Protein-Restricted / Q000379:methods*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010013:Osteogenesis Imperfecta / Q000178:diet therapy* / Q000378:metabolism; D017510:Protein Folding
chemical_list: C000619309:Col1a2 protein, mouse; D024042:Collagen Type I
keywords: Biomechanics; Bone; Collagen; Mineralization; Osteogenesis imperfecta; Raman microspectroscopy