Multimodal Regulation of the Osteoclastogenesis Process by Secreted Group IIA Phospholipase A

Increasing evidence points to the involvement of group IIA secreted phospholipase A (sPLA-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-IIA activities and recombinant sPLA-IIA (wild-type or catalytically inactive forms, full-length or partial protein sequences) were instrumental to dissect out sPLA-IIA function, in conjunction with reduction of sPLA-IIA expression using small-interfering-RNAs and precursor cells from knock-out mice. The reported data indicate sPLA-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-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-IIA binding to interacting partners implicated in osteoclast syncytium formation.