Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy.
Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy.
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DOI：
10.1172/jci20504
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发表时间：
2004-07
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影响因子：
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通讯作者：
H. Hikiji;S. Ishii;H. Shindou;T. Takato;Takao Shimizu
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文献类型：
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作者：
H. Hikiji;S. Ishii;H. Shindou;T. Takato;Takao Shimizu
虽然血小板活化因子（PAF）在与骨吸收相关的各种疾病中产生，但其在骨代谢中的功能仍不清楚。使用PAF受体缺陷小鼠，我们评估了PAF在绝经后骨质疏松症模型卵巢切除术后骨吸收发展中的作用。通过观察骨密度和组织形态计量学参数，发现PAF受体缺陷小鼠的骨吸收明显减弱，表明PAF在体内连接雌激素耗竭和骨质疏松症。破骨细胞比成骨细胞表达更高量的PAF生物合成所需的酶。TNF-α和IL-1 β增加破骨细胞中乙酰辅酶A：lyso-PAF乙酰转移酶的活性。破骨细胞，而不是成骨细胞，表达功能性PAF受体。PAF受体的刺激延长破骨细胞在体外的存活。此外，破骨细胞与PAF受体拮抗剂治疗，也从PAF受体缺陷的小鼠，表现出生存率和钙再吸收活性降低。一致地，在器官培养中，骨吸收被PAF受体拮抗剂治疗或遗传性PAF受体缺陷显著抑制。因此，这些结果表明，通过炎症细胞因子，雌激素耗竭增强PAF的生产作为一个独特的自分泌因子的破骨细胞功能。抑制PAF功能可能为预防绝经后骨丢失而不干扰成骨细胞功能的新策略铺平道路。
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-alpha and IL-1beta 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.