Age-related changes in bone morphology are accelerated in group VIA phospholipase A2 (iPLA2beta)-null mice.
Phospholipases A(2) (PLA(2)) 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 PLA(2) (iPLA(2)beta), which participates in a variety of signaling events; iPLA(2)beta 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-gamma 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 iPLA(2)beta-null mice. Because adipocytes and osteoblasts share a common mesenchymal stem cell origin, our findings suggest that absence of iPLA(2)beta causes abnormalities in osteoblast function and BMSC differentiation and identify a previously unrecognized role of iPLA(2)beta in bone formation.
Ramanadham
Sasanka
S
Washington University School of Medicine, Department of Internal Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. sramanad@im.wustl.edu
Yarasheski
Kevin E
KE
Silva
Matthew J
MJ
Wohltmann
Mary
M
Novack
Deborah Veis
DV
Christiansen
Blaine
B
Tu
Xiaolin
X
Zhang
Sheng
S
Lei
Xiaoyong
X
Turk
John
J
D015502:Absorptiometry, Photon; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001696:Biomechanical Phenomena; D001823:Body Composition; D015519:Bone Density; D001853:Bone Marrow / Q000201:enzymology; D016723:Bone Remodeling; D001842:Bone and Bones / Q000201:enzymology* / Q000473:pathology*; D002452:Cell Count; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D054522:Group VI Phospholipases A2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000201:enzymology; D010010:Osteoclasts / Q000166:cytology / Q000201:enzymology; D010012:Osteogenesis; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000201:enzymology
D050659:Core Binding Factor Alpha 1 Subunit; D005452:Fluoresceins; D047495:PPAR gamma; D012333:RNA, Messenger; C493716:Runx2 protein, mouse; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; C007740:fluorexon