Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy
Hisako Hikiji, Satoshi Ishii, Hideo Shindou, Tsuyoshi Takato, Takao Shimizu
Hisako Hikiji, Satoshi Ishii, Hideo Shindou, Tsuyoshi Takato, Takao Shimizu
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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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Figure 7

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Effect of PAFR on IL-1β–induced osteoclast survival and Ca resorption. (...
Effect of PAFR on IL-1β–induced osteoclast survival and Ca resorption. (A) Effect of WEB 2086 on osteoclast survival stimulated by IL-1β. WEB 2086 (10 μM) inhibited the stimulatory effects of IL-1β (1 ng/ml) on the survival of osteoclasts, while WEB 2086 alone did not have any effects. Similar results were obtained in two independent experiments. *P < 0.0001 vs. control; #P < 0.0001 vs. IL-1β–treated osteoclasts. (B) Effect of WEB 2086 on Ca resorption by osteoclasts treated with IL-1β. In an osteoblast/osteoclast coculture system, WEB 2086 (10 μM) suppressed the stimulatory effect of IL-1β (1 ng/ml) on Ca resorption of osteoclasts. WEB 2086 alone did not affect Ca resorption. Similar results were obtained in three independent experiments. *P < 0.0001 vs. control. P < 0.005 vs. IL-1β–treated osteoclasts. (C) Survival of PAFR-deficient osteoclasts stimulated by IL-1β. When treated with 1 ng/ml IL-1β, osteoclasts from PAFR-KO mice displayed a significantly lower survival rate than those from PAFR-WT mice. Similar results were obtained in two independent experiments. *P < 0.0001 vs. control; #P < 0.0001 vs. IL-1β–treated PAFR-WT osteoclasts. (D) Ca resorption by PAFR-deficient osteoclasts treated with IL-1β. When treated with 0.3 ng/ml IL-1β, osteoclasts from PAFR-KO mice displayed a significantly lower Ca resorption activity than those from PAFR-WT mice. Similar results were obtained in two independent experiments. *P < 0.0001 vs. control. #P < 0.0001 vs. IL-1β–treated PAFR-WT osteoclasts.