Role for vitamin D receptor in the neuronal control of the hematopoietic stem cell niche.
Hematopoietic stem/progenitor cells (HSPCs) are released from the bone marrow to the circulation by the cytokine, granulocyte colony-stimulating factor, via sympathetic nervous system (SNS)-mediated osteoblast suppression. Because the orientation of HSPCs in their osteoblastic niche is reported to be guided by [Ca(2+)], we speculated on a cooperation between the calcium-regulating hormones and SNS in the regulation of HSPC trafficking. Here, we present the severe impairment of granulocyte colony-stimulating factor-induced osteoblast suppression and subsequent HSPC mobilization in vitamin D receptor (VDR)-deficient mice. In osteoblasts, functional VDR possessing, at least in part, a transcriptional activity, was specifically induced by β2-adrenergic receptor (AR) agonists. While β2-AR agonists transiently increased mRNA expression of Vdr and its downstream gene, Rankl, 1α,25-dihydroxyvitamin-D(3) sustained the β2-AR-induced Rankl expression at high level by stabilizing VDR protein. These data suggest that VDR is essential for durable β2-AR signaling in the stem cell niche. Our study demonstrates not only a novel function of VDR as a critical modulator of HSPC trafficking, but also the presence of a SNS-mediated, bone-remodeling mechanism through VDR. VDR contributes to brain-bone-blood integration in an unanticipated way distinct from other classical calcium-regulating hormones.
Kawamori
Yuriko
Y
Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Katayama
Yoshio
Y
Asada
Noboru
N
Minagawa
Kentaro
K
Sato
Mari
M
Okamura
Atsuo
A
Shimoyama
Manabu
M
Nakagawa
Kimie
K
Okano
Toshio
T
Tanimoto
Mitsune
M
Kato
Shigeaki
S
Matsui
Toshimitsu
T
D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000008:administration & dosage; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry; D018167:Receptors, Calcitriol / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology
C547788:Adrb1 protein, mouse; D000322:Adrenergic Agonists; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D053245:RANK Ligand; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D018167:Receptors, Calcitriol; C505689:Tnfsf11 protein, mouse; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D016179:Granulocyte Colony-Stimulating Factor; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D002118:Calcium