Mechanically induced calcium signaling in chondrocytes in situ

Han, Sang Kuy; Wouters, W.; Clark, Arthur W.

doi:10.1002/jor.21536

Cited by 67 publications

(69 citation statements)

References 53 publications

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“…The observed calcium peaks of ex vivo experiments were larger in magnitude and both shorter in duration and delayed compared to in vitro experiments. The duration of the calcium peaks we observed ex vivo agree well with previously reported ex vivo studies utilizing compression-stimulated lapine chondrocytes or osmotically-stimulated murine chondrocytes [14,28] and the magnitude and delay of the [Ca 2+ ] i transients we observed was comparable to the previously reported murine study [14]. Together these observations suggest that chondrocytes utilize contrasting signaling modalities in response to the type of stress (osmotic or mechanical) applied in addition to when surrounded by/isolated from the extracellular matrix.…”

Section: Discussionsupporting

confidence: 90%

Integrin α1β1 participates in chondrocyte transduction of osmotic stress

Jablonski

Ferguson

Pozzi

et al. 2014

Biochemical and Biophysical Research Communications

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Background/purpose: The goal of this study was to determine the role of the collagen binding receptor integrin α1β1 in regulating osmotically induced [Ca2+]i transients in chondrocytes. Methods: The [Ca2+]i transient response of chondrocytes to osmotic stress was measured using real-time confocal microscopy. Chondrocytes from wildtype and integrin α1-null mice were imaged ex vivo (in the cartilage of intact murine femora) and in vitro (isolated from the matrix, attached to glass coverslips). Immunocytochemistry was performed to detect the presence of the osmosensor, transient receptor potential vanilloid-4 (TRPV4), and the agonist GSK1016790A (GSK101) was used to test for its functionality on chondrocytes from wildtype and integrin α1-null mice. Results/interpretation: Deletion of the integrin α1 subunit inhibited the ability of chondrocytes to respond to a hypo-osmotic stress with [Ca2+]i transients ex vivo and in vitro. The percentage of chondrocytes responding ex vivo was smaller than in vitro and of the cells that responded, more single [Ca2+]i transients were observed ex vivo compared to in vitro. Immunocytochemistry confirmed the presence of TRPV4 on wildtype and integrin α1-null chondrocytes, however application of GSK101 revealed that TRPV4 could be activated on wildtype but not integrin α1-null chondrocytes. Integrin α1β1 is a key participant in chondrocyte transduction of a hypo-osmotic stress. Furthermore, the mechanism by which integrin α1β1 influences osmotransduction is independent of matrix binding, but likely dependent on the chondrocyte osmosensor TRPV4.

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Section: Discussionsupporting

confidence: 90%

Integrin α1β1 participates in chondrocyte transduction of osmotic stress

Jablonski

Ferguson

Pozzi

et al. 2014

Biochemical and Biophysical Research Communications

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“…[Ca 2+ ] i signaling is believed to be one of the earliest events in the response of chondrocytes to mechanical stimulation (35)(36)(37). Previous studies have observed [Ca 2+ ] i signaling in response to mechanical loading (38,39); interestingly, these studies detected [Ca 2+ ] i signaling in chondrocyte-laden constructs without substantial preculture (<72 h), although chondrocytes synthesize small amounts of pericellular proteoglycans even within 2 d of culture in agarose (29) that could contribute to mechanically induced [Ca 2+ ] i signaling.…”

Section: Camentioning

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.

384

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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“…Simultaneously, we can also measure selected generic chondrocyte signalling events, such as intracellular calcium ''sparks'' (Han et al, 2012). Although this approach allows for unique insight into the mechanics of physiologically loaded joints in vivo, it is currently not a feasible approach in human studies.…”

Section: Introductionmentioning

confidence: 99%

Muscular loading of joints triggers cellular secretion of PRG4 into the joint fluid

Abusara

Krawetz

Steele

et al. 2013

Journal of Biomechanics

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We developed a novel testing system that allows quantification of joint loading and permits analysis of changes in total protein and PRG4 contents in joint fluid of intact knees in live mice. A sequence of 15 repeat, isometric muscular contractions of "low" intensity (less than 50% of the maximal isometric muscular force), and "high" intensity (greater than 55% of maximal) were applied repeatedly (up to five times with a 15 min rest between contractions) to the mouse knee. Increases in knee joint loading were accompanied with significant increases in total protein (p<0.0001) and PRG4 concentrations in the synovial fluid. Total protein and PRG4 concentrations decreased with repeated "high" intensity loading. However, the addition of cell secretion inhibitors to the knee prior to muscular loading resulted in PRG4 levels that remained below the detection limit for all loading conditions. These results suggest that changes in synovial fluid proteins and PRG4 concentrations upon joint loading are mediated by cells within the joint, and that these changes may be used as quantitative indicators for the intensity and duration of acute joint loading, and might serve as a powerful clinical tool to assess the effectiveness of rehabilitation and prevention exercise programs.

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Mechanically induced calcium signaling in chondrocytes in situ

Cited by 67 publications

References 53 publications

Integrin α1β1 participates in chondrocyte transduction of osmotic stress

Integrin α1β1 participates in chondrocyte transduction of osmotic stress

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

Muscular loading of joints triggers cellular secretion of PRG4 into the joint fluid

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