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

Stem Cells Dev. 2013 Feb 1;22(3):492-500. doi: 10.1089/scd.2012.0308. Epub 2012 Sep 14.

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(Alk)(Phos+) cells (osteoprogenitors), and a higher percentage of CFU-F(Alk)(Phos+) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Differentiation / metabolism
  • Bone Marrow / metabolism
  • Bone Marrow Cells / metabolism
  • Bone Remodeling
  • CD4-Positive T-Lymphocytes / physiology
  • CD8-Positive T-Lymphocytes / physiology
  • Cells, Cultured
  • Female
  • Femur / cytology
  • Femur / physiology
  • Humans
  • Mesenchymal Stem Cells / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Matrix-Associated Proteins / genetics
  • Nuclear Matrix-Associated Proteins / metabolism*
  • Nuclear Matrix-Associated Proteins / physiology
  • Organ Size
  • Osteoblasts / physiology*
  • Osteocalcin / blood
  • Spleen / anatomy & histology
  • Teriparatide / administration & dosage*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology

Substances

  • Antigens, Differentiation
  • Nuclear Matrix-Associated Proteins
  • Transcription Factors
  • Zfp384 protein, mouse
  • Osteocalcin
  • Teriparatide