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PTH Induces Systemically Administered Mesenchymal Stem Cells to Migrate to and Regenerate Spine Injuries.

Abstract Osteoporosis affects more than 200 million people worldwide leading to more than 2 million fractures in the United States alone. Unfortunately, surgical treatment is limited in patients with low bone mass. Parathyroid hormone (PTH) was shown to induce fracture repair in animals by activating mesenchymal stem cells (MSCs). However, it would be less effective in patients with fewer and/or dysfunctional MSCs due to aging and comorbidities. To address this, we evaluated the efficacy of combination i.v. MSC and PTH therapy versus monotherapy and untreated controls, in a rat model of osteoporotic vertebral bone defects. The results demonstrated that combination therapy significantly increased new bone formation versus monotherapies and no treatment by 2 weeks (P < 0.05). Mechanistically, we found that PTH significantly enhanced MSC migration to the lumbar region, where the MSCs differentiated into bone-forming cells. Finally, we used allogeneic porcine MSCs and observed similar findings in a clinically relevant minipig model of vertebral defects. Collectively, these results demonstrate that in addition to its anabolic effects, PTH functions as an adjuvant to i.v. MSC therapy by enhancing migration to heal bone loss. This systemic approach could be attractive for various fragility fractures, especially using allogeneic cells that do not require invasive tissue harvest.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title molecular therapy : the journal of the american society of gene therapy
Publication Year Start




PMID- 26585691
OWN - NLM
STAT- MEDLINE
DCOM- 20161109
LR  - 20170920
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Linking)
VI  - 24
IP  - 2
DP  - 2016 Feb
TI  - PTH Induces Systemically Administered Mesenchymal Stem Cells to Migrate to and
      Regenerate Spine Injuries.
PG  - 318-330
LID - S1525-0016(16)30337-9 [pii]
LID - 10.1038/mt.2015.211 [doi]
AB  - Osteoporosis affects more than 200 million people worldwide leading to more than 
      2 million fractures in the United States alone. Unfortunately, surgical treatment
      is limited in patients with low bone mass. Parathyroid hormone (PTH) was shown to
      induce fracture repair in animals by activating mesenchymal stem cells (MSCs).
      However, it would be less effective in patients with fewer and/or dysfunctional
      MSCs due to aging and comorbidities. To address this, we evaluated the efficacy
      of combination i.v. MSC and PTH therapy versus monotherapy and untreated
      controls, in a rat model of osteoporotic vertebral bone defects. The results
      demonstrated that combination therapy significantly increased new bone formation 
      versus monotherapies and no treatment by 2 weeks (P &lt; 0.05). Mechanistically, we 
      found that PTH significantly enhanced MSC migration to the lumbar region, where
      the MSCs differentiated into bone-forming cells. Finally, we used allogeneic
      porcine MSCs and observed similar findings in a clinically relevant minipig model
      of vertebral defects. Collectively, these results demonstrate that in addition to
      its anabolic effects, PTH functions as an adjuvant to i.v. MSC therapy by
      enhancing migration to heal bone loss. This systemic approach could be attractive
      for various fragility fractures, especially using allogeneic cells that do not
      require invasive tissue harvest.
FAU - Sheyn, Dmitriy
AU  - Sheyn D
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA;
      Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 
      Los Angeles, California, USA.
FAU - Shapiro, Galina
AU  - Shapiro G
AD  - Skeletal Biotech Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
FAU - Tawackoli, Wafa
AU  - Tawackoli W
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA;
      Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 
      Los Angeles, California, USA; Biomedical Imaging Research Institute, Cedars-Sinai
      Medical Center, Los Angeles, California, USA.
FAU - Jun, Douk Soo
AU  - Jun DS
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
FAU - Koh, Youngdo
AU  - Koh Y
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
FAU - Kang, Kyu Bok
AU  - Kang KB
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
FAU - Su, Susan
AU  - Su S
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA;
      Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 
      Los Angeles, California, USA.
FAU - Da, Xiaoyu
AU  - Da X
AD  - Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, 
      California, USA.
FAU - Ben-David, Shiran
AU  - Ben-David S
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA;
      Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 
      Los Angeles, California, USA.
FAU - Bez, Maxim
AU  - Bez M
AD  - Skeletal Biotech Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
FAU - Yalon, Eran
AU  - Yalon E
AD  - Skeletal Biotech Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
FAU - Antebi, Ben
AU  - Antebi B
AD  - Skeletal Biotech Laboratory, Hebrew University of Jerusalem, Jerusalem, Israel.
FAU - Avalos, Pablo
AU  - Avalos P
AD  - Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 
      Los Angeles, California, USA.
FAU - Stern, Tomer
AU  - Stern T
AD  - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
FAU - Zelzer, Elazar
AU  - Zelzer E
AD  - Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
FAU - Schwarz, Edward M
AU  - Schwarz EM
AD  - The Center for Musculoskeletal Research, University of Rochester Medical Center, 
      Rochester, New York, USA; Department of Orthopedics, University of Rochester
      Medical Center, Rochester, New York, USA.
FAU - Gazit, Zulma
AU  - Gazit Z
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA;
      Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 
      Los Angeles, California, USA; Skeletal Biotech Laboratory, Hebrew University of
      Jerusalem, Jerusalem, Israel.
FAU - Pelled, Gadi
AU  - Pelled G
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA;
      Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 
      Los Angeles, California, USA; Skeletal Biotech Laboratory, Hebrew University of
      Jerusalem, Jerusalem, Israel.
FAU - Bae, Hyun M
AU  - Bae HM
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
FAU - Gazit, Dan
AU  - Gazit D
AD  - Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA;
      Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 
      Los Angeles, California, USA; Skeletal Biotech Laboratory, Hebrew University of
      Jerusalem, Jerusalem, Israel; Biomedical Imaging Research Institute, Cedars-Sinai
      Medical Center, Los Angeles, California, USA. Electronic address:
      [email protected]
LA  - eng
GR  - P50 AR054041/AR/NIAMS NIH HHS/United States
GR  - R01 DE019902/DE/NIDCR NIH HHS/United States
GR  - R01DE019902/DE/NIDCR NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20151120
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Parathyroid Hormone)
SB  - IM
EIN - Mol Ther. 2016 Apr;24(4):843. Bae, Hyun M [Corrected to Bae, Hyun W]. PMID:
      27081722
MH  - Animals
MH  - Bone Regeneration/*drug effects
MH  - Cell Differentiation/drug effects
MH  - Cell Movement/drug effects
MH  - Combined Modality Therapy
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Mesenchymal Stem Cell Transplantation/*methods
MH  - Mesenchymal Stromal Cells/cytology/*drug effects
MH  - Osteoporosis/complications/*therapy
MH  - Parathyroid Hormone/*pharmacology
MH  - Rats
MH  - Spinal Fractures/etiology/*therapy
MH  - Swine
PMC - PMC4817819
EDAT- 2015/11/21 06:00
MHDA- 2016/11/10 06:00
CRDT- 2015/11/21 06:00
PHST- 2015/05/08 00:00 [received]
PHST- 2015/11/13 00:00 [accepted]
PHST- 2015/11/21 06:00 [entrez]
PHST- 2015/11/21 06:00 [pubmed]
PHST- 2016/11/10 06:00 [medline]
AID - S1525-0016(16)30337-9 [pii]
AID - 10.1038/mt.2015.211 [doi]
PST - ppublish
SO  - Mol Ther. 2016 Feb;24(2):318-330. doi: 10.1038/mt.2015.211. Epub 2015 Nov 20.