The CECM is cartilage’s hidden engine. Its principal constituents include collagen, proteoglycans, and glycosaminoglycans, each performing a specialized role. Type II collagen, the predominant collagen form, provides the tissue with strength and toughness, maintaining cartilage architecture under constant mechanical demand. Proteoglycans, studded with hydrophilic glycosaminoglycan side chains, attract and retain water molecules, allowing cartilage to withstand compressive loads and absorb impact forces. Beyond physical support, the matrix actively participates in intercellular signalling, harbouring growth factors and cytokines that orchestrate chondrocyte proliferation, differentiation, and metabolic activity. Under physiological conditions, matrix synthesis and degradation remain in dynamic equilibrium, with transforming growth factor-β promoting synthesis and preserving cartilage integrity. Osteoarthritis disrupts this equilibrium, triggering hyperactivation of matrix-degrading enzymes, substantial loss of crucial matrix components, and initiation of pathological cascades that feed on themselves.

Mechanical forces are among the chief provocateurs. Chondrocytes sense mechanical loading through an array of mechanosensitive receptors and ion channels on their cell membranes, and the review highlights two channels with opposite personalities. Transient Receptor Potential Vanilloid 4, or TRPV4, is activated by physiological levels of mechanical loading and promotes chondrogenic gene expression and cartilaginous matrix production. Piezo1, by contrast, is preferentially activated by supraphysiologic or excessive mechanical deformation and drives catabolic responses, cell death, and senescence. Excessive mechanical stress upregulates Piezo1 expression, which activates the PI3K/AKT/mTORC1 pathway, reducing synthesis of type II collagen and aggrecan while promoting matrix degradation. Piezo1 channels also increase calcium influx and trigger ferroptosis, an iron-dependent form of cell death, via the same signalling axis. Meanwhile, integrins αVβ3 and αVβ5 on the chondrocyte surface translate abnormal mechanical cues through phosphorylation of Focal Adhesion Kinase and Mitogen-Activated Protein Kinases, upregulating interleukin-1β, tumour necrosis factor-α, and the matrix metalloproteinases MMP-3 and MMP-13. This integrin-FAK-MAPK mechanotransduction cascade represents a key axis linking abnormal loading to cartilage destruction.

The review also reveals a vicious cycle at the heart of the disease. The TRPV4-GSK3β signalling axis is impaired in osteoarthritic chondrocytes, rendering these cells unable to sense and respond to changes in matrix viscoelasticity. Aberrant mechanotransduction activates catabolic signalling and promotes matrix degradation, which in turn alters the mechanical microenvironment and further impairs chondrocyte mechanosensing, ultimately accelerating degradation and disease progression. The composition and structure of the matrix undergo profound alterations, including increased degradation of type II collagen and reduced proteoglycan content, diminishing cartilage hydrophilicity and shock-absorbing capacity. These changes impair load-bearing and cushioning functions, trigger abnormal remodelling of the subchondral bone, promote osteophyte formation, and further alter the lower-limb biomechanical environment, establishing a self-reinforcing loop that drives progression.

Beyond mechanics, the review documents a complex web of biological alterations. Matrix degradation is predominantly driven by increased expression of matrix metalloproteinases and ADAMTS enzymes. The damage-associated molecular pattern HMGB1, via activation of the PI3K/AKT/GSK-3β/β-catenin signalling pathway, significantly upregulates MMP-2, MMP-3, MMP-9, MMP-13, ADAMTS4, and ADAMTS5, inducing chondrocyte apoptosis and promoting pathological differentiation. Multiple programmed cell death modalities are deeply involved. Pyroptosis, mediated by caspase-1 activation, leads to cell rupture and massive release of IL-1β and IL-18, profoundly exacerbating inflammation. The microRNA miR-107 acts as a pivotal negative regulator, and its downregulation relieves inhibition on caspase-1, triggering pyroptosis and accelerating type II collagen degradation. Ferroptosis represents another significant mechanism: downregulation of the endoplasmic reticulum-resident protein Selenoprotein M activates the PERK/EIF2α/ATF4 signalling pathway, upregulating CHAC1, which depletes intracellular glutathione and induces ferroptosis. Autophagy, a crucial mechanism for maintaining intracellular homeostasis, is functionally impaired in osteoarthritic chondrocytes. Proteomic analysis identified significant upregulation of the small GTPase Rab1a, which activates the mTORC1-S6K signalling pathway, inhibiting key autophagy initiation complexes such as the ULK1 complex and potently suppressing autophagic flux. Conversely, targeted inhibition of Rab1a activates autophagy and delays disease progression.

