Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1+/mov13 mouse model of type I Osteogenesis Imperfecta

Christina M. Jacobsen, Marissa A. Schwartz, Heather J. Roberts, Kyung Eun Lim, Lyudmila Spevak, Adele L. Boskey, David Zurakowski, Alexander G. Robling, Matthew L. Warman

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1+/Mov13) with a high bone mass (HBM) mouse (Lrp5+/p.A214V) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI + HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1.

Original languageEnglish (US)
Pages (from-to)127-132
Number of pages6
JournalBone
Volume90
DOIs
StatePublished - Sep 1 2016

Keywords

  • Lrp5
  • Mov13
  • Osteogenesis Imperfecta
  • Wnt signaling

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

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    Jacobsen, C. M., Schwartz, M. A., Roberts, H. J., Lim, K. E., Spevak, L., Boskey, A. L., Zurakowski, D., Robling, A. G., & Warman, M. L. (2016). Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1+/mov13 mouse model of type I Osteogenesis Imperfecta. Bone, 90, 127-132. https://doi.org/10.1016/j.bone.2016.06.005