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The Generation of Closed Femoral Fractures in Mice: A Model to Study Bone Healing
Published on: August 16, 2018
Osteoblast-specific Krm2 overexpression and Lrp5 deficiency have different effects on fracture healing in mice
Astrid Liedert1, Viktoria Röntgen1, Thorsten Schinke2
1Institute of Orthopaedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany.
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.
Insights
Impaired Wnt/β-catenin signaling via Lrp5 deficiency or Kremen 2 (Krm2) overexpression severely hinders fracture healing in mice. Krm2 overexpression caused more significant bone formation deficits, suggesting KRM2 antagonism as a potential therapeutic strategy for compromised fracture repair.
Area of Science:
- Bone biology
- Regenerative medicine
- Molecular signaling
Background:
- The Wnt/β-catenin pathway is crucial for bone remodeling.
- Low-density lipoprotein receptor related protein 5 (Lrp5) and Kremen 2 (Krm2) negatively regulate this pathway.
- Lrp5 deficiency or Krm2 overexpression leads to severe osteoporosis.
Purpose of the Study:
- To investigate the impact of Lrp5 deficiency and osteoblast-specific Krm2 overexpression on fracture healing in mice.
- To compare the severity of fracture healing impairment between these two genetic models.
- To explore potential therapeutic targets for improving fracture repair.
Main Methods:
- Utilized Lrp5 knockout (Lrp5-/-) and osteoblast-specific Krm2 overexpressing (Col1a1-Krm2) mouse models.
- Assessed fracture healing under flexible and semi-rigid fixation conditions.
- Employed microarray analysis to identify gene expression changes in healing bone.
Main Results:
- Both Lrp5-/- and Col1a1-Krm2 mice exhibited severely impaired fracture healing, with Col1a1-Krm2 mice showing greater impairment.
- Fracture healing was more compromised under flexible fixation.
- Col1a1-Krm2 mice displayed reduced bone formation and increased osteoclast numbers compared to Lrp5-/- mice.
- Microarray analysis revealed downregulated osteogenesis-related genes, including sphingomyelin phosphodiesterase 3 (Smpd3), and reduced β-catenin activity in Col1a1-Krm2 mice.
Conclusions:
- Kremen 2 (Krm2) plays a significant role in regulating bone formation during fracture healing.
- Antagonizing KRM2 may represent a viable therapeutic strategy to enhance fracture healing in conditions like osteoporosis.
- Understanding the molecular mechanisms underlying Krm2's role can inform future regenerative therapies.
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