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-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.

• Authors: Hisako Hikiji, Satoshi Ishii, Hideo Shindou, Tsuyoshi Takato, Takao Shimizu
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 114 Issue 1 Pg. 85-93 (Jul 2004) ISSN: 0021-9738 [Print] United States
• PMID: 15232615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Platelet Membrane Glycoproteins
• Receptors, G-Protein-Coupled
• platelet activating factor receptor

Topics

• Animals
• Bone Resorption (prevention & control)
• Disease Models, Animal
• Female
• Mice
• Mice, Knockout
• Osteoporosis (etiology, prevention & control)
• Ovariectomy (adverse effects)
• Platelet Membrane Glycoproteins (deficiency, genetics, physiology)
• Receptors, G-Protein-Coupled (deficiency, genetics, physiology)