Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

Yi Fan; Jun ichi Hanai; Phuong T. Le; Ruiye Bi; David Maridas; Victoria DeMambro; Carolina A. Figueroa; Serkan Kir; Xuedong Zhou; Michael Mannstadt; Roland Baron; Roderick T. Bronson; Mark C. Horowitz; Joy Y. Wu; John P. Bilezikian; David W. Dempster; Clifford J. Rosen; Beate Lanske

doi:10.1016/j.cmet.2017.01.001

Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

Yi Fan, Jun ichi Hanai, Phuong T. Le, Ruiye Bi, David Maridas, Victoria DeMambro, Carolina A. Figueroa, Serkan Kir, Xuedong Zhou, Michael Mannstadt, Roland Baron, Roderick T. Bronson, Mark C. Horowitz, Joy Y. Wu, John P. Bilezikian, David W. Dempster, Clifford J. Rosen, Beate Lanske

Research output: Contribution to journal › Article › peer-review

314 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	661-672
Number of pages	12
Journal	Cell Metabolism
Volume	25
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2017.01.001
State	Published - 7 Mar 2017
Externally published	Yes

Keywords

PTH
RANKL
bone resorption
lineage
receptor

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10.1016/j.cmet.2017.01.001

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Fan, Y., Hanai, J. I., Le, P. T., Bi, R., Maridas, D., DeMambro, V., Figueroa, C. A., Kir, S., Zhou, X., Mannstadt, M., Baron, R., Bronson, R. T., Horowitz, M. C., Wu, J. Y., Bilezikian, J. P., Dempster, D. W., Rosen, C. J., & Lanske, B. (2017). Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate. Cell Metabolism, 25(3), 661-672. https://doi.org/10.1016/j.cmet.2017.01.001

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title = "Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate",

abstract = "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.",

keywords = "PTH, RANKL, bone resorption, lineage, receptor",

author = "Yi Fan and Hanai, {Jun ichi} and Le, {Phuong T.} and Ruiye Bi and David Maridas and Victoria DeMambro and Figueroa, {Carolina A.} and Serkan Kir and Xuedong Zhou and Michael Mannstadt and Roland Baron and Bronson, {Roderick T.} and Horowitz, {Mark C.} and Wu, {Joy Y.} and Bilezikian, {John P.} and Dempster, {David W.} and Rosen, {Clifford J.} and Beate Lanske",

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year = "2017",

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doi = "10.1016/j.cmet.2017.01.001",

language = "English",

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AU - Fan, Yi

AU - Hanai, Jun ichi

AU - Le, Phuong T.

AU - Bi, Ruiye

AU - Maridas, David

AU - DeMambro, Victoria

AU - Figueroa, Carolina A.

AU - Kir, Serkan

AU - Zhou, Xuedong

AU - Mannstadt, Michael

AU - Baron, Roland

AU - Bronson, Roderick T.

AU - Horowitz, Mark C.

AU - Wu, Joy Y.

AU - Bilezikian, John P.

AU - Dempster, David W.

AU - Rosen, Clifford J.

AU - Lanske, Beate

PY - 2017/3/7

Y1 - 2017/3/7

N2 - 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.

AB - 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.

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KW - receptor

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ER -

Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

Abstract

Keywords

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