Mechanical Cues: Bidirectional Reciprocity in the Extracellular Matrix Drives Mechano-Signalling in Articular Cartilage

Abstract

The composition and organisation of the extracellular matrix (ECM), particularly the pericellular matrix (PCM), in articular cartilage is critical to its biomechanical functionality; the presence of proteoglycans such as aggrecan, entrapped within a type II collagen fibrillar network, confers mechanical resilience underweight-bearing. Furthermore, components of the PCM including type VI collagen, perlecan, small leucine-rich proteoglycans—decorin and biglycan—and fibronectin facilitate the transduction of both biomechanical and biochemical signals to the residing chondrocytes, thereby regulating the process of mechanotransduction in cartilage. In this review, we summarise the literature reporting on the bidirectional reciprocity of the ECM in chondrocyte mechano-signalling and articular cartilage homeostasis. Specifically, we discuss studies that have characterised the response of articular cartilage to mechanical perturbations in the local tissue environment and how the magnitude or type of loading applied elicits cellular behaviours to effect change. In vivo, including transgenic approaches, and in vitro studies have illustrated how physiological loading maintains a homeostatic balance of anabolic and catabolic activities, involving the direct engagement of many PCM molecules in orchestrating this slow but consistent turnover of the cartilage matrix. Furthermore, we document studies characterising how abnormal, non-physiological loading including excessive loading or joint trauma negatively impacts matrix molecule biosynthesis and/or organisation, affecting PCM mechanical properties and reducing the tissue’s ability to withstand load. We present compelling evidence showing that reciprocal engagement of the cells with this altered ECM environment can thus impact tissue homeostasis and, if sustained, can result in cartilage degradation and onset of osteoarthritis pathology. Enhanced dysregulation of PCM/ECM turnover is partially driven by mechanically mediated proteolytic degradation of cartilage ECM components. This generates bioactive breakdown fragments such as fibronectin, biglycan and lumican fragments, which can subsequently activate or inhibit additional signalling pathways including those involved in inflammation. Finally, we discuss how bidirectionality within the ECM is critically important in enabling the chondrocytes to synthesise and release PCM/ECM molecules, growth factors, pro-inflammatory cytokines and proteolytic enzymes, under a specified load, to influence PCM/ECM composition and mechanical properties in cartilage health and disease.

A Progress Report and Roadmap for Microphysiological Systems and Organ-On-A-Chip Technologies to Be More Predictive Models in Human (Knee) Osteoarthritis

“…2% of the total volume of adult articular cartilage) as the sole resident cell type adapted to the low oxygen levels in its environment. Chondrocytes are phenotypically stable, maturationally arrested differentiated cells that maintain tissue homeostasis by synthesizing a very low level of matrix components to replace damaged matrix molecules, thereby preserving the structural integrity of the cartilage matrix ( Goldring et al, 2011 ; Gilbert et al, 2021 ). Within their ECM, chondrocytes are surrounded by a narrow (2–4 μm thick) pericellular matrix (PCM) that is both biochemically and biomechanically (Young’s modulus 23–59 kPa) distinct from the ECM (Young’s modulus ≈500 kPa) and together with the ensconced cells is referred to as a chondron ( Mow and Guo, 2002 ; Guilak et al, 2005 ; Gao et al, 2014 ; Chery et al, 2021 ).…”

“…Within their ECM, chondrocytes are surrounded by a narrow (2–4 μm thick) pericellular matrix (PCM) that is both biochemically and biomechanically (Young’s modulus 23–59 kPa) distinct from the ECM (Young’s modulus ≈500 kPa) and together with the ensconced cells is referred to as a chondron ( Mow and Guo, 2002 ; Guilak et al, 2005 ; Gao et al, 2014 ; Chery et al, 2021 ). The extra- and pericellular matrix zones transmit the depth-dependent dynamic mechanical stimuli, comprising a combination of compression, hydrostatic pressure, shear stress, osmotic stress, and tensile strain, to the mechanosensitive chondrocytes, which in turn adjust cartilage metabolism depending on the magnitude, frequency, strain rate and nature of the applied load ( Natenstedt et al, 2015 ; Gilbert et al, 2021 ; Statham et al, 2021 ). The bidirectional reciprocity in cartilage mechano-signaling enables chondrocytes to sense load application, including altered loading patterns, and in turn adjust matrix composition in response to mechanical cues.…”

“…The PCM has a pivotal role in the bidirectional reciprocity of cartilage mechanosignaling and homeostasis. Moreover, PCM degeneration is one of the earliest events during OA onset, altering the stress-strain microenvironment of chondrocytes leading to aberrant chondrocyte mechanotransduction ( Gao et al, 2014 ; Gilbert et al, 2021 ). Microphysiological systems must start to recreate PCM and ECM compositions and architectures that are seen in actual OA tissues.…”

Natural Compounds Affecting Inflammatory Pathways of Osteoarthritis

“…Therewithal, NO suppresses the synthesis of proteoglycan by preventing the attachment of chondrocytes to fibronectin in the ECM. This will compromise the cell survival, hence causing chondrocyte apoptosis [ 45 ].…”

Release of Matrix-Bound Growth Factors; the role of increase in Sodium Concentration with Cartilage Compression

“…Yet throughout life, the chondrocytes integrate complex and varying extracellular signals to produce and maintain a matrix able to promote joint mobility yet support high and varying mechanical loads. 1 …”