Ca²⁺-independent phospholipase A₂β-derived PGE₂ contributes to osteogenesis

Bone modeling can be modulated by lipid signals such as arachidonic acid (AA) and its cyclooxygenase 2 (COX2) metabolite, prostaglandin E₂ (PGE₂), which are recognized mediators of optimal bone formation. Hydrolysis of AA from membrane glycerophospholipids is catalyzed by phospholipases A₂ (PLA₂s). We reported that mice deficient in the Ca²⁺- independent PLA₂beta (iPLA₂β), encoded by Pla2g6, exhibit a low bone phenotype, but the cause for this remains to be identified. Here, we examined the mechanistic and molecular roles of iPLA₂β in bone formation using bone marrow stromal cells and calvarial osteoblasts from WT and iPLA₂β-deficient mice, and the MC3T3-E1 osteoblast precursor cell line. Our data reveal that transcription of osteogenic factors (Bmp2, Alpl, and Runx2) and osteogenesis are decreased with iPLA₂β-deficiency. These outcomes are corroborated and recapitulated in WT cells treated with a selective inhibitor of iPLA₂ β (10 μM S-BEL), and rescued in iPLA₂β-deficient cells by additions of 10 μM PGE₂. Further, under osteogenic conditions we find that PGE₂ production is through iPLA₂β activity and that this leads to induction of Runx2 and iPLA₂β transcription. These findings reveal a strong link between osteogenesis and iPLA₂β-derived lipids and raise the intriguing possibility that iPLA₂β-derived PGE₂ participates in osteogenesis and in the regulation of Runx2 and also iPLA₂β.