Metabolic Dynamics in Osteoarthritis Pathogenesis

Osteoarthritis is increasingly recognised as a metabolic disease of the joint rather than a purely mechanical “wear-and-tear” condition. Chondrocytes adapt their energy production pathways in response to inflammation, hypoxia and mechanical stress. Early in disease onset, cells shift from oxidative phosphorylation to glycolysis, supporting rapid ATP generation but at the cost of increased acidification, reactive oxygen species and senescence. Concurrently, dysregulated lipid metabolism and de novo lipogenesis drive extracellular matrix breakdown through enhanced matrix-degrading enzyme activity. Mitochondrial quality control, via mitophagy and renewal, emerges as a central mechanism preserving chondrocyte homeostasis. Perturbations in post-translational modifications, such as SUMOylation and acetylation, further modulate the stability of key metabolic enzymes. Collectively, these imbalances in energy production, biosynthesis and redox homeostasis interconnect to promote chondrocyte hypertrophy, inflammation and cartilage degradation. Understanding these dynamic metabolic networks opens avenues for targeted interventions that restore energy balance, reduce oxidative damage and maintain cartilage integrity on a global scale.

Research from Nature Portfolio

Recent studies have elucidated how circular RNAs regulate lipid pathways in cartilage. One report demonstrates that a highly expressed circRNA stabilises fatty acid synthase, amplifying lipid accumulation, senescence and matrix breakdown via PI3K–AKT signalling, and that local depletion reverses osteoarthritic progression in animal models. Another investigation identifies a nuclear receptor-driven axis that suppresses excessive de novo lipogenesis by controlling acetyl-CoA availability; genetic restoration of the downstream hydrolase in disease models rescues cartilage homeostasis and curtails matrix metalloproteinase activity. In parallel, a novel biohybrid system harnessing plant-derived photosynthetic units encapsulated in chondrocyte membranes has been shown to boost intracellular ATP and NADPH under light exposure, thereby restoring anabolic capacity in degenerated cartilage and attenuating disease progression in vivo.

Metabolic Dynamics in Osteoarthritis Pathogenesis publication trend

The graph below shows the total number of articles in metabolic dynamics in osteoarthritis pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

CircRNA: covalently closed RNA molecule that can regulate protein stability or gene expression.

Fatty acid synthase (FASN): enzyme catalysing the synthesis of long-chain fatty acids from acetyl-CoA.

SUMOylation: post-translational attachment of small ubiquitin-like modifiers modulating protein function.

De novo lipogenesis (DNL): metabolic process converting acetyl-CoA into fatty acids for lipid storage and signalling.

Oxidative phosphorylation (OxPhos): mitochondrial pathway generating ATP via electron transport and proton gradient.

Mitophagy: selective autophagic degradation of dysfunctional mitochondria to maintain cellular health.

Glycolysis: cytosolic pathway breaking down glucose to pyruvate, yielding ATP anaerobically and biosynthetic intermediates.

References

1. CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications. Nature Communications (2023).
2. PPARα−ACOT12 axis is responsible for maintaining cartilage homeostasis through modulating de novo lipogenesis. Nature Communications (2022).
3. A plant-derived natural photosynthetic system for improving cell anabolism. Nature (2022).
4. SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch. Bone Research (2025).
5. Increased oxidative phosphorylation through pyruvate dehydrogenase kinase 2 deficiency ameliorates cartilage degradation in mice with surgically induced osteoarthritis. Experimental & Molecular Medicine (2025).
6. HK2: a potential regulator of osteoarthritis via glycolytic and non-glycolytic pathways. Cell Communication and Signaling (2022).