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

• Published in: Experimental & molecular medicine Vol. 57; no. 2; pp. 323 - 334
• Main Authors: Lee, Dong-Kyo, Jin, Xian, Choi, Poo-Reum, Cui, Ying, Che, Xiangguo, Lee, Sihoon, Hur, Keun, Kim, Hyun-Ju, Choi, Je-Yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2025; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13/109; 14/34; 38/61; 42/89; 45/22; 631/443/63; 631/80/86; 64/60; 82/80; 96; 96/1; 96/63; Animals; Artificial intelligence; Biomedical and Life Sciences; Biomedicine; Bone diseases; Bone growth; Bone mass; Cell Differentiation; Down-regulation; Immunofluorescence; Isoforms; Kinases; Male; MAP kinase; MAP Kinase Kinase 3 - metabolism; Medical Biochemistry; Mice; Mice, Knockout; MKK3 protein; Molecular Medicine; Neurogenesis; Osteoclastogenesis; Osteoclasts; Osteoclasts - cytology; Osteoclasts - metabolism; Osteogenesis - genetics; Osteoporosis; p38 Mitogen-Activated Protein Kinases - metabolism; Phospholipase; Phospholipase C; Phospholipase C beta - genetics; Phospholipase C beta - metabolism; Phosphorylation; Protein Binding; RANK Ligand - metabolism; Signal transduction; Stem Cells; TRANCE protein; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-025-01390-8

Phospholipase C β (PLCβ) is involved in diverse biological processes, including inflammatory responses and neurogenesis; however, its role in bone cell function is largely unknown. Among the PLCβ isoforms (β1–β4), we found that PLCβ4 was the most highly upregulated during osteoclastogenesis. Here we used global knockout and osteoclast lineage-specific PLCβ4 conditional knockout ( LysM-PLCβ4 −/− ) mice as subjects and demonstrated that PLCβ4 is a crucial regulator of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation. The deletion of PLCβ4, 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-PLCβ4 −/− mice presented greater bone mass and fewer osteoclasts in vivo than their wild-type littermates, without altered osteoblast function. Mechanistically, we found that PLCβ4 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 PLCβ4 with p38 after RANKL exposure. Moreover, p38 activation rescued impaired osteoclast formation and restored the reduction in p38 phosphorylation caused by PLCβ4 deficiency. Thus, our findings reveal that PLCβ4 controls osteoclastogenesis via the RANKL-dependent MKK3–p38 MAPK pathway and that PLCβ4 may be a potential therapeutic candidate for bone diseases such as osteoporosis. Key role of PLCβ4 in osteoclastogenesis revealed Osteoclasts are cells that break down bone tissue, and their formation is crucial for bone health. This study explores the role of a protein called PLCβ4 in osteoclast development. Researchers found that PLCβ4 levels increase during osteoclast differentiation, suggesting its importance. The study used mice with specific gene modifications to understand PLCβ4’s role. The researchers used gene knockdown techniques and studied mice lacking PLCβ4 to observe changes in bone cells. They found that reducing PLCβ4 led to fewer osteoclasts and increased bone mass, especially in male mice. This suggests that PLCβ4 is vital for normal bone breakdown. The study concludes that PLCβ4 is crucial for osteoclast development by affecting a signaling pathway involving MKK3 and p38 MAPK. Understanding this process could lead to new treatments for bone diseases such as osteoporosis, where bone breakdown is excessive. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.