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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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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Prevented bone loss and unaltered bone turnover in ovariectomized PAFR-K...
Prevented bone loss and unaltered bone turnover in ovariectomized PAFR-KO mice. (A) Representative toluidine blue sections of the metaphyseal region in the excised tibiae. Scale bar: 1.0 mm. (B) Bone histomorphometry. The ovariectomy-induced reductions in BV/TV and Tb.N were prevented in PAFR-KO mice. The ovariectomy-induced increase in Tb.Sp was also prevented in PAFR-KO mice. O.Th and Oc.S/BS in WT-OVX mice were significantly increased compared with values seen in KO-OVX mice, suggesting that the reduction in bone mass in PAFR-WT mice was associated with an increase in bone turnover. Values are mean ± SD. WT-OVX: n = 6 animals; WT-sham: n = 7 animals; KO-OVX: n = 5 animals; KO-sham: n = 6 animals. *P < 0.05 vs. KO-OVX; #P < 0.05 vs. WT-sham.