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bioRxiv · 10.1101/2024.03.19.585823

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

Lee, D.-K.·Jin, X.·Choi, P.-R.·Cui, Y.·Che, X.·Lee, S.·Hur, K.·Kim, H.-J.·Choi, J.-Y.
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Abstract

Phospholipase C beta (PLC{beta}) exerts 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 most highly upregulated during osteoclastogenesis. In this study, we used global knockout and osteoclast lineage-specific PLC{beta}4 conditional knockout (LysM-PLC{beta}4-/-) mice and demonstrated that PLC{beta}4 is a crucial regulator of receptor activator of nuclear factor {kappa}B ligand (RANKL)-induced osteoclast differentiation. 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. Importantly, LysM-PLC{beta}4-/- male mice exhibited greater bone mass and a lower number of osteoclasts in vivo than their wild-type littermates, without altering 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, thereby modulating p38 activation. An immunofluorescence assay further confirmed the colocalization of PLC{beta}4 with p38 after RANKL exposure. Moreover, p38 activation rescued the impaired osteoclast formation and restored the reduced p38 phosphorylation due to PLC{beta}4 deficiency. Thus, our findings reveal that PLC{beta}4 controls osteoclastogenesis via the RANKL-dependent MKK3-p38 MAPK pathway, and PLC{beta}4 may be a potential therapeutic candidate for bone diseases such as osteoporosis.

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Lee, D.-K., Jin, X., Choi, P.-R., Cui, Y., Che, X., Lee, S., Hur, K., Kim, H.-J., Choi, J.-Y.. 2024-03-23. Phospholipase C β4 promotes RANKL-dependent osteoclastogenesis by interacting with MKK3 and p38 MAPK. https://doi.org/10.1101/2024.03.19.585823

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