The emerging chondrocyte channelome

Barrett‐Jolley, Richard; Lewis, Rebecca; Fallman, Rebecca; Mobasheri, Ali

doi:10.3389/fphys.2010.00135

Cited by 109 publications

(125 citation statements)

References 148 publications

(184 reference statements)

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“…The contributions of ion channels to cell proliferation of chondrocytes have been discussed (Wu and Chen, 2000;Wohlrab et al, 2001;Barrett-Jolley et al, 2010;Mobasheri et al, 2012). A corresponding moderate increase in [Ca 21 ] i promotes cell proliferation whereas larger, maintained [Ca 21 ] i increases cause cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Various types of ion channels have been identified on the plasma membrane in mammalian chondrocytes: voltage-dependent Na 1 channels, epithelial Na 1 channels, voltage-dependent Ca 21 channels, voltage-dependent K 1 channels, Ca 21 -dependent K 1 channels, ATP-sensitive K 1 channels, transient receptor potential channels, aquaporin water channels, N-methyl-D-aspartate receptor channels, and Cl 2 channels (Barrett-Jolley et al, 2010;Mobasheri et al, 2012). In articular chondrocytes, voltage-dependent K 1 channels and two-pore domain K 1 channels contribute to the maintenance of the resting membrane potential (Wilson et al, 2004;Clark et al, 2011;Mobasheri et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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The ClC-7 Chloride Channel Is Downregulated by Hypoosmotic Stress in Human Chondrocytes

et al. 2015

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Articular chondrocytes in osteoarthritis (OA) patients are exposed to hypoosmotic stress because the osmolality of this synovial fluid is significantly decreased. Hypoosmotic stress can cause an efflux of Cl 2 and an associated decrease of cell volume. We have previously reported that a Cl 2 conductance contributes to the regulation of resting membrane potential and thus can alter intracellular Ca 21 concentration ([Ca 21 ] i ) in human chondrocytes. The molecular identity and pathologic function of these Cl 2 channels, however, remained to be determined. Here, we show that the ClC-7 Cl 2 channel is strongly expressed in a human chondrocyte cell line (OUMS-27) and that it is responsible for Cl 2 currents that are activated by extracellular acidification (pH 5.0). These acid-sensitive currents are inhibited by 4,4ʹ-diisothiocyanatostilbene-2,2ʹ-disulfonic acid (DIDS; IC 50 5 13 mM) and are markedly reduced by small-interfering RNA-induced knockdown of ClC-7. DIDS hyperpolarized these chondrocytes, and this was followed by an increase in [Ca 21 ] i . ClC-7 knockdown caused a similar hyperpolarization of the membrane potential. Short-term culture (48 hours) in hypoosmotic medium (270 mOsm) reduced the expression of ClC-7 and decreased the acid-sensitive currents. Interestingly, these hypoosmotic culture conditions, or ClC-7 knockdown, resulted in enhanced cell death. Taken together, our results show that the significant hyperpolarization due to ClC-7 impairment in chondrocytes can significantly increase [Ca 21 ] i and cell death. Thus, downregulation of ClC-7 channels during the hypoosmotic stress that accompanies OA progression is one important concept of the complex etiology of OA. These findings suggest novel targets for therapeutic intervention(s) and drug development for OA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The ClC-7 Chloride Channel Is Downregulated by Hypoosmotic Stress in Human Chondrocytes

et al. 2015

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“…There appear to be multiple, functionally specific mechanisms of mechanical signal transduction in this nonneural cell type. Functional expression of TRPV4 and PIEZO1/2 (and potentially other channels) (55,56) in articular chondrocytes allow cells to respond to the continuum of mechanical loads in cartilage. The findings of this study, together with those in the literature, suggest that chondrocyte mechanosensation involves an integrated set of pathways that may also include transmission of pericellular mechanical and osmotic signals to the cell and nucleus via integrins and various cytoskeletal components (17,(57)(58)(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

