Advisory Committee Chair
Sasanka Ramanadham
Advisory Committee Members
Susan L Bellis
Barbra A Gower
Amjad Javed
Selvarangan Ponnazhagan
Document Type
Dissertation
Date of Award
2017
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Bone modeling can be modulated by lipid signals and arachidonic acid (AA); its cyclo-oxygenase 2 (COX2) metabolite, prostaglandin E2 (PGE2), is an important mediator 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, have decreased bone formation, relative to wild type (WT) mouse bones. Here, we examined at the mechanistic and molecular levels the role of iPLA2β in bone formation using bone marrow stromal cells and calvarial osteoblasts from WT and iPLA2β-deficient mice and MC3T3-E1 osteoblast precursor cell line. Our data reveal that osteogenesis and osteogenic factors (BMP2, alkaline phosphatase, and Runx2) are decreased with iPLA2β-deficiency. These results are corroborated and recapitulated in WT cells treated with a selective inhibitor of iPLA2β, and rescued in iPLA2β-deficient preparations by additions of AA and more prominently by PGE2. Further, under osteogenic conditions we find an association of Runx2 with its promoter region, enhanced PLA2G6 transcriptional activity, and a surprisingly strong association of iPLA2β with both Runx2 and PLA2G6 promoter regions when transcriptional activity is high. These findings reveal a strong link between osteogenesis and iPLA2β-derived lipids and raise the intriguing possibility that iPLA2β itself participates in transcriptional regulation of Runx2 and PLA2G6. We postulate that targeting the link between iPLA2β and Runx2 may be a means to decrease bone loss associated with disease states
Recommended Citation
Hancock, William, "Ca2+-Independent Phospholipase A2 beta-derived Lipid Signals and Osteogenesis" (2017). All ETDs from UAB. 1858.
https://digitalcommons.library.uab.edu/etd-collection/1858