Transient receptor potential vanilloid 4 deficiency suppresses unloading‐induced bone loss

Mizoguchi, Fumitaka; Mizuno, Atsuko; Hayata, Tadayoshi; Nakashima, Kazuhisa; Heller, Stefan; Ushida, Takashi; Sokabe, Masahiro; Miyasaka, Nobuyuki; Suzuki, Makoto; Ezura, Yoichi; Noda, Masaki

doi:10.1002/jcp.21374

Cited by 101 publications

(88 citation statements)

References 44 publications

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“…Beyond the control of systemic osmolarity (1,29), TRPV4 has been implicated in other force-related transductions in vivo, including flow-mediated dilation of arteries (30), strain-induced endothelial cell reorientation (31), viscosity-coupled epithelial ciliary activity (32,33), and osteoclast response to weight load on bones (19). In these instances, a direct mechanosensitivity of the TRPV4 channel itself provides the simplest explanation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Wild-type and Brachyolmia-causing Mutant TRPV4 Channels Respond Directly to Stretch Force

Loukin

Zhou

et al. 2010

Journal of Biological Chemistry

127

136

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Whether animal ion channels functioning as mechanosensors are directly activated by stretch force or indirectly by ligands produced by the stretch is a crucial question. TRPV4, a key molecular model, can be activated by hypotonicity, but the mechanism of activation is unclear. One model has this channel being activated by a downstream product of phospholipase A 2 , relegating mechanosensitivity to the enzymes or their regulators. We expressed rat TRPV4 in Xenopus oocytes and repeatedly examined >200 excised patches bathed in a simple buffer. We found that TRPV4 can be activated by tens of mm Hg pipette suctions with open probability rising with suction even in the presence of relevant enzyme inhibitors. Mechanosensitivity of TRPV4 provides the simplest explanation of its various forcerelated physiological roles, one of which is in the sensing of weight load during bone development. Gain-of-function mutants cause heritable skeletal dysplasias in human. We therefore examined the brachyolmia-causing R616Q gain-of-function channel and found increased whole-cell current densities compared with wild-type channels. Single-channel analysis revealed that R616Q channels maintain mechanosensitivity but have greater constitutive activity and no change in unitary conductance or rectification.In stark contrast with vision, smell, and most tastes, which are based on G-protein-coupled receptors, the mechanical senses (hearing, touch, balance, monitoring blood pressure or systemic osmolarity etc.) are poorly understood in molecular terms. Although prokaryotic mechanosensitive channels are clearly activated directly by membrane stretch force (6), how eukaryotic mechanosensitive channels are activated is still under debate. Models range from direct activation by stretches from membrane and/or cytoskeleton to indirect activation through stretch-produced ligands (7,8). The mammalian twopore K ϩ channels TREK1 and TAASK are activated by both membrane stretch and polyunsaturated fatty acids (PUFAs) 2 (9). There, cytoskeletal disruption actually increases mechanosensitivity, suggesting that the cytoskeleton does not transmit stretch force to these channels (10).Among the Ca 2ϩ -permeable transient receptor potential channels, yeast TRPY1 (11) and animal TRPV4 (transient receptor potential channel subtype V4) (12) have been studied extensively for their response to osmotic or mechanical stimuli. TRPY1 can be activated directly by suctions applied to excised membrane patches (11, 13). However, results from such a test from limited preliminary studies found in the TRPV4 literature are inconsistent and even contradictory (1, 2, 14), likely reflecting mechanical complexities of patches excised from animal cells and/or molecular heterogeneity.Rodent TRPV4 channels were first cloned repeatedly by following hypotonicity-induced Ca 2ϩ signals (1, 2). Rat trpv4 complements the mechano-and osmosensitivity defects of the osm-9 mutant worm (15). How osmotic force activates TRPV4 is unclear, however. Besides hypotonicity, this polymodal channel is a...

