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

Abstract

Increasing evidence points to the involvement of group IIA secreted phospholipase A₂ (sPLA₂-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 sPLA₂-IIA activities and recombinant sPLA₂-IIA (wild-type or catalytically inactive forms, full-length or partial protein sequences) were instrumental to dissect out sPLA₂-IIA function, in conjunction with reduction of sPLA₂-IIA expression using small-interfering-RNAs and precursor cells from Pla2g2a knock-out mice. The reported data indicate sPLA₂-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 sPLA₂-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 sPLA₂-IIA binding to interacting partners implicated in osteoclast syncytium formation.

Keywords: LLKYK cyclic peptide; group IIA secreted phospholipase A2 (sPLA2-IIA); osteoclast syncytia; osteoclastogenesis; p38 SAPK.