AUTHOR=Mangini Maria , D’Angelo Rosa , Vinciguerra Caterina , Payré Christine , Lambeau Gérard , Balestrieri Barbara , Charles Julia F. , Mariggiò Stefania 

TITLE=Multimodal regulation of the osteoclastogenesis process by secreted group IIA phospholipase A2

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.966950

DOI=10.3389/fcell.2022.966950

ISSN=2296-634X

ABSTRACT=<p>Increasing evidence points to the involvement of group IIA secreted phospholipase A<sub>2</sub> (sPLA<sub>2</sub>-IIA) in pathologies characterized by abnormal osteoclast bone-resorption activity. Here, the role of this moonlighting protein has been deepened in the osteoclastogenesis process driven by the RANKL cytokine in RAW264.7 macrophages and bone-marrow derived precursor cells from BALB/cJ mice. Inhibitors with distinct selectivity toward sPLA<sub>2</sub>-IIA activities and recombinant sPLA<sub>2</sub>-IIA (wild-type or catalytically inactive forms, full-length or partial protein sequences) were instrumental to dissect out sPLA<sub>2</sub>-IIA function, in conjunction with reduction of sPLA<sub>2</sub>-IIA expression using small-interfering-RNAs and precursor cells from <italic>Pla2g2a</italic> knock-out mice. The reported data indicate sPLA<sub>2</sub>-IIA participation in murine osteoclast maturation, control of syncytium formation and resorbing activity, by mechanisms that may be both catalytically dependent and independent. Of note, these studies provide a more complete understanding of the still enigmatic osteoclast multinucleation process, a crucial step for bone-resorbing activity, uncovering the role of sPLA<sub>2</sub>-IIA interaction with a still unidentified receptor to regulate osteoclast fusion through p38 SAPK activation. This could pave the way for the design of specific inhibitors of sPLA<sub>2</sub>-IIA binding to interacting partners implicated in osteoclast syncytium formation.</p>