Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Oct 30;2(1):e962971.
doi: 10.4161/2167549X.2014.962971. eCollection 2014.

Unraveling the mechanism by which TRPV4 mutations cause skeletal dysplasias

Holly A Leddy  1 , Amy L McNulty  1 , Farshid Guilak  1 , Wolfgang Liedtke  2
Affiliations

Unraveling the mechanism by which TRPV4 mutations cause skeletal dysplasias

Holly A Leddy et al. Rare Dis. .

Erratum in

  • doi: 10.1096/fj.13-245936

Abstract

Transient Receptor Potential Vanilloid 4 (TRPV4) is a mechano- and osmosensitive cation channel that is highly expressed in chondrocytes, the cells in cartilage. A large number of mutations in TRPV4 have been linked to skeletal dysplasias, and the goal of this addendum is to shed light on the mechanisms by which mutations in TRPV4 can cause skeletal dysplasias by focusing on 3 recent publications. These papers suggest that skeletal dysplasia-causing TRPV4 mutations reprogram chondrocytes to increase follistatin production, which inhibits BMP signaling, thus slowing the process of endochondral ossification and leading to skeletal dysplasia. In spite of these important advances in our understanding of the disease mechanism, much remains to be elucidated. Nonetheless, these new data suggest that inhibiting aberrant TRPV4 activity in the cartilage may be a promising direction for therapeutic intervention.

Keywords: arthritis; arthropathy; bone morphogenetic protein; brachyolmia; calcium signaling; cartilage; growth plate; osteoarthritis; skeletal dysplasia.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Schematic of the mechanisms by which TRPV4 mutations may lead to skeletal dysplasias. Ca2+ enters through the mutant channel, causing phosphorylation of CREB, which binds CRE and causes FST transcription. FST inhibits BMP activity, which prevents chondrocytes from undergoing hypertrophy and forming bone, thus leading to skeletal dysplasia.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kuipers AJ, Middelbeek J, van Leeuwen FN. Mechanoregulation of cytoskeletal dynamics by Trp channels. Eur J Cell Biol 2012; 91:834-46; PMID:22727433; http://dx.doi.org/10.1016/j.ejcb.2012.05.006 - DOI - PubMed
    1. Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichling DB, Levine JD. Hypotonicity Induces Trpv4-Mediated Nociception in Rat. Neuron 2003; 39:497-511; PMID:12895423; http://dx.doi.org/10.1016/S0896-6273(03)00462-8 - DOI - PubMed
    1. Chen Y, Williams SH, McNulty AL, Hong JH, Lee SH, Rothfusz NE, Parekh PK, Moore C, Gereau RWt, Taylor AB, et al. . Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion. Pain 2013; 154:1295-304; PMID:23726674; http://dx.doi.org/10.1016/j.pain.2013.04.004 - DOI - PMC - PubMed
    1. Moore C, Cevikbas F, Pasolli HA, Chen Y, Kong W, Kempkes C, Parekh P, Lee SH, Kontchou NA, Yeh I, et al. . Uvb radiation generates sunburn pain and affects skin by activating epidermal Trpv4 ion channels and triggering endothelin-1 signaling. Proc Natl Acad Sci U S A 2013; 110:E3225-34; PMID:23929777; http://dx.doi.org/10.1073/pnas.1312933110 - DOI - PMC - PubMed
    1. Pochynyuk O, Zaika O, O’Neil RG, Mamenko M. Novel insights into Trpv4 function in the kidney. Pflugers Arch 2013; 465:177-86; PMID:23207579; http://dx.doi.org/10.1007/s00424-012-1190-z - DOI - PMC - PubMed

LinkOut - more resources