Published online before print March 18, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070756

Accepted for publication December 18, 2007.

Article

Age-Related Changes in Bone Morphology Are Accelerated in Group VIA Phospholipase A₂ (iPLA₂)-Null Mice

Sasanka Ramanadham^*@, Kevin E. Yarasheski^*, Matthew J. Silva, Mary Wohltmann^*, Deborah Veis Novack, Blaine Christiansen, Xiaolin Tu, Sheng Zhang^*, Xiaoyong Lei^*, and John Turk^*

From the Medicine Department, Mass Spectrometry Facility, and Division of Endocrinology, Metabolism, and Lipid Research,* and the Departments of Orthopaedic Surgery and Medicine Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri

^@ To whom correspondence should be addressed. E-mail: sramanad{at}im.wustl.edu.

	Abstract

Phospholipases A₂ (PLA₂) hydrolyze the sn-2 fatty acid substituent, such as arachidonic acid, from phospholipids, and arachidonate metabolites are recognized mediators of bone modeling. We have previously generated knockout (KO) mice lacking the group VIA PLA₂ (iPLA₂), which participates in a variety of signaling events; iPLA₂ mRNA is expressed in bones of wild-type (WT) but not KO mice. Cortical bone size, trabecular bone volume, bone mineralizing surfaces, and bone strength are similar in WT and KO mice at 3 months and decline with age in both groups, but the decreases are more pronounced in KO mice. The lower bone mass phenotype observed in KO mice is not associated with an increase in osteoclast abundance/activity or a decrease in osteoblast density, but is accompanied by an increase in bone marrow fat. Relative to WT mice, undifferentiated bone marrow stromal cells (BMSCs) from KO mice express higher levels of PPAR- and lower levels of Runx2 mRNA, and this correlates with increased adipogenesis and decreased osteogenesis in BMSCs from these mice. In summary, our studies indicate that age-related losses in bone mass and strength are accelerated in iPLA₂-null mice. Because adipocytes and osteoblasts share a common mesenchymal stem cell origin, our findings suggest that absence of iPLA₂ causes abnormalities in osteoblast function and BMSC differentiation and identify a previously unrecognized role of iPLA₂ in bone formation.