Wnt signaling as a therapeutic target for bone diseases

Expert Opin Ther Targets. 2009 Apr;13(4):485-96. doi: 10.1517/14728220902841961.

Abstract

Background: There is a need to develop new bone anabolic agents because current bone regeneration regimens have limitations. The Wingless-type MMTV integration site (Wnt) pathway has emerged as a regulator of bone formation and regeneration.

Objective: To review the molecular basis for Wnt pathway modulation and discuss strategies that target it and improve bone mass.

Methods: Data in peer-reviewed reports and meeting abstracts are discussed.

Results/conclusions: Neutralizing inhibitors of Wnt signaling have emerged as promising strategies. Small-molecule inhibitors of glycogen synthase kinase 3beta increase bone mass, lower adiposity and reduce fracture risk. Neutralizing antibodies to Dickkopf 1, secreted Frizzled-related protein 1 and sclerostin produce similar outcomes in animal models. These drugs are exciting breakthroughs but are not without risks. The challenges include tissue-specific targeting and consequently, long-term safety.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Bone Diseases / drug therapy*
  • Bone Diseases / physiopathology
  • Bone Morphogenetic Proteins / antagonists & inhibitors
  • Bone Morphogenetic Proteins / physiology
  • Bone Resorption / drug therapy
  • Drug Evaluation, Preclinical
  • Fractures, Bone / drug therapy
  • Gene Expression Regulation / drug effects
  • Genetic Markers / physiology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / physiology
  • LDL-Receptor Related Proteins / deficiency
  • LDL-Receptor Related Proteins / genetics
  • LDL-Receptor Related Proteins / physiology
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology
  • Mice
  • Mice, Knockout
  • Organ Specificity
  • Osteoblasts / drug effects*
  • Osteoblasts / physiology
  • Osteogenesis / drug effects
  • Osteoporosis / drug therapy
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Regeneration / physiology
  • Signal Transduction / drug effects*
  • Wnt Proteins / antagonists & inhibitors*
  • Wnt Proteins / physiology
  • beta Catenin / biosynthesis
  • beta Catenin / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Bone Morphogenetic Proteins
  • DKK1 protein, human
  • Dkk1 protein, mouse
  • Genetic Markers
  • Intercellular Signaling Peptides and Proteins
  • LDL-Receptor Related Proteins
  • LRP5 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Lrp5 protein, mouse
  • Membrane Proteins
  • Protein Kinase Inhibitors
  • SFRP1 protein, human
  • SOST protein, human
  • Sfrp1 protein, mouse
  • Wnt Proteins
  • beta Catenin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3