Follistatin in chondrocytes: The link between TRPV4 channelopathies and skeletal malformations

Holly A. Leddy, Amy L. McNulty, Nicole E. Rothfusz, Farshid Guilak, Suk Hee Lee, Bernd Gloss, Margaret L. Kirby, Mary R. Hutson, Daniel H. Cohn, Wolfgang Liedtke

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Point mutations in the calcium-permeable TRPV4 ion channel have been identified as the cause of autosomal-dominant human motor neuropathies, arthropathies, and skeletal malformations of varying severity. The objective of this study was to determine the mechanism by which TRPV4 channelopathy mutations cause skeletal dysplasia. The human TRPV4V620I channelopathy mutation was transfected into primary porcine chondrocytes and caused significant (2.6-fold) up-regulation of follistatin (FST) expression levels. Pore altering mutations that prevent calcium influx through the channel prevented significant FST up-regulation (1.1-fold). We generated a mouse model of theTRPV4V620I mutation, and found significant skeletal deformities (e.g., shortening of tibiae and digits, similar to the human disease brachyolmia) and increases in Fst/TRPV4 mRNA levels (2.8-fold). FST was significantly up-regulated in primary chondrocytes transfected with 3 different dysplasia-causing TRPV4 mutations (2- to 2.3-fold), but was not affected by an arthropathy mutation (1.1-fold). Furthermore, FST-loaded microbeads decreased bone ossification in developing chick femora (6%) and tibiae (11%). FST gene and protein levels were also increased 4-fold in human chondrocytes from an individual natively expressing the TRPV4T89I mutation. Taken together, these data strongly support that up-regulation of FST in chondrocytes by skeletal dysplasia-inducing TRPV4 mutations contributes to disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)2525-2537
Number of pages13
JournalFASEB Journal
Issue number6
StatePublished - Jun 2014


  • Bone morphogenetic protein
  • Calcium signaling
  • Cartilage
  • Growth plate

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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