William Hancock is completing his PhD at the University of Alabama at Birmingham School of Medicine in the Department of Cell, Developmental, and Integrative Biology. Utilizing an undergraduate background in Physics, he is pursuing a wider understanding of the impact of potent lipid derived signals in the control of transcriptional events related to physiology and pathophisiology.


Bone modeling is modulated by lipid signals, especially arachidonic acid and its metabolites. These lipid signals can be generated by phospholipases A2 which hydrolyze the sn-2 fatty acid substituent from membrane phospholipids; cellular AA is esterified in this position within membrane glycerophospholipids. Knockout mice lacking the group VIA calcium-independent phospholipases A2 beta (iPLA2β) exhibit an enhanced, age-related decline in cortical bone size, trabecular bone volume, and bone mineralizing surfaces. They also reveal a dramatic decrease in mineral apposition rate by 6-months of age and accelerated age-related lipid droplet accumulation in their bone marrow.  Current studies demonstrate that osteoblasts from calvaria of iPLA2β-knockout mice express lower levels of Runx2, bone morphogenetic protein 2, and alkaline phosphatase mRNA, relative to WT osteoblasts.  These findings correlate with decreased osteoblastogenesis and osteoblast activity, as reflected by reduced mineralization determined by Alizarin Red staining and quantification. This reduction can be rescued by the treatment of osteoblasts with arachidonic acid and prostaglandin E2, a cyclo-oxygenase-catalyzed metabolite of arachidonic acid, which is hydrolysed through activation of iPLA2β.  Prostaglandin E2 is known to increase osteoblast replication and differentiation. Our studies indicate that induction of differentiation factors and bone mineralization occur, in part, by activation of iPLA2β and subsequent generation of iPLA2β-derived lipid signals.  These findings indicate a prominent role for iPLA2β in determining mesenchymal stem cell fate, bone maintenance, and bone remodeling.