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Nmp4/CIZ suppresses parathyroid hormone‐induced increases in trabecular bone
Author(s) -
Robling Alexander G.,
Childress Paul,
Yu Jun,
Cotte Jessica,
Heller Aaron,
Philip Binu K.,
Bidwell Joseph P.
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21717
Subject(s) - parathyroid hormone , medicine , endocrinology , anabolism , null allele , osteoblast , biology , bone mineral , hormone , gene expression , osteoporosis , allele , gene , calcium , genetics , in vitro
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 µg/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. © 2009 Wiley‐Liss, Inc.