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 (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.
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA 02115, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
Yi
Y
Fan
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Jun-Ichi
JI
Hanai
Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Phuong T
PT
Le
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China; Endocrine Unit, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
Ruiye
R
Bi
Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
David
D
Maridas
Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Victoria
V
DeMambro
Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Carolina A
CA
Figueroa
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Serkan
S
Kir
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
Xuedong
X
Zhou
Endocrine Unit, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
Michael
M
Mannstadt
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA 02115, USA; Endocrine Unit, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
Roland
R
Baron
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02215, USA.
Roderick T
RT
Bronson
Department of Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, CT 06510, USA.
Mark C
MC
Horowitz
Division of Endocrinology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Joy Y
JY
Wu
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
John P
JP
Bilezikian
Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
David W
DW
Dempster
Maine Medical Center Research Institute, Scarborough, ME 04074, USA. Electronic address: rosenc@mmc.org.
Clifford J
CJ
Rosen
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA 02115, USA; Endocrine Unit, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. Electronic address: beate_lanske@hsdm.harvard.edu.
Beate
B
Lanske
D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D001842:Bone and Bones; D002452:Cell Count; D019070:Cell Lineage / Q000187:drug effects*; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010024:Osteoporosis / Q000473:pathology; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010641:Phenotype; D053245:RANK Ligand / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000166:cytology
D015415:Biomarkers; D010281:Parathyroid Hormone; D053245:RANK Ligand; D044168:Receptor, Parathyroid Hormone, Type 1; C045073:Cre recombinase; D019426:Integrases
PTH; RANKL; bone resorption; lineage; receptor