RRC ID 43583
Author Schwaerzer GK, Hiepen C, Schrewe H, Nickel J, Ploeger F, Sebald W, Mueller T, Knaus P.
Title New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): mutation within the GDF5 knuckle epitope causes noggin-resistance.
Journal J Bone Miner Res
Abstract Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS). SYNS is characterized by progressive symphalangism, carpal/tarsal fusions, deafness and mild facial dysmorphism. Here we present a novel molecular mechanism of a GDF5 mutation affecting chondrogenesis and osteogenesis. GDF5-S94N exhibits impaired binding to BMPRII causing alleviated Smad and non-Smad signaling and reduced chondrogenic differentiation of ATDC5 cells. Surprisingly, chondrogenesis in mouse micromass cultures was strongly enhanced by GDF5-S94N. By using quantitative techniques (SPR, reporter gene assay, ALP assay, qPCR), we uncovered that this gain of function is caused by strongly reduced affinity of GDF5-S94N to the BMP/GDF antagonist noggin and the consequential lack of noggin inhibition. Thus, since noggin is upregulated during chondrogenic differentiation, GDF5-S94N exceeds the GDF5 action, which results in the phenotypic outcome of SYNS. The detailed molecular characterization of GDF5-S94N as a noggin-resistant growth factor illustrates the potential of GDF5 mutants in applications with defined therapeutical needs.
Volume 27(2)
Pages 429-42
Published 2012-2-1
DOI 10.1002/jbmr.532
PMID 21976273
MeSH Amino Acid Sequence Animals Bone Morphogenetic Protein Receptors / metabolism Carrier Proteins / pharmacology Cell Differentiation / drug effects Cells, Cultured Chondrogenesis / drug effects Enzyme Activation / drug effects Epitopes / genetics* Growth Differentiation Factor 5 / chemistry* Growth Differentiation Factor 5 / genetics* Humans Immobilized Proteins / pharmacology Mice Molecular Sequence Data Mutant Proteins / metabolism Mutation / genetics* Myoblasts / drug effects Myoblasts / metabolism Myoblasts / pathology Osteoblasts / drug effects Osteoblasts / metabolism Osteoblasts / pathology Protein Binding / drug effects Signal Transduction / drug effects Smad Proteins / metabolism Syndrome Synostosis / enzymology Synostosis / genetics* Synostosis / pathology p38 Mitogen-Activated Protein Kinases / metabolism
IF 5.854
Times Cited 23
Human and Animal Cells ATDC5(RCB0565)