Cardiovascular disease, such as
atherosclerosis, has been associated with reduced bone mineral density and fracture risk. A major etiologic factor in
atherogenesis is believed to be oxidized
phospholipids. We previously found that these
phospholipids inhibit spontaneous osteogenic differentiation of marrow stromal cells, suggesting that they may account for the clinical link between
atherosclerosis and
osteoporosis. Currently,
anabolic agents that promote bone formation are increasingly used as a new treatment for
osteoporosis. It is not known, however, whether atherogenic
phospholipids alter the effects of bone
anabolic agents, such as
bone morphogenetic protein (BMP)-2 and
parathyroid hormone (PTH). Therefore we investigated the effects of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (
ox-PAPC) on osteogenic signaling induced by BMP-2 and PTH in MC3T3-E1 cells. Results showed that
ox-PAPC attenuated BMP-2 induction of osteogenic markers
alkaline phosphatase and
osteocalcin.
Ox-PAPC also inhibited both spontaneous and BMP-induced expression of PTH receptor. Consistently, pretreatment of cells with
ox-PAPC inhibited PTH-induced cAMP production and expression of immediate early genes Nurr1 and
IL-6. Results from immunofluorescence and Western blot analyses showed that inhibitory effects of
ox-PAPC on BMP-2 signaling were associated with inhibition of SMAD 1/5/8 but not p38-MAPK activation. These effects appear to be due to
ox-PAPC activation of the ERK pathway, as the ERK inhibitor
PD98059 reversed
ox-PAPC inhibitory effects on BMP-2-induced
alkaline phosphatase activity,
osteocalcin expression, and SMAD activation. These results suggest that atherogenic
lipids inhibit osteogenic signaling induced by BMP-2 and PTH, raising the possibility that
hyperlipidemia and atherogenic
phospholipids may interfere with anabolic
therapy.