PKM2 regulates osteoclastogenesis by affecting osteoclast precursor cell fusion via downregulation of OC-STAMP and...

Osteoporosis is a common bone disease that has become a serious public health problem with the aging of population. Osteoclasts are the only cells in body that can resorb bone, whose dysfunction is closely related to osteoporosis. Pyruvate kinase M2 (PKM2) is one of the essential rate-limiting enzymes in the process of glycolysis. This study aimed to elucidate the role of PKM2 in osteoclastogenesis and bone resorption. Bone marrow-derived macrophages were transfected with adenovirus to knock down the expression of PKM2 gene or treated with the PKM2 activators, DASA-58 and TEPP-46. Osteoclast formation was detected by tartrate-resistant acid phosphatase staining, osteoclast-specific gene and protein expression was detected by RT-quantitative PCR and Western blotting, and the effect of DASA-58 on osteoclast gene expression at the transcriptional level was examined by RNA sequencing. The results showed that knockdown of PKM2 by adenoviral transfection or treatment with PKM2 activators, DASA-58 and TEPP-46, inhibited osteoclast differentiation and suppressed the expression of osteoclast-associated genes in bone marrow-derived macrophages. Furthermore, PKM2 activators, DASA-58 and TEPP-46, could inhibit several signaling pathways in osteoclasts; knockdown of PKM2 or treatment with PKM2 activators, DASA-58 and TEPP-46, both affected osteoclast precursor cell fusion by inhibiting the expression of osteoclast stimulatory transmembrane protein (OC-STAMP) and dendritic cell-specific transmembrane protein (DC-STAMP). Therefore, PKM2 is closely related to osteoclast differentiation and formation, and the development of new therapeutic strategies targeting the PKM2 gene in osteoclasts may be feasible for the prevention and treatment of osteoporosis.