Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption, and high bone marrow adipose tissue...

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Bibliographic Details
Published inCell metabolism Vol. 25; no. 3; pp. 661 - 672
Main Authors Fan, Yi, Hanai, Jun-ichi, Le, Phuong T., Bi, Ruiye, Maridas, David, DeMambro, Victoria, Figueroa, Carolina A., Kir, Serkan, Zhou, Xuedong, Mannstadt, Michael, Baron, Roland, Bronson, Roderick T., Horowitz, Mark C., Wu, Joy Y., Bilezikian, John P., Dempster, David W., Rosen, Clifford J., Lanske, Beate
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 07.03.2017
Subjects
Adipocytes - metabolism
Adipogenesis
Adipose Tissue - metabolism
Animals
Biomarkers - metabolism
Bone and Bones
Bone Marrow Cells - cytology
Bone Marrow Cells - drug effects
Bone Marrow Cells - metabolism
bone resorption
Cell Count
Cell Lineage - drug effects
Humans
Integrases - metabolism
lineage
Male
Mesenchymal Stromal Cells - cytology
Mesenchymal Stromal Cells - drug effects
Mesenchymal Stromal Cells - metabolism
Mice
Osteoblasts - metabolism
Osteoporosis - pathology
Parathyroid Hormone - pharmacology
Phenotype
PTH
RANK Ligand - metabolism
RANKL
receptor
Receptor, Parathyroid Hormone, Type 1 - metabolism
Signal Transduction
Skull - cytology
lineage
RANKL
receptor
PTH
bone resorption
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ISSN1550-4131
1932-7420
1932-7420
DOI10.1016/j.cmet.2017.01.001

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Summary:Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption, and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1+RANKL+ marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotic patients. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH’s therapeutic action through its ability to direct mesenchymal cell fate. [Display omitted] •PTH1R regulates lineage allocation in the marrow•Bone marrow adipocytes compose a unique adipose depot and produce RANKL•PTH reduced marrow adipogenesis in mice and humans Fan et al. show that PTH regulates mesenchymal stem cell fate between bone and adipocyte in the marrow. Bone marrow adipocytes have distinct origins and properties from other adipocytes and are responsive to PTH, underlying the reduction in marrow adiposity in mouse models and idiopathic osteoporosis patients treated with PTH.
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Lead Contact
Co-Corresponding author description: Dr. Lanske (lead contact): Dr. Lanske was involved in designing the original study, in generating the mutant mouse strains, planning the experiments, discovering and analyzing the phenotype of mice, supervising all in vivo and in vitro experiments performed at HSDM, setting up required collaborations for the completion of the study, writing and revising the manuscript. She has discussed all steps of the study with the postdoc and co-authors on a daily basis, reviewed the results, coordinated the experiments, and exchanged the design and ideas with Dr. Rosen on a regular basis.
Dr. Rosen was involved in planning experiments, writing the manuscript with Dr. Lanske, and writing the revisions with Dr. Lanske. Specifically, Dr. Rosen focused on the marrow adipose phenotype and supervised the osmium micro CT analyses at MMCRI with and without PTH, the tibial histology for counting of the marrow adipocytes in mutant and controls, the human studies of marrow adiposity in iliac crest biopsies pre- and post PTH treatment, and the in vitro studies of PTH regulation of 3T3 L1 cells. He provided the methods that Dr. Fan used for isolating marrow adipocytes in the controls and mutants. He also developed the methods for sorting marrow progenitors for Pref-1 and RANKL using FACS that were adapted for this study by Dr. Fan, and supervised the adaptation of the TRAP technology for RANKL expression in inguinal adipose depots performed at MMCRI. Dr. Rosen discussed extensively with Dr. Jack Martin the role of Zfp467 in mediating RANKL expression in adipocytes.
Co-correspondence
ISSN:1550-4131
1932-7420
1932-7420
DOI:10.1016/j.cmet.2017.01.001