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(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.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis 46202, USA.
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: He
authors.forename: Paul
authors.initials: P
authors.lastname: Childress
authors.forename: Mark
authors.initials: M
authors.lastname: Hood
authors.forename: Marta
authors.initials: M
authors.lastname: Alvarez
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Kacena
authors.forename: Michael
authors.initials: M
authors.lastname: Hanlon
authors.forename: Bryce
authors.initials: B
authors.lastname: McKee
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Bidwell
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D016723:Bone Remodeling; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000166:cytology / Q000502:physiology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009929:Organ Size; D010006:Osteoblasts / Q000502:physiology*; D015675:Osteocalcin / Q000097:blood; D013154:Spleen / Q000033:anatomy & histology; D019379:Teriparatide / Q000008:administration & dosage*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D000943:Antigens, Differentiation; D034521:Nuclear Matrix-Associated Proteins; D014157:Transcription Factors; C499081:Zfp384 protein, mouse; D015675:Osteocalcin; D019379:Teriparatide