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Hedi Raizer

Journal 6 min read

Common misconceptions about the extracellular matrix

The extracellular matrix is not inert scaffolding. Research in animal and in vitro models shows it is a dynamic, mechanically active signalling compartment, and several widely repeated claims about it do not hold up.

peptides-pro Editorial

The extracellular matrix (ECM) is the non-cellular, secreted network of proteins and polysaccharides that occupies the space between cells in solid tissues; it is also referred to as the extracellular matrix compartment, the interstitial matrix, or, where it underlies epithelia, the basement membrane. It is a structural class rather than a single molecule, and it has no single sequence, formula or molecular weight — its composition varies by tissue and by disease state. Individual constituents do carry identifiers: fibronectin is a large multidimeric glycoprotein, periostin (POSTN) is a secreted matricellular protein, and collagen, fibronectin and periostin are among the most studied ECM components in the literature surveyed here [1][2][8].

Much of the mechanistic work on ECM signalling centres on integrin receptors and their downstream kinase cascades, with integrin–JNK signalling appearing repeatedly as the route by which matrix proteins are reported to alter cell behaviour [2].

Research Studies

Periostin and integrin–JNK–RIP3–MLKL signalling in arrhythmogenic cardiomyopathy models

Periostin was reported to be significantly elevated in myocardium from arrhythmogenic cardiomyopathy (ACM) mice and from patients with the condition. In ACM mice, periostin deficiency alleviated heart dysfunction, reduced cardiac fibrosis and improved survival. The protein was found to be derived mainly from cardiac myofibroblasts, and it promoted cardiomyocyte necroptosis both in vivo and in vitro. Mechanistically, periostin was reported to drive necroptosis through integrin–JNK–RIP3–MLKL signalling, and to induce CCL3 expression through an integrin–JNK–ETS2 pathway; CCL3 in turn activated cardiac macrophages, forming a feedforward loop [2].

Fibronectin tension as a mechanical signature in idiopathic pulmonary fibrosis models

An in vitro fibrosis assay using patient-derived fibroblasts and the tension-sensitive fibronectin-binding peptide FnBPA5 was established to test whether ECM fibre tension tracks with fibrosis progression. Multivalent binding of the peptide to fibronectin was impaired by fibre strain, and the system was validated against known fibrosis biomarkers at the protein and mRNA levels [8]. This is an in vitro model system; it does not establish that the same readout behaves identically in intact human lung.

Apabetalone and fibrotic activation of cardiac fibroblasts

Accumulation of ECM causes tissue fibrosis that contributes to myocardial dysfunction and heart failure, and no approved anti-fibrotic therapeutic targets it directly. BET protein inhibitors had reduced fibrosis in preclinical heart failure models, and the clinical-stage BET inhibitor apabetalone reduced hospitalisations for heart failure in a phase 3 trial. Apabetalone was tested for anti-fibrotic activity in human immortalised cardiac fibroblasts, cryopreserved cardiac fibroblasts, and ex vivo cultured fibroblasts from patients undergoing bypass grafting [3]. The mechanistic picture remains incomplete.

MAFF and contraction-induced transcription in skeletal muscle

MAFF, a small MAF transcription factor, was consistently induced by acute exercise in both human and mouse skeletal muscle, with induction restricted to muscles recruited by the exercise modality used. In C2C12 cells, Maff was induced by an in vitro electrical pulse stimulation model. CRISPR/Cas9-mediated Maff knockout C2C12 cells showed reduced myogenic fusion with accumulation of unfused nuclei, and RNA sequencing revealed broad reprogramming in Maff-deficient myotubes [4]. This work concerns muscle transcriptional adaptation rather than matrix turnover directly, but it is frequently cited in matrix-remodelling discussions.

Fibronectin matrix assembly in astrocytes versus fibroblasts

Fibrillar fibronectin matrix is the predominant ECM in most tissues, but in neural tissues it is limited to sites of tissue damage and disease. Primary cortical astrocytes were shown to produce fibronectin and assemble it into fibrils through a process that differs from the assembly behaviour of fibroblasts, indicating that cell type shapes how the same matrix protein is deposited [12].

Graphene oxide–hydroxyapatite composites and ECM protein interactions at implant interfaces

Graphene oxide has strong protein-binding ability attributed to its high surface area and oxygen functional groups, but is limited by dose-dependent cytotoxicity; hydroxyapatite is highly biocompatible but shows relatively weak protein–protein interactions at the molecular scale. Molecular docking, pharmacophore modelling and molecular dynamics simulations were used to explore interactions of graphene oxide, hydroxyapatite and graphene oxide–hydroxyapatite nanocomposites with ECM proteins in the context of dental implant osseointegration [6]. These are computational and materials-science findings, not clinical outcomes.

BDNF and intervertebral disc degeneration

BDNF expression has been confirmed within intervertebral disc tissue, with degenerated discs showing increased BDNF expression compared with normal discs, and expression reported to increase further with degeneration severity. Intervertebral disc degeneration is closely associated with intradiscal nerve ingrowth. A registered study is examining correlations between serum BDNF levels, Pfirrmann grading and IL-1β [5]. This is a study record; it does not by itself establish a causal role for BDNF in disc degeneration.

Matrix metalloproteinases and related targets in skin biology

A review of molecular targets in cosmetic science lists matrix metalloproteinases alongside telomerase, histone deacetylases (particularly sirtuins), antioxidant enzymes, CD44 receptor, tyrosinase, microphthalmia-associated transcription factor and melanocortin receptors as regulators of DNA repair, gene expression and extracellular matrix processes relevant to skin ageing, pigmentation, inflammation and tissue regeneration [7]. This is a review of targets, not a body of controlled outcome data.

Bone ageing as multiscale matrix degeneration

Bone ageing is described not merely as bone mass loss but as a multi-level, networked degenerative phenomenon spanning molecular, cellular, tissue and system levels. At the macroscopic level it is characterised by declines in bone mass, microstructure and biomechanical properties [1]. This framing is relevant because it treats the matrix as one layer in a coupled system rather than as an isolated scaffold.

Comparison of selected ECM-related findings

Model / systemKey moleculeReported observationEvidence level
ACM mouse myocardium and patient tissuePeriostin (POSTN)Elevated; deficiency alleviated dysfunction and fibrosis in miceAnimal and human tissue; in vitro mechanism [2]
Patient-derived fibroblast fibrosis assayFibronectinFibre tension tracked with fibrosis progressionIn vitro [8]
Human cardiac fibroblasts (immortalised, cryopreserved, ex vivo)BET proteinsApabetalone suppressed fibrotic activationCell models; phase 3 trial data referenced [3]
C2C12 myotubes and human/mouse muscleMAFFInduced by exercise and electrical pulse stimulation; knockout reduced myogenic fusionHuman and mouse tissue; cell line [4]
Primary cortical astrocytes vs fibroblastsFibronectinAstrocytes assemble fibronectin fibrils by a distinct processIn vitro [12]

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