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Abstract
The joints of mammals are lined with cartilage, comprised of individual chondrocytes embedded in a specialized extracellular matrix. Chondrocytes experience a complex mechanical environment and respond to changing mechanical loads in order to maintain cartilage homeostasis. It has been proposed that mechanically gated ion channels are of functional importance in chondrocyte mechanotransduction; however, direct evidence of mechanical current activation in these cells has been lacking. We have used high-speed pressure clamp and elastomeric pillar arrays to apply distinct mechanical stimuli to primary murine chondrocytes, stretch of the membrane and deflection of cell-substrate contacts points, respectively. Both TRPV4 and PIEZO1 channels contribute to currents activated by stimuli applied at cell-substrate contacts but only PIEZO1 mediates stretch-activated currents. These data demonstrate that there are separate, but overlapping, mechanoelectrical transduction pathways in chondrocytes.
Highlights
In diarthrodial joints, which allow a large degree of movement, the surfaces of the opposing bones are lined with hyaline cartilage which reduces friction
When we treated Trpv4-/- cells with Piezo1-targeting miRNA we found that peak current amplitude (5.2 ± 0.9 pA, n = 7; mean ± s.e.m.) was significantly reduced, in comparison with the WT chondrocytes treated with scrambled miRNA (Student’s t-test, p=0.002)
We have addressed the questions of whether mechanically gated channel activity can be directly measured in primary murine chondrocytes, which channels mediate this process and how the specific type of mechanical stimulus affects mechanoelectrical transduction
Summary
In diarthrodial joints, which allow a large degree of movement, the surfaces of the opposing bones are lined with hyaline cartilage which reduces friction This tissue is avascular and non-innervated and comprised of individual chondrocytes embedded in an extracellular matrix (ECM). Chondrocytes sense changes in the physical microenvironment and mechanical loading within the joints and adjust the balance of anabolic and catabolic processes to maintain the integrity and physical properties of the ECM (Buckwalter and Mankin, 1997a; Goldring and Marcu, 2009) Disrupting these homeostatic processes can lead to osteoarthritis (OA) whereby inappropriate activation of catabolic pathways leads to cartilage degradation (Buckwalter and Mankin, 1997b). It is important to define how chondrocytes respond to mechanical stimuli and to understand how the sensitivity of the mechanotransduction pathways is modulated as both excessive and insufficient mechanical loading of the joint can lead to joint dysfunction
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