An Activator of the cAMP/PKA/CREB Pathway Promotes Osteogenesis From Human Mesenchymal Stem Cells

J Cell Physiol. 2013 Mar;228(3):617-26. doi: 10.1002/jcp.24171.

Abstract

Mesenchymal stem cells (MSCs) are multipotent adult stem cells capable of differentiating along the osteoblast, adipocyte, and chondrocyte lineages. Regulation of MSCs differentiation may be a useful tool for regenerative medicine and cell-based therapy. The discovery of small molecule that activates the osteogenic differentiation of MSCs could aid in the development of a new anabolic drug for osteoporosis treatment. We identified CW008, a derivative of pyrazole-pyridine, that stimulates osteoblast differentiation of human MSCs and increases bone formation in ovariectomized mice. CW008 promotes osteogenesis by activating cAMP/PKA/CREB signaling pathway and inhibiting leptin secretion. These results suggest that CW008 is an agonist of cAMP/PKA/CREB pathway in osteogenic differentiation and that application of CW008 may be useful for the treatment of bone-related diseases and for the study of bone biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / cytology
  • Adult Stem Cells / drug effects
  • Adult Stem Cells / physiology
  • Animals
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Leptin / biosynthesis
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / physiology
  • Mice
  • Osteogenesis / drug effects*
  • Osteogenesis / physiology
  • Osteoporosis / drug therapy
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • Signal Transduction / drug effects

Substances

  • CW008
  • Cyclic AMP Response Element-Binding Protein
  • Leptin
  • Pyrazoles
  • Pyridines
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases