Risk of metabolic abnormalities in osteoarthritis: a new perspective to understand its pathological mechanisms

Abstract

Although aging has traditionally been viewed as the most important risk factor for osteoarthritis (OA), an increasing amount of epidemiological evidence has highlighted the association between metabolic abnormalities and OA, particularly in younger individuals. Metabolic abnormalities, such as obesity and type II diabetes, are strongly linked to OA, and they affect both weight-bearing and non-weight-bearing joints, thus suggesting that the pathogenesis of OA is more complicated than the mechanical stress induced by overweight. This review aims to explore the recent advances in research on the relationship between metabolic abnormalities and OA risk, including the impact of abnormal glucose and lipid metabolism, the potential pathogenesis and targeted therapeutic strategies.

Fig. 1

Effect of Glucose Metabolism on Osteoarthritis. a Obesity and diabetes lead to increased pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and ROS, activate the NF-κB pathway and promote the expression of MMP3, MMP13, ADAMTS4 and ADAMTS5. b Normal synovial cells can receive insulin, which acts as an anti-inflammatory. Insulin-resistant synovial cells are insensitive to insulin, resulting in increased levels of the proinflammatory cytokines IL-1β, IL-6, growth factor BMP-2, protease MMP13 and ADAMTS4, aggravating the degree of osteoarthritis. c Hyperglycemia induces the production of AGEs, which promote cartilage matrix stiffness as well as ROS production. AGEs bind to RAGE, activate the MAPK signaling pathway in chondrocytes, and promote the production of IL, MMP and ADAMTS. d Hyperglycemia promotes the expression of ROS and M1 macrophage activation. ROS activate the MAPK and NF-κB pathways, promote MMP13 and ADAMTS5 and inhibit the expression of Col-2 and Aggrecan. ROS inhibitors inhibit the activation of this pathway. IL-1β interleukin-1β, IL-6 interleukin-6, TNF-α tumor necrosis factor-α, ROS reactive oxygen species, NF-κB nuclear factor-κ-gene binding, MMP3 matrix metalloproteinases 3, MMP13 matrix metalloproteinases 13, ADAMTS4 a disintegrin and metalloproteinase protein 4, ADAMTS5 a disintegrin and metalloproteinase protein 5, BMP-2 bone morphogenetic protein-2, AGEs advanced glycation end products, RAGE receptor for advanced glycation end products, MAPK mitogen-activated protein kinase, Col-2 Collagen-2

Fig. 2

The mechanism of fatty acids in osteoarthritis. Excess SFAs and n-6 PUFAs in the blood directly or indirectly activate the NF-κB pathway by binding to the corresponding receptors, promoting the expression of PTGS, IL-1, MMP13, ADAMTS5, and COL10 and aggravating OA. MUFAs and n-3 PUFAs can inhibit the expression of proinflammatory factors such as TNF-α and IL-1 and block the activation of the MAPK and NF-κB pathways. SFAs saturated fatty acids, n-6 PUFAs omega-6 polyunsaturated fatty acids, NF-κB nuclear factor-k-gene binding, PTGS prostaglandin-endoperoxide synthase, IL-1 interleukin-1, MMP13 matrix metalloproteinases 13, ADAMTS5 a disintegrin and metalloproteinase protein 5, Col-X Collagen-10, MUFA monounsaturated fatty acids, n-3 PUFA omega-3 polyunsaturated fatty acids, TNF-α tumor necrosis factor-α, MAPK mitogen-activated protein kinase

Fig. 3

The role of liver nuclear receptor LXR in osteoarthritis. The liver nuclear receptor LXR binds to ABCA1, promotes the efflux of cholesterol in chondrocytes, inhibits the activation of the NF-κB pathway and reduces the expression of IL-1β, TNF-α, MMP13 and ADAMTS5. LXR agonists can promote LXR expression and strengthen the above two pathways. LXR liver X receptor, ABCA1 ATP-binding cassette transporter A1, NF-κB nuclear factor-k-gene binding, IL-1β interleukin-1β, TNF-α tumor necrosis factor-α, MMP13 matrix metalloproteinases 13, ADAMTS5 a disintegrin and metalloproteinase protein 5

Fig. 4

The mechanisms of leptin and adiponectin in osteoarthritis. The adiponectin and leptin secreted by white adipose tissue bind to the corresponding receptors, activate MAPK and NF-κB pathways, and promote the expression of IL-1β, TNF-α, MMP2 and MMP9. Proinflammatory cytokines and matrix metalloproteinases act on articular cartilage, subchondral bone, synovial membrane and other areas, aggravating the phenotype of osteoarthritis. MAPK mitogen-activated protein kinase, NF-κB nuclear factor-k-gene binding, IL-1β interleukin-1β, TNF-α tumor necrosis factor-α, MMP2 matrix metalloproteinases 2, MMP9 matrix metalloproteinases 9