Absence of platelet-activating factor receptor protects mice from osteoporosis following ovariectomy.
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.
Hikiji
Hisako
H
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, The University of Tokyo, Bunkyo, Japan.
Ishii
Satoshi
S
Shindou
Hideo
H
Takato
Tsuyoshi
T
Shimizu
Takao
T
D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D010024:Osteoporosis / Q000209:etiology / Q000517:prevention & control*; D010052:Ovariectomy / Q000009:adverse effects*; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor