Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway.
Previously, a small molecule, purmorphamine, was identified that selectively induces osteogenesis in multipotent mesenchymal progenitor cells. In order to gain insights into the mechanism of action of purmorphamine, high-density oligonucleotide microarrays were used to profile gene expression in multipotent mesenchymal progenitor cells treated with either purmorphamine or bone morphogenetic protein-4 (BMP-4). In contrast to BMP-4 treatment, purmorphamine activates the Hedgehog (Hh) signaling pathway, resulting in the up- and downregulation of its downstream target genes, including Gli1 and Patched. Moreover, the known Hh signaling antagonists, cyclopamine and forskolin, completely block the osteogenesis and Glimediated transcription induced by purmorphamine. These results demonstrate that purmorphamine is a small molecule agonist of Hedgehog signaling, and it may ultimately be useful in the treatment of bone-related disease and neurodegenerative disease.
Wu
Xu
X
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Walker
John
J
Zhang
Jie
J
Ding
Sheng
S
Schultz
Peter G
PG
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D016000:Cluster Analysis; D005576:Colforsin / Q000494:pharmacology; D005347:Fibroblasts; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D009025:Morpholines / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D011687:Purines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014704:Veratrum Alkaloids / Q000494:pharmacology
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D009025:Morpholines; D011687:Purines; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D005576:Colforsin; D000469:Alkaline Phosphatase; C470893:purmorphamine; C000541:cyclopamine