The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway.

Abstract

Bone morphogenetic proteins (BMPs) are multifunctional cytokines that belong to the transforming growth factor-β family. BMPs were originally identified based on their unique activity, inducing heterotopic bone formation in skeletal muscle. This unique BMP activity is transduced by specific type I and type II transmembrane kinase receptors. Among the downstream pathways activated by these receptors, the Smad1/5/8 transcription factors appear to play critical roles in BMP activity. Smad1/5/8 transcription factors are phosphorylated at the C-terminal SVS motif by BMP type I receptors and then induce the transcription of early BMP-responsive genes by binding to conserved sequences in their enhancer regions. The linker regions of Smad1/5/8 contain multiple kinase phosphorylation sites, and phosphorylation and dephosphorylation of these sites regulate the transcriptional activity of Smad proteins. Gain-of-function mutations in one BMP type I receptor have been identified in patients with fibrodysplasia ossificans progressiva, a rare genetic disorder that is characterized by progressive heterotopic bone formation in the skeletal muscle. The mutant receptors activate the Smad signaling pathway even in the absence of BMPs, therefore novel inhibitors for the BMP receptor - Smad axis are being developed to prevent heterotopic bone formation in fibrodysplasia ossificans progressiva. Taken together, the data in the literature show that the BMP type I receptor - Smad signaling axis is the critical pathway for the unique activity of BMPs and is a potential therapeutic target for pathological conditions caused by inappropriate BMP activity.

• Authors: Takenobu Katagiri, Sho Tsukamoto
• Journal: Biological chemistry (Biol Chem) Vol. 394 Issue 6 Pg. 703-14 (Jun 2013) ISSN: 1437-4315 [Electronic] Germany
• PMID: 23324379 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Bone Morphogenetic Proteins
• Smad Proteins

Topics

• Animals
• Bone Morphogenetic Proteins (metabolism)
• Bone and Bones (metabolism)
• Humans
• Myositis Ossificans (metabolism)
• Osteogenesis
• Signal Transduction
• Smad Proteins (metabolism)