Discovery of Novel Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists as Regulators of Chondrogenic Differentiation: Identification of Quinazolin-4(3<i>H</i>)-ones and in Vivo Studies on a Surgically Induced Rat Model of Osteoarthritis

Atobe, Masakazu; Nagami, Takamichi; Muramatsu, Shuji; Ohno, Takeshi; Kitagawa, Masayuki; Suzuki, Hiroko; Ishiguro, Masashi; Watanabe, Atsushi; Kawanishi, Masashi

doi:10.1021/acs.jmedchem.8b01615

Cited by 36 publications

(31 citation statements)

References 32 publications

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“…We could not find any direct thermo and/or mechano-biological study in the literature reporting even partial effect of TRPV4 blocking on Sox9 expression in chondrogenic cells. However, in agreement with our findings, in vivo and in vitro studies have shown that pharmacological activation/inhibition of TRPV4 channels could mediate Sox9 expression [31,48].…”

Section: Calcium Signaling Is a Major Mechanism Of Action In Transduction Of Thermomechanical Cues Sensed By Trpv4 Channelssupporting

confidence: 93%

“…TRPV4 activity can modulate intracellular calcium transients and literature findings indicate that a welladjusted TRPV4-mediated Ca 2+ signaling is necessary for correct biological functioning of chondrocytes [5,[29][30][31][32]. We found that full removal of external calcium sources could further diminish the enhanced chondrogenic response obtained by thermo-mechanical cues when compared with TRPV4 inhibition alone.…”

Section: Calcium Signaling Is a Major Mechanism Of Action In Transduction Of Thermomechanical Cues Sensed By Trpv4 Channelsmentioning

confidence: 65%

“…Among different calcium mediators, transient receptor potential vanilloid 4 (TRPV4) is a multimodal ion channel that significantly contributes to the transduction of physical cues [26][27][28]. The literature suggests that over-activation and full inhibition of TRPV4 channels in chondrocytes cause negative effects on joint development and cartilage homeostasis [29][30][31][32]. Of note, TRPV4 channels are responsive to mechanical loading [5,24] and temperature rise [33,34], making it a potential sensory system for translation of stimuli involved in loading induced self-heating phenomenon.…”

Section: Figurementioning

confidence: 99%

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Temperature Evolution Following Joint Loading Promotes Chondrogenesis by Synergistic Cues via Calcium Signaling

Nasrollahzadeh

Karami²,

Wang

et al. 2021

Preprint

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During loading of viscoelastic tissues, part of the mechanical energy is transformed into heat that can locally increase the tissue temperature, a phenomenon known as self-heating. In the framework of mechanobiology, it has been accepted that cells react and adapt to mechanical stimuli. However, the cellular effect of temperature increase as a by-product of loading has been widely neglected. In this work, we focused on cartilage self-heating to present a thermo-mechanobiological paradigm, and demonstrate how the synergy of a biomimetic temperature evolution and mechanical loading could influence cell behavior. We thereby developed a customized in vitro system allowing to recapitulate pertinent in vivo physical cues and determined the cells chondrogenic response to thermal and/or mechanical stimuli. Cellular mechanisms of action and potential signaling pathways of thermo-mechanotransduction process were also investigated. We found that co-existence of thermo-mechanical cues had a superior effect on chondrogenic gene expression compared to either signal alone. Specifically, a synergetic effect was observed for upregulation of Sox9 by application of the physiological thermo-mechanical stimulus. Multimodal TRPV4 channels were identified as key mediators of thermo-mechanotransduction process, which becomes ineffective without external calcium sources. We also observed that the isolated temperature evolution, as a by-product of loading, is a contributing factor to the cells response and this could be considered as important as the conventional mechanical loading. Providing an optimal thermo-mechanical environment by synergy of heat and loading portrays new opportunity for development of novel treatments for cartilage regeneration and can furthermore signal key elements for emerging cell-based therapies.

