Mutations in TRPV4 cause an inherited arthropathy of hands and feet

Lamandé, Shireen R.; Yuan, Yuan; Gresshoff, Irma; Rowley, Lynn; Belluoccio, Daniele; Kaluarachchi, Kumara; Little, Christopher B.; Botzenhart, Elke; Zerres, Klaus; Amor, David J.; Cole, William G.; Savarirayan, Ravi; McIntyre, Peter; Bateman, John F.

doi:10.1038/ng.945

Cited by 131 publications

(123 citation statements)

References 32 publications

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“…Interestingly, a recent study demonstrated that mutations in TRPV4 associated with diminished glycosylation abolished responses to environmental stimuli (such as hypotonicity) and decreased responses to GSK1016790A. 54 Such impaired posttranslational TRPV4 processing has been implicated in the development of familial digital arthropathy-brachydactyly. 54 Interestingly, the beneficial effects of TRPV4 activation during ARPKD might not be limited to the kidney.…”

Section: Discussionmentioning

confidence: 99%

“…54 Such impaired posttranslational TRPV4 processing has been implicated in the development of familial digital arthropathy-brachydactyly. 54 Interestingly, the beneficial effects of TRPV4 activation during ARPKD might not be limited to the kidney. A recent study identifies an antiproliferative role for TRPV4 in cholangiocytes from ARPKD rats and TRPV4 activation has a tendency to decrease liver cysts.…”

Section: Discussionmentioning

confidence: 99%

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TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease

Zaika

Mamenko

Berrout

et al. 2013

Journal of the American Society of Nephrology

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease

Zaika

Mamenko

Berrout

et al. 2013

Journal of the American Society of Nephrology

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“…Human TRPV4 mutations that alter channel function are known to disrupt normal skeletal development and joint health (14,(16)(17)(18), and similarly, targeted deletion of TRPV4 in mice leads to loss of chondrocyte osmotransduction and subsequently, severe joint degeneration (19). TRPV4-mediated Ca 2+ signaling has also been shown to enhance chondrogenic gene expression in chondroprogenitor cell lines (20), as well as increase matrix synthesis in chondrocyte-based self-assembled constructs (21).…”

mentioning

confidence: 99%

TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading

O’Conor

Leddy

Benefield

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

375

448

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Mechanical loading of joints plays a critical role in maintaining the health and function of articular cartilage. The mechanism(s) of chondrocyte mechanotransduction are not fully understood, but could provide important insights into new physical or pharmacologic therapies for joint diseases. Transient receptor potential vanilloid 4 (TRPV4), a Ca 2+ -permeable osmomechano-TRP channel, is highly expressed in articular chondrocytes, and loss of TRPV4 function is associated with joint arthropathy and osteoarthritis. The goal of this study was to examine the hypothesis that TRPV4 transduces dynamic compressive loading in articular chondrocytes. We first confirmed the presence of physically induced, TRPV4-dependent intracellular Ca 2+ signaling in agarose-embedded chondrocytes, and then used this model system to study the role of TRPV4 in regulating the response of chondrocytes to dynamic compression. Inhibition of TRPV4 during dynamic loading prevented acute, mechanically mediated regulation of proanabolic and anticatabolic genes, and furthermore, blocked the loadinginduced enhancement of matrix accumulation and mechanical properties. Furthermore, chemical activation of TRPV4 by the agonist GSK1016790A in the absence of mechanical loading similarly enhanced anabolic and suppressed catabolic gene expression, and potently increased matrix biosynthesis and construct mechanical properties. These findings support the hypothesis that TRPV4-mediated Ca 2+ signaling plays a central role in the transduction of mechanical signals to support cartilage extracellular matrix maintenance and joint health. Moreover, these insights raise the possibility of therapeutically targeting TRPV4-mediated mechanotransduction for the treatment of diseases such as osteoarthritis, as well as to enhance matrix formation and functional properties of tissue-engineered cartilage as an alternative to bioreactor-based mechanical stimulation. mechanobiology | ion channel | calcium signaling | TGF-beta | tissue engineering

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“…Even here, the literature is far from clear. While multiple skeletal-dysplasia alleles were reported to have higher activities, (gain-of-function, GOF) 4,21 , several were reported to have reduced activities (loss-of-function, LOF) 10,22 . A systematic study of 14 alleles found them to all be GOF mutations (below) 23 .…”

mentioning

confidence: 99%

Yeast Luminometric and <em>Xenopus</em> Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4

Teng

Loukin

Kung

2013

JoVE

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TRPV4 (Transient Receptor Potentials, vanilloid family, type 4) is widely expressed in vertebrate tissues and is activated by several stimuli, including by mechanical forces. Certain TRPV4 mutations cause complex hereditary bone or neuronal pathologies in human. Wild-type or mutant TRPV4 transgenes are commonly expressed in cultured mammalian cells and examined by Fura-2 fluorometry and by electrodes. In terms of the mechanism of mechanosensitivity and the molecular bases of the diseases, the current literature is confusing and controversial. To complement existing methods, we describe two additional methods to examine the molecular properties of TRPV4. (1) Rat TRPV4 and an aequorin transgene are transformed into budding yeast. A hypo-osmtic shock of the transformant population yields a luminometric signal due to the combination of aequorin with Ca 2+ , released through the TRPV4 channel. Here TRPV4 is isolated from its usual mammalian partner proteins and reveals its own mechanosensitivity. (2) cRNA of TRPV4 is injected into Xenopus oocytes. After a suitable period of incubation, the macroscopic TRPV4 current is examined with a two-electrode voltage clamp. The current rise upon removal of inert osmoticum from the oocyte bath is indicative of mechanosensitivity. The microAmpere (10 -6 to 10 -4 A) currents from oocytes are much larger than the subnano-to nanoAmpere (10 -10 to 10 -9 A) currents from cultured cells, yielding clearer quantifications and more confident assessments. Microscopic currents reflecting the activities of individual channel proteins can also be directly registered under a patch clamp, in on-cell or excised mode. The same oocyte provides multiple patch samples, allowing better data replication. Suctions applied to the patches can activate TRPV4 to directly assess mechanosensitivity. These methods should also be useful in the study of other types of TRP channels. Video LinkThe video component of this article can be found at

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Mutations in TRPV4 cause an inherited arthropathy of hands and feet

Cited by 131 publications

References 32 publications

TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease

TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease

TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading

Yeast Luminometric and <em>Xenopus</em> Oocyte Electrophysiological Examinations of the Molecular Mechanosensitivity of TRPV4

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