Journal
JOURNAL OF CELL BIOLOGY
Volume 178, Issue 1, Pages 121-128Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200703113
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Funding
- NIAMS NIH HHS [R01 AR045548, R01 AR 045548] Funding Source: Medline
- NICHD NIH HHS [U01 HD039372, U01 HD39372] Funding Source: Medline
- NIEHS NIH HHS [P01 ES011253, P01 ES11253] Funding Source: Medline
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FILAMIN B, which encodes a cytoplasmic actin binding protein, is mutated in several skeletal dysplasias . To further investigate how an actin binding protein influences skeletogenesis, we generated mice lacking intact Filamin B. As observed in spondylocarpotarsal synostosis syndrome patients, Filamin B mutant mice display ectopic mineralization in many cartilaginous elements. This aberrant mineralization is due to ectopic chondrocyte hypertrophy similar to that seen in mice expressing Runx2 in chondrocytes. Accordingly, removing one copy of Runx2 rescues the Filamin B mutant phenotype, indicating that Filamin B is a regulator of Runx2 function during chondrocyte differentiation. Filamin B binds Smad3, which is known to interact with Runx2. Smad3 phosphorylation is increased in the mutant mice. Thus, Filamin B inhibits Runx2 activity at least in part, through the Smad3 pathway. Our results uncover the involvement of actin binding proteins during chol genesis and provide a molecular basis to a human genetic disease.
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