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

Increasing evidence points to the involvement of group IIA secreted phospholipase A(2) (sPLA(2)-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(2)-IIA activities and recombinant sPLA(2)-IIA (wild-type or catalytically inactive forms, full-length or partial protein sequences) were instrumental to dissect out sPLA(2)-IIA function, in conjunction with reduction of sPLA(2)-IIA expression using small-interfering-RNAs and precursor cells from Pla2g2a knock-out mice. The reported data indicate sPLA(2)-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(2)-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(2)-IIA binding to interacting partners implicated in osteoclast syncytium formation.