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Osteoblast-Specific Krm2 Overexpression and Lrp5 Deficiency Have Different Effects on Fracture Healing in Mice

Please always quote using this URN: urn:nbn:de:bvb:20-opus-115782
  • The canonical Wnt/beta-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 theThe canonical Wnt/beta-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 beta-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.show moreshow less

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Metadaten
Author: Astrid Liedert, Viktoria Röntgen, Thorsten Schinke, Peggy Benisch, Regina Ebert, Franz Jakob, Ludger Klein-Hitpass, Jochen K. Lennerz, Michael Amling, Anita Ignatius
URN:urn:nbn:de:bvb:20-opus-115782
Document Type:Journal article
Faculties:Medizinische Fakultät / Lehrstuhl für Orthopädie
Language:English
Parent Title (English):PLOS ONE
ISSN:1932-6203
Year of Completion:2014
Volume:9
Issue:7
Pagenumber:e103250
Source:PLoS ONE 9(7): e103250. doi:10.1371/journal.pone.0103250
DOI:https://doi.org/10.1371/journal.pone.0103250
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25061805
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:WNT pathway; autosomal-dominant osteopetrosis; cells; gene; high-bone-mass; in-vitro; mutations; osteoclasts; proliferation; receptor related protein
Release Date:2015/07/21
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung