title: Osteoblastic Lrp4 promotes osteoclastogenesis by regulating ATP release and adenosine-A2AR signaling.
abstract: Bone homeostasis depends on the functional balance of osteoblasts (OBs) and osteoclasts (OCs). Lrp4 is a transmembrane protein that is mutated in patients with high bone mass. Loss of Lrp4 in OB-lineage cells increases bone mass by elevating bone formation by OBs and reducing bone resorption by OCs. However, it is unclear how Lrp4 deficiency in OBs impairs osteoclastogenesis. Here, we provide evidence that loss of Lrp4 in the OB lineage stabilizes the prorenin receptor (PRR) and increases PRR/V-ATPase-driven ATP release, thereby enhancing the production of the ATP derivative adenosine. Both pharmacological and genetic inhibition of adenosine-2Areceptor (A2AR) in culture and Lrp4 mutant mice diminishes the osteoclastogenic deficit and reduces trabecular bone mass. Furthermore, elevated adenosine-A2AR signaling reduces receptor activator of nuclear factor κB (RANK)-mediated osteoclastogenesis. Collectively, these results identify a mechanism by which osteoblastic Lrp4 controls osteoclastogenesis, reveal a cross talk between A2AR and RANK signaling in osteoclastogenesis, and uncover an unrecognized pathophysiological mechanism of high-bone-mass disorders.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, GA 30912.|Department of Neurology, Medical College of Georgia, Augusta, GA 30912.|Charlie Norwood VA Medical Center, Augusta, GA 30912.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, GA 30912.|Department of Neurology, Medical College of Georgia, Augusta, GA 30912.
authors.forename: Ji-Ung
authors.initials: JU
authors.lastname: Jung
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, GA 30912.|Department of Neurology, Medical College of Georgia, Augusta, GA 30912.|Charlie Norwood VA Medical Center, Augusta, GA 30912.
authors.forename: Hao-Han
authors.initials: HH
authors.lastname: Guo
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, GA 30912.|Department of Neurology, Medical College of Georgia, Augusta, GA 30912.|Charlie Norwood VA Medical Center, Augusta, GA 30912.
authors.forename: Jin-Xiu
authors.initials: JX
authors.lastname: Pan
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, GA 30912.|Department of Neurology, Medical College of Georgia, Augusta, GA 30912.|Charlie Norwood VA Medical Center, Augusta, GA 30912.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Sun
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, GA 30912 lmei@augusta.edu wxiong@augusta.edu.|Department of Neurology, Medical College of Georgia, Augusta, GA 30912.|Charlie Norwood VA Medical Center, Augusta, GA 30912.
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta, GA 30912 lmei@augusta.edu wxiong@augusta.edu.|Department of Neurology, Medical College of Georgia, Augusta, GA 30912.|Charlie Norwood VA Medical Center, Augusta, GA 30912.
authors.forename: Wen-Cheng
authors.identifier: 0000-0001-9071-7598
authors.initials: WC
authors.lastname: Xiong
mesh_terms: D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism / Q000503:physiopathology; D001842:Bone and Bones / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D019070:Cell Lineage; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism* / Q000502:physiology; D010010:Osteoclasts / Q000378:metabolism / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D026502:LDL-Receptor Related Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D043705:Receptor, Adenosine A2A; D000255:Adenosine Triphosphate