title: Myeloid lineage skewing due to exacerbated NF-κB signaling facilitates osteopenia in Scurfy mice.
abstract: Immune surveillance through Foxp3+ regulatory T cells plays a crucial role in bone homeostasis. Scurfy, the mouse model of autoimmune IPEX syndrome, bears a loss-of-function mutation in Foxp3 that leads to multi-organ inflammation. Herein, we report that scurfy mice exhibit severe bone loss mediated by accelerated osteoclastogenesis. Mechanistically, Foxp3 deficiency results in the upregulation of NF-κB in T helper cells through the loss of repressive Foxp3/NEMO interaction, thereby unleashing NF-κB-mediated over-production of pro-osteoclastogenic cytokines. Flow cytometry analysis shows marked increase in lin-Sca-1+c-kit+ hematopoietic stem cells (LSK HSCs) and granulocyte/macrophage progenitors (GMPs) in bone marrow of scurfy mice with corresponding exacerbated osteoclastogenic potential, implying that osteoclast progenitors are affected at a very primitive stage in this disorder. Scurfy LSK HSCs exhibit greater sensitivity to M-CSF and contain abundant PU.1+ Sf LSK HSCs compared with WT. Accordingly, genetic or pharmacological inhibition of M-CSF or mTOR signaling, but not IL-17 signaling, attenuates osteoclastogenesis and osteopenia in scurfy. Thus, our study suggests that Foxp3 deficiency leads to osteopenia owing to dysregulated NF-κB activity and subsequent cytokine-mediated hyper-proliferation of myeloid precursors, and positions the NF-κB pathway as a potential target for therapeutic intervention for this disorder.
authors.affiliation: Department of Orthopaedic Surgery and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: T H-P
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Department of Orthopaedic Surgery and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: G
authors.initials: G
authors.lastname: Swarnkar
authors.affiliation: Department of Internal Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mbalaviele
authors.affiliation: Department of Orthopaedic Surgery and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Abu-Amer
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016328:NF-kappa B