Mechanosensory and mechanotransductive processes mediated by ion channels in articular chondrocytes: Potential therapeutic targets for osteoarthritis

Abstract

Articular cartilage consists of an extracellular matrix including many proteins as well as embedded chondrocytes. Articular cartilage formation and function are influenced by mechanical forces. Hind limb unloading or simulated microgravity causes articular cartilage loss, suggesting the importance of the healthy mechanical environment in articular cartilage homeostasis and implying a significant role of appropriate mechanical stimulation in articular cartilage degeneration. Mechanosensitive ion channels participate in regulating the metabolism of articular chondrocytes, including matrix protein production and extracellular matrix synthesis. Mechanical stimuli, including fluid shear stress, stretch, compression and cell swelling and decreased mechanical conditions (such as simulated microgravity) can alter the membrane potential and regulate the metabolism of articular chondrocytes via transmembrane ion channel-induced ionic fluxes. This process includes Ca 2+ influx and the resulting mobilization of Ca 2+ that is due to massive released Ca 2+ from stores, intracellular cation efflux and extracellular cation influx. This review brings together published information on mechanosensitive ion channels, such as stretch-activated channels (SACs), voltage-gated Ca 2+ channels (VGCCs), large conductance Ca 2+ -activated K + channels (BK Ca channels), Ca 2+ -activated K + channels (SK Ca channels), voltage-activated H + channels (VAHCs), acid sensing ion channels (ASICs), transient receptor potential (TRP) family channels, and piezo1/2 channels. Data based on epithelial sodium channels (ENaCs), purinergic receptors and N-methyl-d-aspartate (NMDA) receptors are also included. These channels mediate mechanoelectrical physiological processes essential for converting physical force signals into biological signals. The primary channel-mediated effects and signaling pathways regulated by these mechanosensitive ion channels can influence the progression of osteoarthritis during the mechanosensory and mechanoadaptive process of articular chondrocytes.

Computational and experimental studies of a cell-imprinted-based integrated microfluidic device for biomedical applications

“…Excessive activation of the Piezo1 ion channel, which can sense mechanical stimulus too, can cause apoptosis and mechanical injury. When a high-strain mechanical load is transferred to chondrocytes, which may cause injury, Piezo1 channel protein is activated, whereas low-strain physiologic loading is mediated by TRPV4 [73][74][75][76][77][78] . One of the earliest responses of chondrocytes to physical stimulus is [Ca 2+ ] i signaling.…”

L‐type Voltage‐Gated calcium channels partly mediate Mechanotransduction in the intervertebral disc

“…In bovine cells, the complete inhibition of calcium influx provides further support to the physiological role of these channels. As hypotonic solution causes membrane depolarization in healthy human chondrocytes but fails to do so in degenerate chondrocytes, 63 IL‐1 was introduced to model a degenerate environment in monolayer for this study, as done previously. 28 , 36 However, IL‐1 supplementation alone caused no observable effect in calcium influx in human cells and had the opposite effect in bovine cells, causing an increase in calcium influx in response to an osmotic and, potentially, fluid‐induced shear stress (by media injection) load.…”

TRPV4 and PIEZO Channels Mediate the Mechanosensing of Chondrocytes to the Biomechanical Microenvironment

“…TRPV4 channels, first cloned repeatedly by following hypotonicity-induced Ca 2+ signals, have been implicated in a wide variety of mechanosensory processes [30,31]. TRPV4 is a nonselective cation channel that is calcium permeable and shows polymodal activation by diverse mechanical stimuli including substrate elastic and viscoelastic, cell swelling, and dynamic strain [32,33]. Distinct from Piezo1, TRPV4 channels play prominent roles in regulating the intracellular Ca 2+ concentration in nonexcitable cells.…”