Blockade of acid-sensing ion channels protects articular chondrocytes from acid-induced apoptotic injury

Hu, Wei; Chen, Feihu; Yuan, Feng-Lai; Zhang, Tengyue; Wu, Fan-Rong; Chen, Rong; Jiang, Sheng; Tang, Jie; Zhang, Chengcheng; Lin, Ming‐Fong

doi:10.1007/s00011-011-0414-6

Cited by 51 publications

(43 citation statements)

References 35 publications

(40 reference statements)

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“…This signal transduction chain is in keeping with a recent publication (48) that reports a key role for L-type voltage-gated channels in osteoarthritis, evoked and aggravated by mechanical trauma. We consider it an appealing possibility that the chondrocytic Ca 2+ signal of cartilage traumatic injury impacts chondrocytes' cytoskeleton, energy homeostasis, apoptotic equilibrium, and inflammatory phenotype (15,(62)(63)(64)(65).…”

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.

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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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.

348

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“…Similarly, the ASIC1a-specific blocker PcTX venom attenuated acid-induced articular chondrocyte damage [25]. Furthermore, blocking ASICs markedly decreased calpain and calcineurin expression levels as well as caspase-3/9 activity, and led to recovery of mitochondrial membrane potential via regulation of B-cell lymphoma-2 family gene expression in acid-induced chondrocytes [9,73]. A more recent study reported that interleukin-6 promotes acid-induced articular chondrocyte apoptosis to a significant extent by activating the JAK2/STAT3 and MAPK/NF-κB signaling pathways, resulting in upregulation of ASIC1a expression and function [4].…”

Section: Asics and Arthritismentioning

confidence: 99%

Novel Insights into Acid-Sensing Ion Channels: Implications for Degenerative Diseases

Zhou

Wang³

et al. 2016

Aging and disease

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“…Information on the mechanisms that govern cell responses to mechanical stimuli in IVD is now emerging (38), and the presence of putative mechanoproteins in IVD cells has been recently reported (30). It must be noted that ASIC2 also serves as a mechanoprotein in certain cell types (11,15), and we have observed in this study that it is expressed in the AF and NP cells of healthy IVD and that its expression increased in degenerated IVD.…”

Section: Discussionmentioning

confidence: 83%

“…Blockade of ASICs attenuates articular cartilage destruction in adjuvantinduced arthritis by reducing the increase in intracellular [Ca(2+)]i, whereas ColI and aggrecan mRNA and protein expression were significantly increased (18). Blockade of ASICs in cultured chondrocytes significantly decreased the cell death by reducing acid-induced [Ca(2+)]i rises and inhibiting calpain and calcineurin expression, as well as caspase-3 activity (30). Furthermore, the ASIC blocker, amiloride, inhibited chondrocyte apoptosis in a dosedependent manner by regulating Bcl-2 family gene expression and activity of caspase 3/9 (31).…”

Section: Discussionmentioning

confidence: 93%

“…Although previous studies in rats demonstrated expression of ASIC3 in both the AF and NP (19,20), as far as we know, the expression of ASICs in human IVD is reported here for the first time. ASICs and other ion channels involved in the control of osmolarity and pH are expressed by chondrocytes in different anatomical localizations and animal species (8,17,18,(26)(27)(28)(29)(30)(31)(32), and therefore it can be assumed that they play identical or similar roles in chondrocytes and chondrocyte-related cells as in other cells. Figure 2. (a) Western blot detection of ASIC proteins in homogenates of healthy human intervertebral disc.…”

Section: Discussionmentioning

confidence: 99%

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Acid-sensing ion channels in healthy and degenerated human intervertebral disc

Cuesta¹,

Soto

García‐Suárez³

et al. 2014

Connective Tissue Research

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Acid-sensing ion channels (ASICs) are a family of H(+)-gated voltage-insensitive ion channels that respond to extracellular acidification by regulating transmembrane Ca(2+) flux. Moreover, ASICs can also be gated by mechanical forces and may function as mechanosensors. The cells of the intervertebral disc (IVD) have an unusual acidic and hyperosmotic microenvironment. Changes in the pH and osmolarity determine the viability of IVD cells and the composition of the extracellular matrix, and both are the basis of IVD degeneration. In this study, the expression of ASICs (ASIC1, ASIC2, ASIC3 and ASIC4) mRNAs and proteins in human healthy and degenerated IVD was evaluated by quantitative reverse transcription-quantitative polymerase chain reaction and Western blot. The distribution of ASIC proteins was determined by immunohistochemistry. The mRNAs for all ASICs were detected in normal human IVD, and significantly increased levels were found in degenerated IVD. Western blots demonstrated the presence of proteins with estimated molecular weights of approximately 68-72 kDa. In both the annulus fibrosus (AF) and nucleus pulposus (NP) of normal IVD, ASIC2 is the most frequently expressed ASIC followed by ASIC3, ASIC1 and ASIC4. In the AF of degenerated IVD, there was a significant increase in the number of ASIC1 and ASIC4 positive cells, whereas in the NP, we found significant increase of expression of ASIC1, ASIC2 and ASIC3. These results describe the occurrence and localization of different ASICs in human healthy IVD, and their increased expression in degenerated IVD, thus suggesting that ASICs may be involved in IVD degeneration.

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Blockade of acid-sensing ion channels protects articular chondrocytes from acid-induced apoptotic injury

Abstract: The data presented in this study provided some experimental evidence that blocking ASICs could protect acid-induced apoptotic injury to chondrocytes.

Cited by 51 publications

References 35 publications

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

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

Novel Insights into Acid-Sensing Ion Channels: Implications for Degenerative Diseases

Acid-sensing ion channels in healthy and degenerated human intervertebral disc

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