Age-Related Changes in Bone Morphology Are Accelerated in Group VIA Phospholipase A2 (iPLA2β)-Null Mice

Abstract

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 ␤), which participates in a variety of signaling events; iPLA 2 ␤ 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 iPLA 2 ␤-null mice. Because adipocytes and osteoblasts share a common mesenchymal stem cell origin, our findings suggest that absence of iPLA 2 Bioactive arachidonic acid (AA) metabolites (eicosanoids) generated by the actions of various oxygenases, such as the 5-lipoxygenase (5-LO) and cyclooxygenase (COX) isozymes, are important mediators of bone remodeling. The 5-LO products leukotrienes and 5-HETE (hydroxyeicosatetraenoic acid) function as negative modulators of bone formation by inhibiting osteoblast differentiation and bone formation.1 In contrast, prostaglandins (PGs), eg, PGE 2 , derived from COX metabolism of AA enhance bone formation and mass by increasing osteoblast replication and differentiation and/or by inhibiting osteoclastic resorption, [2][3][4][5]

Establishment of an Improved Mouse Model for Infantile Neuroaxonal Dystrophy That Shows Early Disease Onset and Bears a Point Mutation in Pla2g6

“…22 We also detected similar changes in the bone morphology in Pla2g6-inad mutant. At least 12-week-old or older mutants showed decreases in both cortical and trabecular bone volume (Supplemental Figure S1, see http://ajp.amjpathol.org).…”

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A2β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

“…There have been no reported descriptions of non-neurological symptoms, laboratory findings, or pathological changes in internal organs in INAD (Cowen and Olmstead, 1963;Nardocci et al, 1999), although dysfunction of spermatozoa (Bao et al, 2004), a reduced insulin secretory response (Zhao et al, 2010), and acceleration of age-related changes in bone morphology (Ramanadham et al, 2008) have been reported in adult iPLA 2 ␤-KO mice. The relatively mild phenotypes of iPLA 2 ␤ deficiency in nonneurological tissues suggest that iPLA 2 ␤ plays an especially important role in the nervous system, although it is widely distributed in various organs (Bao et al, 2004).…”

Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca2+-independent phospholipase A2γ-deficient mice

“…The fi rst one is group VIA iPLA 2 (also called iPLA 2 ␤ ) ( 5, 6 ), which was initially assumed to be the housekeeping enzyme responsible for phospholipid acyl group turnover and generation of the lysophospholipids necessary for AA incorporation ( 7 ). Subsequent studies employing iPLA 2 ␤ -knockdown cells and knockout (KO) mice have provided evidence that iPLA 2 ␤ plays roles not only in phospholipid homeostasis but also in signaling in diverse biological events (8)(9)(10)(11)(12)(13)(14)(15)(16). The second isoform of iPLA 2 , group VIB iPLA 2 (also called iPLA 2 ␥ ), was identifi ed by a search of the expressed sequence tag database for sequences homologous to iPLA 2 ␤ .…”