Lactic Acid Regulation: A Potential Therapeutic Option in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic, persistent autoimmune disease that causes severe joint tissue damage and irreversible disability. Cumulative evidence suggests that patients suffering from RA for long durations are at risk of functional damage to cardiovascular, kidney, lung, and other tissues. This seriously affects the quality of work and life of patients. To date, no clear etiology of RA has been found. Recent studies have revealed that the massive proliferation of synoviocytes and immune cells requires a large amount of energy supply. Rapid energy supply depends on the anaerobic glucose metabolic pathway in both RA animal models and clinical patients. Anaerobic glycolysis can increase intracellular lactic acid (LA) content. LA induces the overexpression of monocarboxylate transporters (MCTs) in cell membranes. MCTs rapidly transport LA from the intracellular to the intercellular or articular cavity. Hence, a relatively high accumulation of LA could be formed in the intercellular and articular cavities of inflammatory joints. Moreover, LA contributes to the migration and activation of immune cells. Immune cells proliferate and secrete interleukins (IL) including IL-1, IL-2, IL-13, IL-17, and other inflammatory factors. These inflammatory factors enhance the immune inflammatory response of the body and aggravate the condition of RA patients. In this paper, the effects of LA on RA pathogenesis will be summarized from the perspective of the production, transport, and metabolism of synoviocytes and immune cells. Additionally, the drugs involved in the production, transport, and metabolism of LA are highlighted.

Andrographolide Ameliorates Inflammatory Changes Induced by D-Lactate in Bovine Fibroblast-like Synoviocytes

“…Conversely, ruminal fermentative disorders lead to the excessive accumulation of D-lactate, disrupting normal metabolic processes and causing pathological effects such as polysynovitis [ 1 , 5 ]. The presence of lactate within the joint during arthritis progression is considered a pivotal indicator linked to the inflammatory cascade, currently emerging as a promising target for the advancement of novel therapeutic interventions [ 3 , 41 , 42 ]. Lactate induces the release of Neutrophil Extracellular Traps (NETs) [ 43 ] and activates the secretion of pro-inflammatory cytokines in FLS [ 15 , 17 ], thereby contributing to the inflammation observed in arthritis.…”

“…Lactate, once considered solely a metabolic waste product, is now recognized as a pleiotropic signal involved in various physiological and pathological conditions [ 1 , 2 , 3 , 4 ]. Lactate exists in two enantiomers: L-lactate, which is produced during glycolysis under anaerobic conditions, and D-lactate, which is generated through the methylglyoxal detoxification pathway [ 1 ].…”

Gut microbiome-immune interactions and their role in rheumatoid arthritis development

“…Fermentation pathway: mixed fermentation acid fermentation, showed the most predictable power and demonstrated positive association with the most abundant in RA group Lachnospiraceae and negative association with the most abundant in Control group Oscillospiraceae is essential in lactic acid regulation, the latter is broadly studied in perspective of autoimmunity, precisely rheumatoid arthritis. Its key role in synoviocytes’ proliferation, proinflammatory cytokines secretion, immune cell activation, and even ACPA secretion is widely discussed in Wang et al (2022a) , and it is also being considered as a new potential therapeutic approach.…”

Network Pharmacology and Molecular Docking Explore the Mechanism of Mubiezi‐Yinyanghuo Herb Pair in the Treatment of Rheumatoid Arthritis

“…Although some neovascularization provides oxygen to the increased infammatory cell mass, the neovascularization network is dysfunctional and unable to restore tissue oxygen homeostasis, keeping RA joints in a hypoxic environment [21]. Due to the high metabolic demand of synovial cells, the lactate content in the synovial fuid of RA is signifcantly increased and the glucose concentration is signifcantly decreased [22][23][24]. Te results of the present study are in accordance with the fndings of the abovementioned, as increased glycolytic enzyme activity in RA synovial tissue, RA synovial cell proliferation, and massive infammatory cell infltration lead to increased local capillary oxygen difusion distance and oxygen consumption, resulting in RA joint cavity hypoxia [25,26].…”