The Metabolic Landscape in Osteoarthritis

Abstract

Articular cartilage function depends on the temporal and zonal distribution of coordinated metabolic regulation in chondrocytes. Emerging evidence shows the importance of cellular metabolism in the molecular control of the cartilage and its dysregulation in degenerative diseases like osteoarthritis (OA). Compared to most other tissues, chondrocytes are sparsely located in the extracellular matrix, lacking the typical proximity of neural, vascular, and lymphatic tissue. Making up under 5% of the total tissue weight of cartilage, chondrocytes have a relative deficiency of access to nutrients and oxygen, as well as limited pathways for metabolite removal. This makes cartilage a unique tissue with hypocellularity, prolonged metabolic rate, and tissue turnover. Studies in the past decade have shown that several pathways of central carbon metabolism are essential for cartilage homeostasis. Here, we summarised the literature findings on the role of cellular metabolism in determining the chondrocyte function and how this metabolic dysregulation led to cartilage aging in OA and provided an outlook on how the field may evolve in the coming years. Although the various energy metabolism pathways are inextricably linked with one another, for the purpose of this review, we initially endeavoured to examine them individually and in relative isolation. Subsequently, we comment on what is known regarding the integration and linked signalling pathways between these systems and the therapeutic opportunities for targeting OA metabolism.

Keywords: articular cartilage; chondrocyte; energy metabolism; glycolysis; osteoarthritis; oxidative phosphorylation.

Figure 1.

Schematic illustration of central carbon metabolism in chondrocytes. Glucose enters the cell through transporters like glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3) and can be converted to glyceraldehyde 6-phosphate (G6P) by hexokinase. G6P derived pyruvate via glycolysis, thereby producing lactate or entering the tricarboxylic acid (TCA) cycle and providing energy for the cells. On the other hand, G6P acts as a starter for glycogen metabolism to support glycogen synthesis and phosphorylation

Figure 2.

Summary of glycogen storage diseases. Glycogen is a multibranched polysaccharide of glucose that serves as energy storage in specific tissue types such as the liver, muscle, kidney, and brain. Improper form or release of glycogen in different tissues causes a group of inherited genetic disorders in the body.

Figure 3.

The balance between glycolysis and oxidative phosphorylation in chondrocytes. In chondrocytes, whether glucose entering glycolysis or oxidative phosphorylation is affected by various factors, including oxygen level, the nicotinamide adenine dinucleotide (NAD⁺, oxidized form)/NADH (NAD⁺reduced form) ratio, and mitochondrial function.

Figure 4.

Molecular interface between bioenergetics, signaling pathways, and chondrocytes metabolism. Regulation of chondrocytes metabolism by (A) Nicotinamide adenine dinucleotide metabolism pathway, (B) Mitogen-activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) signaling pathways, (C) Hypoxia-inducible factors (HIFs) pathway, (D) The AMP-activated protein kinase (AMPK) signaling pathway and (E) Phosphatase and tensin homologue (PTEN)/ Phosphoinositide 3-kinase (PI3K)/ Protein kinase B (AKT) signaling pathway.

Figure 5.

Novel tools for monitoring chondrocyte bioenergetics. Schematic overview of the Seahorse metabolic flux assay integration at the biochemical level, LC/MS isotope tracer at the molecular level, and data analysis workflow.