Nmp4/CIZ suppresses the parathyroid hormone anabolic window by restricting mesenchymal stem cell and osteoprogenitor frequency

Yongzheng He, Paul Childress, Mark Hood, Marta Alvarez, Melissa Kacena, Michael Hanlon, Bryce McKee, Joseph Bidwell, Feng Chun Yang

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Parathyroid hormone (PTH) anabolic osteoporosis therapy is intrinsically limited by unknown mechanisms. We previously showed that disabling the transcription factor Nmp4/CIZ in mice expanded this anabolic window while modestly elevating bone resorption. This enhanced bone formation requires a lag period to materialize. Wild-type (WT) and Nmp4-knockout (KO) mice exhibited equivalent PTH-induced increases in bone at 2 weeks of treatment, but by 7 weeks, the null mice showed more new bone. At 3-week treatment, serum osteocalcin, a bone formation marker, peaked in WT mice, but continued to increase in null mice. To determine if 3 weeks is the time when the addition of new bone diverges and to investigate its cellular basis, we treated 10-week-old null and WT animals with human PTH (1-34) (30 μg/kg/day) or vehicle before analyzing femoral trabecular architecture and bone marrow (BM) and peripheral blood phenotypic cell profiles. PTH-treated Nmp4-KO mice gained over 2-fold more femoral trabecular bone than WT by 3 weeks. There was no difference between genotypes in BM cellularity or profiles of several blood elements. However, the KO mice exhibited a significant elevation in CFU-F cells, CFU-F AlkPhos+ cells (osteoprogenitors), and a higher percentage of CFU-FAlkPhos+ cells/CFU-F cells consistent with an increase in CD45-/CD146+/CD105+/nestin+ mesenchymal stem cell frequency. Null BM exhibited a 2-fold enhancement in CD8+ T cells known to support osteoprogenitor differentiation and a 1.6-fold increase in CFU-GM colonies (osteoclast progenitors). We propose that Nmp4/CIZ limits the PTH anabolic window by restricting the number of BM stem, progenitor, and blood cells that support anabolic bone remodeling.

Original languageEnglish
Pages (from-to)492-500
Number of pages9
JournalStem Cells and Development
Volume22
Issue number3
DOIs
StatePublished - Feb 1 2013

Fingerprint

Parathyroid Hormone
Mesenchymal Stromal Cells
Knockout Mice
Bone Marrow
Thigh
Osteogenesis
Bone and Bones
Blood Cells
Stem Cells
Teriparatide
Nestin
Granulocyte-Macrophage Progenitor Cells
Wild Animals
Bone Remodeling
Osteocalcin
Osteoclasts
Bone Resorption
Bone Marrow Cells
Osteoporosis
Transcription Factors

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology

Cite this

Nmp4/CIZ suppresses the parathyroid hormone anabolic window by restricting mesenchymal stem cell and osteoprogenitor frequency. / He, Yongzheng; Childress, Paul; Hood, Mark; Alvarez, Marta; Kacena, Melissa; Hanlon, Michael; McKee, Bryce; Bidwell, Joseph; Yang, Feng Chun.

In: Stem Cells and Development, Vol. 22, No. 3, 01.02.2013, p. 492-500.

Research output: Contribution to journalArticle

He, Yongzheng ; Childress, Paul ; Hood, Mark ; Alvarez, Marta ; Kacena, Melissa ; Hanlon, Michael ; McKee, Bryce ; Bidwell, Joseph ; Yang, Feng Chun. / Nmp4/CIZ suppresses the parathyroid hormone anabolic window by restricting mesenchymal stem cell and osteoprogenitor frequency. In: Stem Cells and Development. 2013 ; Vol. 22, No. 3. pp. 492-500.
@article{4e5988bab14244689e03db81c882524a,
title = "Nmp4/CIZ suppresses the parathyroid hormone anabolic window by restricting mesenchymal stem cell and osteoprogenitor frequency",
abstract = "Parathyroid hormone (PTH) anabolic osteoporosis therapy is intrinsically limited by unknown mechanisms. We previously showed that disabling the transcription factor Nmp4/CIZ in mice expanded this anabolic window while modestly elevating bone resorption. This enhanced bone formation requires a lag period to materialize. Wild-type (WT) and Nmp4-knockout (KO) mice exhibited equivalent PTH-induced increases in bone at 2 weeks of treatment, but by 7 weeks, the null mice showed more new bone. At 3-week treatment, serum osteocalcin, a bone formation marker, peaked in WT mice, but continued to increase in null mice. To determine if 3 weeks is the time when the addition of new bone diverges and to investigate its cellular basis, we treated 10-week-old null and WT animals with human PTH (1-34) (30 μg/kg/day) or vehicle before analyzing femoral trabecular architecture and bone marrow (BM) and peripheral blood phenotypic cell profiles. PTH-treated Nmp4-KO mice gained over 2-fold more femoral trabecular bone than WT by 3 weeks. There was no difference between genotypes in BM cellularity or profiles of several blood elements. However, the KO mice exhibited a significant elevation in CFU-F cells, CFU-F AlkPhos+ cells (osteoprogenitors), and a higher percentage of CFU-FAlkPhos+ cells/CFU-F cells consistent with an increase in CD45-/CD146+/CD105+/nestin+ mesenchymal stem cell frequency. Null BM exhibited a 2-fold enhancement in CD8+ T cells known to support osteoprogenitor differentiation and a 1.6-fold increase in CFU-GM colonies (osteoclast progenitors). We propose that Nmp4/CIZ limits the PTH anabolic window by restricting the number of BM stem, progenitor, and blood cells that support anabolic bone remodeling.",
author = "Yongzheng He and Paul Childress and Mark Hood and Marta Alvarez and Melissa Kacena and Michael Hanlon and Bryce McKee and Joseph Bidwell and Yang, {Feng Chun}",
year = "2013",
month = "2",
day = "1",
doi = "10.1089/scd.2012.0308",
language = "English",
volume = "22",
pages = "492--500",
journal = "Stem Cells and Development",
issn = "1547-3287",
publisher = "Mary Ann Liebert Inc.",
number = "3",

