WNT signaling in bone homeostasis and disease: from human mutations to treatments

Nat Med. 2013 Feb;19(2):179-92. doi: 10.1038/nm.3074. Epub 2013 Feb 6.

Abstract

Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Bone Density
  • Bone Development
  • Bone Morphogenetic Proteins / physiology
  • Bone and Bones / metabolism*
  • Hematopoiesis
  • Homeostasis*
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-5 / physiology
  • Low Density Lipoprotein Receptor-Related Protein-6 / physiology
  • Mice
  • Mutation*
  • Wnt Signaling Pathway / physiology*
  • beta Catenin / physiology

Substances

  • Bone Morphogenetic Proteins
  • LRP5 protein, human
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Low Density Lipoprotein Receptor-Related Protein-6
  • beta Catenin