Cellular senescence and oxidative stress further compound the crisis. Fibroblast activation protein is highly expressed in osteoarthritic cartilage and promotes release of senescence-associated secretory phenotype factors by activating the NF-κB pathway, accelerating matrix degradation. Activity of the nuclear deacetylase SIRT6 is significantly reduced in senescent chondrocytes, suppressing insulin-like growth factor-1 and impairing downstream Akt signalling, leading to decreased synthesis of key matrix components such as COL2A1. Excessive accumulation of reactive oxygen species directly damages collagen and proteoglycans, activates matrix-degrading enzymes while inhibiting their synthesis, and triggers chondrocyte apoptosis. Sex-specific differences add another layer of complexity. Transcriptomic analyses of human articular cartilage revealed fundamental molecular distinctions between male and female tissue: healthy female and male cartilage exhibit 36 differentially expressed genes, while in the osteoarthritic state, female cartilage displays 923 differentially expressed genes enriched in 15 signalling pathways compared with only 419 genes in 6 pathways in male cartilage. Loss of 17β-estradiol and progesterone in menopause amplifies chondrocyte senescence and matrix disassembly, while hormone supplementation reduces senescence markers and increases chondrogenic markers, underscoring the necessity of incorporating sex as a critical biological variable in future research and therapeutic development.

The review also highlights a sobering intrinsic risk factor: the low-turnover nature of cartilage collagen matrix renders it nearly incapable of effective regeneration following injury. Using in vivo deuterium oxide labelling to quantitatively analyse collagen renewal rates in patients with late-stage knee osteoarthritis, researchers found that despite differing regional mechanical environments, the fractional synthesis rate of collagen was extremely low in both central weight-bearing and meniscus-covered areas, at 0.027% per day and 0.022% per day respectively. This severe failure in chondrocyte collagen synthesis capacity implies that even minor damage to the collagen network is likely irreversible, substantially compromising structural integrity and mechanical function. External factors such as trauma and obesity increase risk by adversely affecting both matrix metabolism and mechanical properties, while calcification regulated by Krüppel-like factor 10 and aberrant expression of genes like TSG-6 further compromise homeostasis.

On the diagnostic front, the review evaluates both fluid and imaging biomarkers for dynamic monitoring. Degradation products such as cartilage oligomeric matrix protein are significantly elevated in serum and synovial fluid of patients and correlate with disease severity, with meta-analyses substantiating diagnostic utility and elevated baseline levels associated with increased risk of radiographic progression over two to three years. Type II collagen degradation products such as uCTX-II show positive correlation with joint tissue damage, with elevated levels conferring a two- to three-fold increased odds of progression. Non-coding RNAs involved in regulating matrix metabolism show considerable potential, with miR-449a promoting degradation by targeting GDF5 and preliminary analyses demonstrating encouraging discriminative performance for differentiating disease grades. Quantitative magnetic resonance imaging techniques enable non-invasive evaluation of cartilage biochemical composition and subchondral bone microarchitecture. T2 mapping sequences measure tissue relaxation times to reflect collagen fibre network integrity and water content, with elevated T2 values indicating collagen network disruption and serving as a sensitive indicator of early matrix degeneration. Subchondral trabecular parameters measured as early as three months postoperatively effectively predicted superior graft morphology and less severe whole-joint degenerative changes at two-year follow-up. Critically, integration of imaging metrics with fluid biomarkers yields synergistic predictive value for mid-term clinical outcomes, bridging molecular perturbations with their structural consequences.

