Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy
Hisako Hikiji, … , Tsuyoshi Takato, Takao Shimizu
Hisako Hikiji, … , Tsuyoshi Takato, Takao Shimizu
Published July 1, 2004
Citation Information: J Clin Invest. 2004;114(1):85-93. https://doi.org/10.1172/JCI20504.
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Article Bone Biology

Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy

Abstract

While platelet-activating factor (PAF) is produced in various diseases associated with bone resorption, its functions in bone metabolism remain unknown. Using PAF receptor–deficient mice, we evaluated the role of PAF in the development of bone resorption following ovariectomy, a model of postmenopausal osteoporosis. Through observations of bone mineral density and histomorphometric parameters, it was found that bone resorption was markedly attenuated in PAF receptor–deficient mice, indicating that PAF links estrogen depletion and osteoporosis in vivo. Osteoclasts expressed higher amounts of the enzymes required for PAF biosynthesis than osteoblasts. TNF-α and IL-1β increased the acetyl-coenzyme A:lyso-PAF acetyltransferase activity in osteoclasts. Osteoclasts, but not osteoblasts, expressed the functional PAF receptor. PAF receptor stimulation prolonged the survival of osteoclasts in vitro. Furthermore, osteoclasts treated with a PAF receptor antagonist, and also those from PAF receptor–deficient mice, showed reductions in survival rate and Ca resorption activity. Consistently, in organ cultures, bone resorption was significantly suppressed by a PAF receptor antagonist treatment or genetic PAF receptor deficiency. Thus, these results suggest that, through the inflammatory cytokines, estrogen depletion enhances PAF production as a unique autocrine factor for osteoclast functions. Inhibition of PAF function might pave the way for a new strategy to prevent postmenopausal bone loss without disturbing osteoblast functions.

Authors

Hisako Hikiji, Satoshi Ishii, Hideo Shindou, Tsuyoshi Takato, Takao Shimizu

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Lyso-PAF acetyltransferase activity and cPLA2α expression in bone cells....
Lyso-PAF acetyltransferase activity and cPLA2α expression in bone cells. (A) Lyso-PAF acetyltransferase activity. MC3T3-E1 mouse osteogenic cells and primary mouse osteoblasts (gray bars) had low lyso-PAF acetyltransferase activities even after stimulation with TNF-α and IL-1β as designated by (+). Osteoclasts derived from RAW 264.7 cells, spleen-derived osteoclasts, and bone marrow–derived osteoclasts (black bars) had significantly higher lyso-PAF acetyltransferase activities compared with osteoblasts. In addition, cytokine stimulation, denoted by (+), raised the activities. Values are mean ± SD measured in triplicate or quadruplicate. Similar results were obtained in another experiment. *P < 0.05 vs. primary osteoblasts; #P < 0.05 vs. unstimulated spleen-derived osteoclasts; P < 0.05 vs. unstimulated bone marrow–derived osteoclasts. (B) Western blot analysis of cPLA2α. The cell lysates (16 μg of protein) were subjected to SDS-PAGE and immunoblotted with an anti-mouse cPLA2α monoclonal antibody. Spleen-derived osteoclasts and bone marrow–derived osteoclasts expressed higher amounts of cPLA2α than primary osteoblasts. Similar results were obtained in another experiment.