Nmp4/CIZ suppresses parathyroid hormone-induced increases in trabecular bone.
The nucleocytoplasmic shuttling transcription factor Nmp4/CIZ (nuclear matrix protein 4/cas interacting zinc finger protein) is a ubiquitously expressed protein that regulates both cytoplasmic and nuclear activities. In the nucleus, Nmp4/CIZ represses transcription of genes crucial to osteoblast differentiation and genes activated by various anabolic stimuli, including parathyroid hormone (PTH). We investigated the role of Nmp4/CIZ in the PTH-induced increase in bone by engineering mice with loss-of-function mutations in the Nmp4/CIZ gene, and treating 10-week-old female mice with anabolic doses of human PTH (1-34) at 30 microg/kg/day, 7 day/week, for 7 weeks or vehicle control. The untreated, baseline phenotype of the Nmp4-null mice between 8 and 16 weeks of age included a modest but significant increase in bone mineral density (BMD) and bone mineral content (BMC) compared to wild-type (WT) mice. Type I collagen mRNA expression was moderately elevated in the femurs of the Nmp4-null mice. The Nmp4 mutant alleles decreased body weight by 4% when expressed on a mixed background but the same alleles on a pure B6 background yielded a significant, 15% increase in body weight among the KO mice, compared to their WT controls. Hormone treatment equally enhanced BMD and BMC over vehicle-treated mice in both the WT and Nmp4-null groups but Nmp4-KO mice exhibited a significantly greater PTH-induced acquisition of femoral trabecular bone as compared to WT mice. These data support our hypothesis that Nmp4/CIZ is a transcriptional attenuator that suppresses osteoid synthesis and PTH-mediated acquisition of cancellous bone. J. Cell. Physiol. 219: 734-743, 2009. (c) 2009 Wiley-Liss, Inc.
Robling
Alexander G
AG
Department of Anatomy & Cell Biology, Indiana University School of Medicine (IUSM), Indianapolis, Indiana, USA.
Childress
Paul
P
Yu
Jun
J
Cotte
Jessica
J
Heller
Aaron
A
Philip
Binu K
BK
Bidwell
Joseph P
JP
D000818:Animals; D001483:Base Sequence; D015519:Bone Density / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D024042:Collagen Type I / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D018390:Gene Targeting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034521:Nuclear Matrix-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D024042:Collagen Type I; D017931:DNA Primers; D034521:Nuclear Matrix-Associated Proteins; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D014157:Transcription Factors; C499081:Zfp384 protein, mouse