Phospholipase C β4 promotes RANKL-dependent osteoclastogenesis by interacting with MKK3 and p38 MAPK

초록

Phospholipase C beta (PLC beta) is involved in diverse biological processes, including inflammatory responses and neurogenesis; however, its role in bone cell function is largely unknown. Among the PLC beta isoforms (beta 1-beta 4), we found that PLC beta 4 was the most highly upregulated during osteoclastogenesis. Here we used global knockout and osteoclast lineage-specific PLC beta 4 conditional knockout (LysM-PLC beta 4-/-) mice as subjects and demonstrated that PLC beta 4 is a crucial regulator of receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclast differentiation. The deletion of PLC beta 4, both globally and in the osteoclast lineage, resulted in a significant reduction in osteoclast formation and the downregulation of osteoclast marker genes. Notably, male LysM-PLC beta 4-/- mice presented greater bone mass and fewer osteoclasts in vivo than their wild-type littermates, without altered osteoblast function. Mechanistically, we found that PLC beta 4 forms a complex with p38 mitogen-activated protein kinase (MAPK) and MAPK kinase 3 (MKK3) in response to RANKL-induced osteoclast differentiation, thereby modulating p38 activation. An immunofluorescence assay further confirmed the colocalization of PLC beta 4 with p38 after RANKL exposure. Moreover, p38 activation rescued impaired osteoclast formation and restored the reduction in p38 phosphorylation caused by PLC beta 4 deficiency. Thus, our findings reveal that PLC beta 4 controls osteoclastogenesis via the RANKL-dependent MKK3-p38 MAPK pathway and that PLC beta 4 may be a potential therapeutic candidate for bone diseases such as osteoporosis.

키워드