Lee¹,

Leddy²,

Chen³

et al. 2014

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

367

348

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Diarthrodial joints are essential for load bearing and locomotion. Physiologically, articular cartilage sustains millions of cycles of mechanical loading. Chondrocytes, the cells in cartilage, regulate their metabolic activities in response to mechanical loading. Pathological mechanical stress can lead to maladaptive cellular responses and subsequent cartilage degeneration. We sought to deconstruct chondrocyte mechanotransduction by identifying mechanosensitive ion channels functioning at injurious levels of strain. We detected robust expression of the recently identified mechanosensitive channels, PIEZO1 and PIEZO2. Combined directed expression of Piezo1 and -2 sustained potentiated mechanically induced Ca 2+ signals and electrical currents compared with single-Piezo expression. In primary articular chondrocytes, mechanically evoked Ca 2+ transients produced by atomic force microscopy were inhibited by GsMTx4, a PIEZO-blocking peptide, and by Piezo1-or Piezo2-specific siRNA. We complemented the cellular approach with an explant-cartilage injury model. GsMTx4 reduced chondrocyte death after mechanical injury, suggesting a possible therapy for reducing cartilage injury and posttraumatic osteoarthritis by attenuating Piezo-mediated cartilage mechanotransduction of injurious strains.A rticular cartilage is a hydrated connective tissue that supports loads and minimizes friction in the diarthrodial joints. It has a highly differentiated extracellular matrix (ECM) composed primarily of type II collagen, the large aggregating proteoglycan, aggrecan, and water. Chondrocytes are the only cells in cartilage and are responsible for maintaining and remodeling cartilage through a homeostatic balance of anabolic and catabolic activities. Under normal physiologic conditions, chondrocytes are exposed to millions of cycles of mechanical loading per year (1). These mechanical signals play an important role in regulating chondrocyte anabolic and biosynthetic activity, as evidenced by cartilage atrophy following periods of disuse or immobilization (2-7). However, under abnormal loading conditions (e.g., due to obesity, trauma, or joint instability), mechanical factors play a critical role in the onset and progression of osteoarthritis (1). Such "injurious" loading has been modeled in vitro using explant culture systems that replicate many of the early cellular and molecular events characteristic of osteoarthritis (8). Osteoarthritis is a painful and debilitating disease of weight-bearing joints that affects over 26 million people in the United States (9) with posttraumatic arthritis being responsible for ∼12% of the incidence of osteoarthritis (10).Despite the critical importance of mechanical loading in health and disease of synovial joints, the mechanisms of mechanotransduction of chondrocytes are not fully understood and are likely to differ under physiologic and pathologic conditions (11)(12)(13)(14). Although many different mechanisms have been shown to be involved in chondrocyte mechanotransduction (13,(15)(16)(17), recent st...

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“…Chondrocytes are surrounded by a pericellular matrix and are situated in cavities called lacunae within the ECM, where they exist in a hypoxic micro-environment [3,4] and control ECM turnover and homeostasis in response to mechanical loading [5] despite having a rather slow (mainly anaerobic) metabolism. Due to the fact that chondrocytes reside within the peculiar milieu of the ECM (which is acidic, hypertonic and hyperosmotic [6][7][8]), and since their function and differentiation is strongly dependent on intracellular calcium homeostasis [9,10], they deploy a whole range of ion channels to enable ion transport across the plasma membrane; the collection of ion channels is referred to as the chondrocyte 'channelome' [11]. Albeit generally considered to be non-excitable cells, chondrocytes and chondroprogenitor cells have been reported to express various voltage-dependent potassium channels (KV), ATP dependent potassium channels (KATP), large and small conductance calcium-activated potassium channels (BK and SK), transient receptor potential channels (primarily TRPV1 and TRPV4), purinergic receptors (both P2X and P2Y subfamily members), voltage gated and epithelial sodium channels, chloride channels, and also voltage-dependent calcium channels (VDCCs) [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

2015

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Chondrocytes, the single cell type in adult articular cartilage, have conventionally been considered to be non-excitable cells. However, recent evidence suggests that their resting membrane potential (RMP) is less negative than that of excitable cells, and they are fully equipped with channels that control ion, water, and osmolyte movement across the chondrocyte membrane. Among calcium-specific ion channels, members of the voltage-dependent calcium channel (VDCC) family are expressed in chondrocytes where they are functionally active. Ltype VDCC inhibitors such as nifedipine and verapamil have contributed to our understanding of the roles of these ion channels in chondrogenesis, chondrocyte signalling, and mechanotransduction. In this narrative review, we discuss published data indicating that VDCC function is vital for chondrocyte health, especially in regulating proliferation and maturation.We also highlight the fact that activation of VDCC function appears to accompany various inflammatory aspects of osteoarthritis (OA) and, based on in vitro data, the application of nifedipine and/or verapamil may be a promising approach for ameliorating OA severity.However, very few studies on clinical outcomes are available regarding the influence of calcium antagonists, which are used primarily for treating cardiovascular conditions in OA patients. This review is intended to stimulate further research on the chondrocyte 'channelome', contribute to the development of novel therapeutic strategies, and facilitate the retargeting and repositioning of existing pharmacological agents currently used for other comorbidities for the treatment of OA.

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The emerging chondrocyte channelome

Cited by 109 publications

References 148 publications

The ClC-7 Chloride Channel Is Downregulated by Hypoosmotic Stress in Human Chondrocytes

The ClC-7 Chloride Channel Is Downregulated by Hypoosmotic Stress in Human Chondrocytes

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

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