Lactate dehydrogenase A inhibition prevents RANKL-induced osteoclastogenesis by reducing enhanced glycolysis

Osteoclasts are multinucleated, specializes bone-resorbing cells that are derived from the monocyte/ macrophage lineage. Excessive resorbing activities of osteoclasts are involved in destructive bone dis-eases. The detailed mechanism of acidification at the bone adhesion surface during the bone resorption process of osteoclasts remains to be defined. During glycolysis, pyruvate proceeds to the tricarboxylic cycle under aerobic conditions and pyruvate is converted to lactate via lactate dehydrogenase A (LDHA) under anaerobic conditions. However, tumor cells produce ATP during aerobic glycolysis and large amounts of pyruvate are converted to lactate and H thorn by LDHA. Lactate and H thorn are excreted outside the cell, whereby they are involved in invasion of tumor cells due to the pH drop around the cell. In this study, we focused on aerobic glycolysis and investigated the production of lactate by LDHA in osteoclasts. Expression of LDHA and monocarboxylate transporter 4 (MCT4) was upregulated during osteoclast differentiation. Intracellular and extracellular lactate levels increased with upregulation of LDHA and MCT4, respectively. FX11 (an LDHA inhibitor) inhibited osteoclast differentiation and suppressed the bone-resorbing activity of osteoclasts. We propose that inhibition of LDHA may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis. (c) 2023 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/ 4.0/).

Automated summary

This study investigated the aerobic glycolysis and lactate production by LDHA in osteoclasts, and found that inhibition of LDHA can suppress osteoclast differentiation and bone-resorbing activity. This finding may provide a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis.