Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1β mediated articular cartilage matrix destruction

Fu, Su; Meng, Huan; Inamdar, Sheetal R.; Das, Biswajit; Gupta, Himadri S.; Wang, W.; Thompson, Claire; Knight, Martin M.

doi:10.1016/j.joca.2020.08.002

Cited by 47 publications

(37 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To model the in vivo biomechanical environment, cyclic tensile system, osmotic loading system, hydrostatic pressure loading system, and load/strain-controlled cyclic loading system have been previously used (Samvelyan et al, 2020;Fu et al, 2021). In this study, we aimed to develop a 3D hydrogel scaffold to perform dynamic loading that mimics cartilage compression during daily activity.…”

Section: Discussionmentioning

confidence: 99%

Urolithin A Protects Chondrocytes From Mechanical Overloading-Induced Injuries

Yocum

Alexander

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Physiological mechanical stimulation has been shown to promote chondrogenesis, but excessive mechanical loading results in cartilage degradation. Currently, the underlying mechanotransduction pathways in the context of physiological and injurious loading are not fully understood. In this study, we aim to identify the critical factors that dictate chondrocyte response to mechanical overloading, as well as to develop therapeutics that protect chondrocytes from mechanical injuries. Specifically, human chondrocytes were loaded in hyaluronic hydrogel and then subjected to dynamic compressive loading under 5% (DL-5% group) or 25% strain (DL-25% group). Compared to static culture and DL-5%, DL-25% reduced cartilage matrix formation from chondrocytes, which was accompanied by the increased senescence level, as revealed by higher expression of p21, p53, and senescence-associated beta-galactosidase (SA-β-Gal). Interestingly, mitophagy was suppressed by DL-25%, suggesting a possible role for the restoration mitophagy in reducing cartilage degeneration with mechanical overloading. Next, we treated the mechanically overloaded samples (DL-25%) with Urolithin A (UA), a natural metabolite previously shown to enhance mitophagy in other cell types. qRT-PCR, histology, and immunostaining results confirmed that UA treatment significantly increased the quantity and quality of cartilage matrix deposition. Interestingly, UA also suppressed the senescence level induced by mechanical overloading, demonstrating its senomorphic potential. Mechanistic analysis confirmed that UA functioned partially by enhancing mitophagy. In summary, our results show that mechanical overloading results in cartilage degradation partially through the impairment of mitophagy. This study also identifies UA’s novel use as a compound that can protect chondrocytes from mechanical injuries, supporting high-quality cartilage formation/maintenance.

show abstract

Section: Discussionmentioning

confidence: 99%

Urolithin A Protects Chondrocytes From Mechanical Overloading-Induced Injuries

Yocum

Alexander

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…Much work thus far has focused on the critical role of TRPV4 in maintaining the health and function of joint tissues, particularly cartilage. 33,34 By activating TRPV4, mechanical stimuli increase intracellular Ca2+ concentrations and mediate metabolic processes. 35 A previous study confirmed that by mediating Ca2+ signaling, TRPV4 was a vital factor in transducing 36 Similarly, Xu et al demonstrated that the upregulation of TRPV4 in OA articular cartilage resulted from excessive mechanical stress and induced chondrocyte apoptosis via Ca2+ influx.…”

Section: Dovepressmentioning

confidence: 99%

Identification of CIRBP and TRPV4 as Immune-Related Diagnostic Biomarkers in Osteoarthritis

Tang¹,

Liu²,

Zhang³

et al. 2021

IJGM

View full text Add to dashboard Cite

Osteoarthritis (OA) is the most common chronic joint disorder in elderly individuals. This study aimed to identify immune-related diagnostic gene signatures for OA. Methods: First, we performed single-sample gene set enrichment analysis (ssGSEA) to evaluate the infiltration of immune cells in OA expression data from the Gene Expression Omnibus (GEO) database. Then, weighted gene coexpression network analysis (WGCNA) was performed to identify hub modules and genes related to immune cell types with significant infiltration. Finally, we screened diagnostic markers from the differentially expressed genes (DEGs) in both the OA group and the hub module using least absolute shrinkage and selection operator (LASSO) logistic regression. Results: Immune filtration analysis showed that immature B cells, mast cells, natural killer T cells, myeloid-derived suppressor cells (MDSCs), and type 2 T helper cells were dysregulated in OA samples. In WGCNA, a total of 120 genes were selected as hub genes associated with mast cell infiltration.The enrichment analysis showed that spliceosome, positive regulation of cell migration, and response to mechanical stimulus were mainly involved. The LASSO regression model for the GSE117999 dataset revealed 15 DEGs for predicting OA. Finally, two genes were obtained by intersection for further investigation. Conclusion: Cold-inducible RNA-binding protein (CIRBP) and transient receptor potential vanilloid 4 (TRPV4) were identified as diagnostic biomarkers for OA, and both were positively correlated with mast cell infiltration.

show abstract

“…Osmotic stresses have been repeatedly identified as the stimuli triggering a series of signalling events in relation to the TRPV4 channel, that are propagated into changes in gene expression and ECM synthesis. Yet, studies have shown that osmotic loading as well as mechanical loading elicit responses of the TRPV4 channel [23,27,28,30]. Furthermore, hydrostatic and osmotic pressures have similar effects on cartilage formation [67], and they both affect intracellular ion signalling in chondrocytes [68,69].…”

Section: Local Fluid Pressure May Promote Tissue Growth During Joint Morphogenesismentioning

confidence: 99%

“…TRPV4 activation in chondrocytes has been linked to osmolarity changes in in vitro studies [25,26]. Recent studies have shown it also responds to physiologic levels of strain loading [27,28], although there is also evidence to the contrary [29,30].…”

Section: Introductionmentioning

confidence: 99%

Local mechanical stimuli shape tissue growth in vertebrate joint morphogenesis

Comellas

Farkas

Kleinberg

et al. 2021

Preprint

View full text Add to dashboard Cite

The correct formation of synovial joints is essential for proper motion throughout life. Movement-induced forces are critical to creating correctly shaped joints, but it is unclear how cells sense and respond to these mechanical cues. To determine how mechanical stimuli drive joint morphogenesis, we combined experiments on regenerating axolotl forelimbs with a poroelastic model of bone rudiment growth. Animals either regrew forelimbs normally (control) or were injected with a TRPV4 agonist to impair chondrocyte mechanosensitivity during joint morphogenesis. We quantified growth and shape in regrown humeri from whole mount light sheet fluorescence images of the regenerated limbs. Results revealed statistically significant differences in morphology and cell proliferation between the two groups, indicating that mechanical stimuli play a role in the shaping of the joint. Local tissue growth in our finite element model was dictated by a biological contribution, proportional to chondrocyte density, and a mechanical one, driven by fluid pore pressure dynamics. Computational predictions agreed with experimental outcomes, suggesting that interstitial pressure might promote local tissue growth. Predictive computational models informed by experimental findings allow us to explore potential physical mechanisms and regulatory dynamics involved in tissue growth to advance our understanding of the mechanobiology of joint morphogenesis.

show abstract

Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1β mediated articular cartilage matrix destruction

Cited by 47 publications

References 58 publications

Urolithin A Protects Chondrocytes From Mechanical Overloading-Induced Injuries

Urolithin A Protects Chondrocytes From Mechanical Overloading-Induced Injuries

Identification of CIRBP and TRPV4 as Immune-Related Diagnostic Biomarkers in Osteoarthritis

Local mechanical stimuli shape tissue growth in vertebrate joint morphogenesis

Contact Info

Product

Resources

About