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Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand

Julia Luther1, Timur Alexander Yorgan1, Tim Rolvien1

  • 1Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Science Translational Medicine
|November 9, 2018
PubMed

Insights

Mutations in WNT1 (Wingless-type MMTV integration site family, member 1) are linked to early-onset osteoporosis. WNT1 signaling enhances bone mass in mice of all ages, independent of LRP5, offering new therapeutic targets.

Area of Science:

  • Bone Biology
  • Genetics
  • Endocrinology

Background:

  • WNT1 mutations are linked to osteogenesis imperfecta and early-onset osteoporosis.
  • The precise role and therapeutic potential of WNT1 in bone regulation, especially during aging, require further elucidation.

Purpose of the Study:

  • To investigate the prevalence of WNT1 mutations in early-onset osteoporosis.
  • To determine the function of WNT1 in bone mass regulation and its therapeutic potential.
  • To explore the WNT1 signaling pathway's independence from the LRP5 co-receptor.

Main Methods:

  • Genotyping of patients with early-onset osteoporosis to identify WNT1 mutations.
  • Inactivation and conditional expression of Wnt1 in mouse osteoblasts.
  • Assessment of bone mass, structure, and fracture incidence in genetically modified mice.
  • Analysis of Wnt1 signaling in the presence and absence of LRP5.

Main Results:

  • High prevalence of heterozygous WNT1 mutations found in patients with early-onset osteoporosis.
  • Wnt1 inactivation in osteoblasts led to severe osteoporosis and fractures in mice.
  • Conditional Wnt1 expression significantly increased bone mass in young, adult, and aged mice by enhancing osteoblast activity.
  • The bone-anabolic effects of Wnt1 were independent of the LRP5 co-receptor.

Conclusions:

  • WNT1 is a critical regulator of bone formation and remodeling.
  • WNT1 signaling promotes bone anabolism independently of LRP5.
  • Targeting WNT1 offers a promising therapeutic strategy for osteoporosis treatment.

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