Integrins, cadherins and channels in cartilage mechanotransduction: perspectives for future regeneration strategies

Abstract

Articular cartilage consists of hyaline cartilage, is a major constituent of the human musculoskeletal system and has critical functions in frictionless joint movement and articular homoeostasis. Osteoarthritis (OA) is an inflammatory disease of articular cartilage, which promotes joint degeneration. Although it affects millions of people, there are no satisfying therapies that address this disease at the molecular level. Therefore, tissue regeneration approaches aim at modifying chondrocyte biology to mitigate the consequences of OA. This requires appropriate biochemical and biophysical stimulation of cells. Regarding the latter, mechanotransduction of chondrocytes and their precursor cells has become increasingly important over the last few decades. Mechanotransduction is the transformation of external biophysical stimuli into intracellular biochemical signals, involving sensor molecules at the cell surface and intracellular signalling molecules, so-called mechano-sensors and -transducers. These signalling events determine cell behaviour. Mechanotransducing ion channels and gap junctions additionally govern chondrocyte physiology. It is of great scientific and medical interest to induce a specific cell behaviour by controlling these mechanotransduction pathways and to translate this knowledge into regenerative clinical therapies. This review therefore focuses on the mechanotransduction properties of integrins, cadherins and ion channels in cartilaginous tissues to provide perspectives for cartilage regeneration.

The Role of Mechanically-Activated Ion Channels Piezo1, Piezo2, and TRPV4 in Chondrocyte Mechanotransduction and Mechano-Therapeutics for Osteoarthritis

“…Inflammation also affects the cytoskeleton, particularly filamentous actin (F-actin), as force transduction through F-actin is important in chondrocyte mechanotransduction ( Wang et al, 1993 ; Haudenschild et al, 2008 ; Trompeter et al, 2021b ; Dieterle et al, 2021 ). With exposure to IL-1α, F-actin of primary chondrocytes was reduced—an effect that was also seen in human OA cartilage samples.…”

Potential Therapeutic Applications of N-Cadherin Antagonists and Agonists

“…Most N-cadherin agonists contain the N-cadherin CAR sequence, HAV ( Utton et al, 2001 ; Williams et al, 2002 ; Skaper et al, 2004 ; Feng et al, 2020 ; Zhang et al, 2020 ; Dieterle et al, 2021 ). For example, the soluble cyclic peptide N-Ac-CHAVDINGHAVDIC-NH2 has been shown to be such an agonist ( Williams et al, 2002 ; Skaper et al, 2004 ).…”

“…Peptides containing the HAV sequence can be attached to scaffolds (e.g., methacrylated hyaluronic acid hydrogels) to form biomaterials that are able to act as N-cadherin agonists in vitro and in vivo ( Bian et al, 2013 ; Feng et al, 2020 ; Zhang et al, 2020 ; Dieterle et al, 2021 ; Kaur and Roy 2021 ; Zhu et al, 2021 ). For example, human MSC displaying N-cadherin can be induced to enter chondrogenesis by culturing them in HAV-containing hydrogels ( Li et al, 2017 ).…”

Mechanoregulatory role of TRPV4 in prenatal skeletal development

“…Mechanical loading of skeletal tissues exposes cells to multiple modes of stress, such as compression, tension, hydrostatic pressure, osmotic pressure and fluid shear. In a process called mechanotransduction, biophysical cues are detected by specialized mechanosensors that convert them into biochemical signals, consequently regulating cell behaviour (Dieterle et al, 2021; Lewis et al, 2017; Liedtke & Kim, 2005). Cell membrane mechanosensors detect physical changes at the cell membrane, such as integrins which sense cell-matrix interactions through focal adhesions with the substrate (Wang et al, 1993), cadherins which transduce cell-cell interactions (Wang et al, 2009), and mechanosensitive ion channels which activate in response to physical changes in the membrane such as tension (Syeda et al, 2016), hypotonicity (Liedtke & Friedman, 2003), deflection of cell-matrix focal adhesions (Servin-Vences et al, 2017) and deflection of the primary cilia (Corrigan et al, 2018).…”