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Section: Discussionmentioning

confidence: 99%

“…Unloading-induced bone loss is suppressed in trpv4 Ϫ/Ϫ mice (19). Recently, TRPV4 gain-of-function (GOF) mutations were found to cause autosomal dominant blockage of bone development in human.…”

mentioning

confidence: 99%

Wild-type and Brachyolmia-causing Mutant TRPV4 Channels Respond Directly to Stretch Force

Loukin

Zhou

et al. 2010

Journal of Biological Chemistry

127

136

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“…TRPV4 seems to regulate vascular tone Zhang et al, 2009) and bone deposition and remodeling (Masuyama et al, 2008;Mizoguchi et al, 2008). It is noteworthy that mutations in TRPV4 have been identified in patients with three dominantly inherited skeletal phenotypes: autosomal-dominant brachyolmia, spondylometaphyseal dysplasia Kozlowski type, and metatropic dysplasia (Rock et al, 2008;Krakow et al, 2009).…”

Section: A Transient Receptor Potential V1-v4 Subgroupmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family

2010

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“…No obstante, el hecho de que las mutaciones en el gen TRPV4 causan displasias óseas es consistente con que el canal se expresa en los osteoblastos y osteoclastos. 8 Presentan un papel importante en el cartílago, en las primeras etapas de la diferenciación de los condrocitos, 9 y modula el gen SOX9 en cultivo de células. 10 Las mutaciones en el genTRPV4 producen una familia de displasias óseas que presentan un espectro fenotípico continuo, que incluye l a e s t u d i a d a e n e s t e c a s o , l a d i s p l a s i a espondilometafisaria tipo Kozlowski (OMIM 184252) y la braquiolmia tipo 3 (OMIM 113500).…”

Section: Discussionunclassified

Displasia metatrópica en una niña con mutación c.1811_1812delinsAT en el exón 11 del gen TRPV4 no informada previamente

et al. 2015

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Presentación de casos clínicos RESUMENLa displasia metatrópica es una alteración esquelética con heterogeneidad clínica, caracterizada por dismorfias craneofaciales, que incluyen prominencia frontal e hipoplasia medio facial, tronco corto con cifoescoliosis progresiva y acortamiento de las extremidades. El gen TRPV4 se localiza en 12q24.11; codifica a un canal de catión con permeabilidad no selectiva al calcio, el cual se expresa y participa en muchos procesos fisiológicos en respuesta a diversos estímulos. Más de 50 mutaciones en TRPV4 han sido descritas. Se presenta el caso de una niña de 7 meses de edad con mutación heterocigota c.1811_1812delinsAT; p.I604N en el intrón 11 no informada previamente en el gen TRPV4 y con hallazgos clínicos compatibles con displasia metatrópica. Palabras clave: displasia metatrópica, TRPV4, c.1811_1812delinsAT. ABSTRACTMetatropic dysplasia is a skeletal disorder with clinical heterogeneity, characterized by craniofacial dysmorphy including frontal bossing and midface hypoplasia, short trunk, progressive kyphoscoliosis and shortened limbs. The TRPV4 gene is located on 12q24.11, coding a cation channel with nonselective permeability to calcium; it is expressed and involved in many physiological processes through responses to different stimuli. Over 50 mutations in TRPV4 have been described. We present a seven months old girl with heterozygous mutation c.1811_1812delinsAT; p.I604N in intron 11 not previously reported in the TRPV4 gene and with clinical findings compatible with metatropic dysplasia.

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Transient receptor potential vanilloid 4 deficiency suppresses unloading‐induced bone loss

Cited by 101 publications

References 44 publications

Wild-type and Brachyolmia-causing Mutant TRPV4 Channels Respond Directly to Stretch Force

Wild-type and Brachyolmia-causing Mutant TRPV4 Channels Respond Directly to Stretch Force

International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family

Displasia metatrópica en una niña con mutación c.1811_1812delinsAT en el exón 11 del gen TRPV4 no informada previamente

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