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.

Nanoparticle-based inhibition of vascular endothelial growth factor receptors alleviates osteoarthritis pain and cartilage damage

“…The latter suggests that pazopanib is released in vivo in sufficient quantities to have beneficial biological effects. One possible explanation of the apparent bioavailability of Nano-PAZII in vivo at near neutral pH is that interactions with inflammation-related cells (e.g., macrophages) and/or the pericellular matrix compartment of the synovium may perhaps alter the local pH (44), and the development of a more acidic microenvironment due to lactate accumulation during OA progression facilitates pazopanib release (45)(46)(47). Future studies will need to resolve the potential benefits of nanoparticles that are engineered to allow the pH-dependent release of pazopanib at near-neutral pH (pH 6 to pH 8) in vitro and what mechanisms would support the controlled release of pazopanib in synovial fluid within the same neutral physiological pH range in vivo.…”

Quercetin Suppresses Ferroptosis in Chondrocytes via Activating the Nrf2/ GPX4 Signaling Pathway

“…OA is a chronic disorder influenced by various factors, such as genetics, metabolism, aging, obesity, and joint trauma. 38,39 Regrettably, OA remains a challenging condition for which there are no specific therapeutic approaches available. The pathogenesis of OA is heavily influenced by chondrocytes, and chondrocyte death is the primary cause of OA.…”

The effects of intra-articular oxamate on anterior cruciate ligament transection-induced experimental osteoarthritic rats

“…Normal chondrocytes receive 75% of their energy from glycolysis, but mitochondria receive 25% of their energy from OXPHOS [9]. An oxygen gradient microenvironment exists in cartilage tissues, and chondrocytes in the deepest part can obtain 1% oxygen.…”

“…In normal chondrocytes, around 25% of ATP originates from mitochondrial OXPHOS. However, as OA is accompanied by mitochondria dysfunctions in the cartilage, OXPHOS capacity decreases, resulting in energy de ciency [9]. Additionally, OA causes changes in energy metabolism pathways in chondrocytes, which are characterized by enhanced glycolysis and decreased OXPHOS capacity [10,11].…”