title: Osteoblast-specific Krm2 overexpression and Lrp5 deficiency have different effects on fracture healing in mice.
abstract: The canonical Wnt/β-catenin pathway plays a key role in the regulation of bone remodeling in mice and humans. Two transmembrane proteins that are involved in decreasing the activity of this pathway by binding to extracellular antagonists, such as Dickkopf 1 (Dkk1), are the low-density lipoprotein receptor related protein 5 (Lrp5) and Kremen 2 (Krm2). Lrp 5 deficiency (Lrp5-/-) as well as osteoblast-specific overexpression of Krm2 in mice (Col1a1-Krm2) result in severe osteoporosis occurring at young age. In this study, we analyzed the influence of Lrp5 deficiency and osteoblast-specific overexpression of Krm2 on fracture healing in mice using flexible and semi-rigid fracture fixation. We demonstrated that fracture healing was highly impaired in both mouse genotypes, but that impairment was more severe in Col1a1-Krm2 than in Lrp5-/- mice and particularly evident in mice in which the more flexible fixation was used. Bone formation was more reduced in Col1a1-Krm2 than in Lrp5-/- mice, whereas osteoclast number was similarly increased in both genotypes in comparison with wild-type mice. Using microarray analysis we identified reduced expression of genes mainly involved in osteogenesis that seemed to be responsible for the observed stronger impairment of healing in Col1a1-Krm2 mice. In line with these findings, we detected decreased expression of sphingomyelin phosphodiesterase 3 (Smpd3) and less active β-catenin in the calli of Col1a1-Krm2 mice. Since Krm2 seems to play a significant role in regulating bone formation during fracture healing, antagonizing KRM2 might be a therapeutic option to improve fracture healing under compromised conditions, such as osteoporosis.
authors: Institute of Orthopaedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany.
authors: Astrid
authors: A
authors: Liedert
authors: Institute of Orthopaedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany.
authors: Viktoria
authors: V
authors: Röntgen
authors: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Thorsten
authors: T
authors: Schinke
authors: Orthopaedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
authors: Peggy
authors: P
authors: Benisch
authors: Orthopaedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
authors: Regina
authors: R
authors: Ebert
authors: Orthopaedic Center for Musculoskeletal Research, University of Würzburg, Würzburg, Germany.
authors: Franz
authors: F
authors: Jakob
authors: Institute of Cell Biology, University of Duisburg-Essen, Duisburg, Germany.
authors: Ludger
authors: L
authors: Klein-Hitpass
authors: Institute of Pathology, University of Ulm, Ulm, Germany.
authors: Jochen K
authors: JK
authors: Lennerz
authors: Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Michael
authors: M
authors: Amling
authors: Institute of Orthopaedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany.
authors: Anita
authors: A
authors: Ignatius
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000096:biosynthesis / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005269:Femur / Q000378:metabolism / Q000473:pathology; D017102:Fracture Healing / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000172:deficiency / Q000235:genetics*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C558680:Kremen-2 protein, mouse; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D008565:Membrane Proteins