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Section: Calcium Signaling Is a Major Mechanism Of Action In Transduction Of Thermomechanical Cues Sensed By Trpv4 Channelssupporting

confidence: 93%

Section: Calcium Signaling Is a Major Mechanism Of Action In Transduction Of Thermomechanical Cues Sensed By Trpv4 Channelsmentioning

confidence: 65%

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Temperature Evolution Following Joint Loading Promotes Chondrogenesis by Synergistic Cues via Calcium Signaling

Nasrollahzadeh

Karami²,

Wang

et al. 2021

Preprint

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“…Most effective is the synthetic lipid GSK1016790A [59,60], which also requires the distant part of the amino-terminus of the channel suggesting a similar activation mechanism as for cell swelling [37]. Recently, local application of quinazolin-4(3 H)-one derivatives as TRPV4 agonists to joint cartilage stimulated chondrocyte matrix production and provided relieve from osteoarthritic damage in a rat model [61].…”

Section: Figure 1 (A)mentioning

confidence: 99%

Ca2+ Signaling by TRPV4 Channels in Respiratory Function and Disease

Rajan

Schremmer

Weber

et al. 2021

Cells

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Members of the transient receptor potential (TRP) superfamily are broadly expressed in our body and contribute to multiple cellular functions. Most interestingly, the fourth member of the vanilloid family of TRP channels (TRPV4) serves different partially antagonistic functions in the respiratory system. This review highlights the role of TRPV4 channels in lung fibroblasts, the lung endothelium, as well as the alveolar and bronchial epithelium, during physiological and pathophysiological mechanisms. Data available from animal models and human tissues confirm the importance of this ion channel in cellular signal transduction complexes with Ca2+ ions as a second messenger. Moreover, TRPV4 is an excellent therapeutic target with numerous specific compounds regulating its activity in diseases, like asthma, lung fibrosis, edema, and infections.

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“…Additionally, stimulation of TRPV4 reduces inflammation by inhibiting interleukin-1β mediated cartilage degradation (Fu et al, 2021). Pharmacological agonism of the TRPV4 channel has also shown therapeutic promise in promoting chondrogenic differentiation and inhibiting cartilage degradation during post-traumatic OA (Atobe et al, 2019). These studies underscore TRPV4 as a regulator of chondrocyte mechanotransduction and as a viable therapeutic target for treating OA.…”

Section: Introductionmentioning

confidence: 98%

Extracellular Matrix Stiffness Alters TRPV4 Regulation in Chondrocytes

Trompeter

Farino

Griffin

et al. 2021

Preprint

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During the progression of osteoarthritis (OA), degradation of the extracellular matrix alters the biomechanical properties of cartilage, especially the compressive modulus. The mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) is required for chondrocyte mechanotransduction, however howOA-mediated cartilage degradation influences TRPV4 signaling remains unknown. To determine if ATDC5 cells alter TRPV4-mediated calcium signaling and cell phenotype in response to softer substrates, we created PEGDA-RGDS hydrogels with Young's moduli that simulated healthy (~350 kPa), OA (~175 kPa) and severe OA (~35 kPa) tissue. We found that softer substrates reduced the influx of calcium through TRPV4 when challenging chondrocytes with hypotonic swelling (HTS). Chondrocyte apoptosis also increased on the OA and severe OA gels due to elevated basal [Ca2+]i, which is attenuated with pharmacological agonism of TRPV4. Pharmacological agonism of TRPV4 rescued the expression of aggrecan and TRPV4 in chondrocytes cultured on OA gels and enhanced the type II collagen (col2) expression in cells on the normal and OA gels. These data suggest that the biomechanical properties of degraded cartilage alter TRPV4-mediated mechanotransduction in chondrocytes. Given that TRPV4 reduced apoptosis and improved the chondrogenic capacity of cells, TRPV4 stimulation could provide a potential therapeutic target in patients with early to moderate OA.

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Discovery of Novel Transient Receptor Potential Vanilloid 4 (TRPV4) Agonists as Regulators of Chondrogenic Differentiation: Identification of Quinazolin-4(3H)-ones and in Vivo Studies on a Surgically Induced Rat Model of Osteoarthritis

Cited by 36 publications

References 32 publications

Temperature Evolution Following Joint Loading Promotes Chondrogenesis by Synergistic Cues via Calcium Signaling

Temperature Evolution Following Joint Loading Promotes Chondrogenesis by Synergistic Cues via Calcium Signaling

Ca2+ Signaling by TRPV4 Channels in Respiratory Function and Disease

Extracellular Matrix Stiffness Alters TRPV4 Regulation in Chondrocytes

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