}

TY - JOUR

T1 - Nmp4/CIZ suppresses the parathyroid hormone anabolic window by restricting mesenchymal stem cell and osteoprogenitor frequency

AU - He, Yongzheng

AU - Childress, Paul

AU - Hood, Mark

AU - Alvarez, Marta

AU - Kacena, Melissa

AU - Hanlon, Michael

AU - McKee, Bryce

AU - Bidwell, Joseph

AU - Yang, Feng Chun

PY - 2013/2/1

Y1 - 2013/2/1

N2 - Parathyroid hormone (PTH) anabolic osteoporosis therapy is intrinsically limited by unknown mechanisms. We previously showed that disabling the transcription factor Nmp4/CIZ in mice expanded this anabolic window while modestly elevating bone resorption. This enhanced bone formation requires a lag period to materialize. Wild-type (WT) and Nmp4-knockout (KO) mice exhibited equivalent PTH-induced increases in bone at 2 weeks of treatment, but by 7 weeks, the null mice showed more new bone. At 3-week treatment, serum osteocalcin, a bone formation marker, peaked in WT mice, but continued to increase in null mice. To determine if 3 weeks is the time when the addition of new bone diverges and to investigate its cellular basis, we treated 10-week-old null and WT animals with human PTH (1-34) (30 μg/kg/day) or vehicle before analyzing femoral trabecular architecture and bone marrow (BM) and peripheral blood phenotypic cell profiles. PTH-treated Nmp4-KO mice gained over 2-fold more femoral trabecular bone than WT by 3 weeks. There was no difference between genotypes in BM cellularity or profiles of several blood elements. However, the KO mice exhibited a significant elevation in CFU-F cells, CFU-F AlkPhos+ cells (osteoprogenitors), and a higher percentage of CFU-FAlkPhos+ cells/CFU-F cells consistent with an increase in CD45-/CD146+/CD105+/nestin+ mesenchymal stem cell frequency. Null BM exhibited a 2-fold enhancement in CD8+ T cells known to support osteoprogenitor differentiation and a 1.6-fold increase in CFU-GM colonies (osteoclast progenitors). We propose that Nmp4/CIZ limits the PTH anabolic window by restricting the number of BM stem, progenitor, and blood cells that support anabolic bone remodeling.

AB - Parathyroid hormone (PTH) anabolic osteoporosis therapy is intrinsically limited by unknown mechanisms. We previously showed that disabling the transcription factor Nmp4/CIZ in mice expanded this anabolic window while modestly elevating bone resorption. This enhanced bone formation requires a lag period to materialize. Wild-type (WT) and Nmp4-knockout (KO) mice exhibited equivalent PTH-induced increases in bone at 2 weeks of treatment, but by 7 weeks, the null mice showed more new bone. At 3-week treatment, serum osteocalcin, a bone formation marker, peaked in WT mice, but continued to increase in null mice. To determine if 3 weeks is the time when the addition of new bone diverges and to investigate its cellular basis, we treated 10-week-old null and WT animals with human PTH (1-34) (30 μg/kg/day) or vehicle before analyzing femoral trabecular architecture and bone marrow (BM) and peripheral blood phenotypic cell profiles. PTH-treated Nmp4-KO mice gained over 2-fold more femoral trabecular bone than WT by 3 weeks. There was no difference between genotypes in BM cellularity or profiles of several blood elements. However, the KO mice exhibited a significant elevation in CFU-F cells, CFU-F AlkPhos+ cells (osteoprogenitors), and a higher percentage of CFU-FAlkPhos+ cells/CFU-F cells consistent with an increase in CD45-/CD146+/CD105+/nestin+ mesenchymal stem cell frequency. Null BM exhibited a 2-fold enhancement in CD8+ T cells known to support osteoprogenitor differentiation and a 1.6-fold increase in CFU-GM colonies (osteoclast progenitors). We propose that Nmp4/CIZ limits the PTH anabolic window by restricting the number of BM stem, progenitor, and blood cells that support anabolic bone remodeling.

UR - http://www.scopus.com/inward/record.url?scp=84872702795&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84872702795&partnerID=8YFLogxK

U2 - 10.1089/scd.2012.0308

DO - 10.1089/scd.2012.0308

M3 - Article

C2 - 22873745

AN - SCOPUS:84872702795

VL - 22

SP - 492

EP - 500

JO - Stem Cells and Development

JF - Stem Cells and Development

SN - 1547-3287

IS - 3

ER -