Therapeutically, the review maps a multi-tiered arsenal. Pharmacological treatment has evolved from traditional symptom relief toward multi-targeted and refined modulation. High-purity, microbially-derived chondroitin sulphate produced via biotechnology demonstrated superior potential in experimental models compared to traditional animal-derived formulations. Natural products with clearly defined mechanisms include the flavonoid casticin, which inhibits the PI3K/AKT/HIF-1α pathway while promoting COL2A1 and aggrecan synthesis and inhibiting MMP-9, MMP-13, and ADAMTS4/5. The polysaccharide from Polygonatum sibiricum targets TLR2 as a key receptor, inhibiting the TLR2/NF-κB axis. The terpenoid curcumenol directly targets the histone demethylase KDM6B, inhibiting H3K27me3 modification and downregulating succinic acid levels. The coumarin compound osthole enhances autophagic flux by activating the AMPK/ULK1 signalling pathway. Traditional Chinese Medicine effective fractions such as Total Glucosides of White Peony Capsule possess dual cartilage-bone protective mechanisms, inhibiting NF-κB while modulating the OPG/RANKL/RANK system to ameliorate abnormal subchondral bone remodelling. Novel agents include three bioactive deer antler peptides identified from the classical formulation Guilu Erxian Jiao, which demonstrated chondroprotective effects comparable or superior to hyaluronic acid in a collagenase-induced rat model.

Regenerative medicine, gene therapy, and smart biomaterials round out the therapeutic landscape. Stem cell transplantation primarily regulates chondrocyte function and matrix metabolism through paracrine effects, with mesenchymal stem cells, adipose-derived stem cells, and Nanofat demonstrating efficacy in preclinical models and early clinical applications. Biomaterial carriers such as gelatin microspheres loaded with Wharton’s jelly-derived mesenchymal stem cells significantly promoted cartilage matrix synthesis and modulated synovial macrophage polarization toward the M2 phenotype. Gene editing using CRISPR/Cas9 to target Rps6ka2 highlighted the potential of optimizing matrix synthesis through genetic optimization. Epigenetic regulation with the SIRT6 agonist MDL-800 promoted Akt phosphorylation and activated anabolic signalling. RNA interference delivered via lipid nanoparticles loaded with FAP siRNA significantly reduced FAP expression in cartilage, inhibited cellular senescence, and alleviated cartilage degeneration and synovitis. Engineered cell therapy with TissueGene-C remodels the immune microenvironment through continuous TGF-β1 secretion, driving M2 macrophage polarization. In a Phase I clinical trial, LNA043, a derived protein targeting integrin α5β1, significantly reversed osteoarthritis-related gene expression patterns, positioning it as a promising disease-modifying candidate. Tissue engineering strategies utilizing functionalized biomaterials, including MXene hydrogels that scavenge reactive oxygen species under near-infrared irradiation, biomimetic bilayered scaffolds, and sustained-release nano-systems, accomplish a transition from passive filling to active regeneration. An aragonite-based biphasic scaffold evaluated in a prospective multicenter study of 86 patients followed for two years revealed a defect fill rate of 78.7% with histology confirming formation of type II collagen-positive hyaline-like cartilage. These strategies demonstrate significant cross-integration trends, exemplified by stem cell-biomaterial composite systems and drug-gene co-delivery platforms, with their collective objective being precise regulation of the dynamic balance between matrix synthesis and degradation, offering potential therapeutic prospects for delaying or even reversing disease progression.

Subject of Research: Knee osteoarthritis research

Article Title: Cartilage Extracellular Matrix Homeostasis in Knee Osteoarthritis: Pathomechanisms and Therapeutic Targeting

Article References: Du, C., Zhong, J., Yang, J., Huang, Y., Liu, Q., Cao, D., Guo, T., Wang, J., & Liu, A. (2026). Cartilage Extracellular Matrix Homeostasis in Knee Osteoarthritis: Pathomechanisms and Therapeutic Targeting. Journal of Cellular and Molecular Medicine, 30(19), Article e71384. https://doi.org/10.1111/jcmm.71384

Image Credits: AI Generated

DOI: 10.1111/jcmm.71384

Keywords: Cartilage, Extracellular, Matrix, Homeostasis, Knee, Osteoarthritis, Pathomechanisms, Therapeutic, Targeting, scientific research