Lactate-upregulated NADPH-dependent NOX4 expression via HCAR1/PI3K pathway contributes to ROS-induced osteoarthritis...

Area of Science:

• Biochemistry
• Cell Biology
• Pathology

Background:

• Metabolic factors are increasingly implicated in osteoarthritis (OA) pathogenesis.
• The role of lactate, a key metabolite, in OA development and its underlying mechanisms require clarification.
• Understanding lactate's impact on chondrocyte function is crucial for developing novel OA therapies.

Purpose of the Study:

• To investigate the involvement of lactate in osteoarthritis pathogenesis.
• To elucidate the mechanisms by which lactate affects chondrocyte function and contributes to OA.
• To explore potential therapeutic strategies targeting lactate-mediated pathways in OA.

Main Methods:

• Analysis of serum and synovial fluid lactate levels in OA patients and healthy controls.
• In vitro studies using human chondrocytes treated with lactate to assess cellular responses.
• In vivo experiments involving intra-articular lactate injection in rat models of OA.
• Assessment of gene and protein expression, reactive oxygen species (ROS) generation, and cartilage integrity.

Main Results:

• Serum and synovial fluid lactate levels were elevated in OA patients and correlated with metabolic parameters.
• Lactate up-regulated lactate receptor (HCAR1) and transporters in chondrocytes, increasing ROS via NOX4 activation.
• Lactate promoted chondrocyte damage, catabolic enzyme expression, and inflammation, while reducing collagen synthesis; these effects were reversed by NOX4 inhibition or ROS scavenging.
• In vivo lactate administration exacerbated cartilage damage in OA rat models, an effect mitigated by NOX4 inhibition.

Conclusions:

• Lactate plays a significant role in osteoarthritis pathogenesis by impairing chondrocyte function through metabolic and signaling pathways.
• Lactate-induced oxidative stress and inflammation contribute to cartilage degradation in OA.
• Targeting lactate-mediated pathways, particularly NOX4, offers a potential therapeutic avenue for osteoarthritis.