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Critical Reviews™ in Eukaryotic Gene Expression
インパクトファクター: 2.156 5年インパクトファクター: 2.255 SJR: 0.649 SNIP: 0.599 CiteScore™: 3

ISSN 印刷: 1045-4403
ISSN オンライン: 2162-6502

Critical Reviews™ in Eukaryotic Gene Expression

DOI: 10.1615/CritRevEukarGeneExpr.v22.i3.40
pages 205-218

Nmp4/CIZ Closes the Parathyroid Hormone Anabolic Window

Joseph Bidwell
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis IN, 46202
Paul Childress
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202
Marta B. Alvarez
Department of Anatomy and Cell Biology, Indiana University School of Dentistry, Indianapolis, IN 46202
Mark Hood, Jr.,
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis IN, 46202
Yongzheng He
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202; Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202
Fredrick M. Pavalko
Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202
Melissa A. Kacena
Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202
Feng-Chun Yang
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis IN, 46202; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202

要約

Chronic degenerative diseases are increasing with the aging U.S. population. One consequence of this phenomenon is the need for long-term osteoporosis therapies. Parathyroid hormone (PTH), the only FDA-approved treatment that adds bone to the aged skeleton, loses its potency within two years of initial treatment but the mechanism regulating its limited "anabolic window" is unknown. We have discovered that disabling the nucleocytoplasmic shuttling transcription factor nuclear matrix protein 4/cas interacting zinc finger protein (Nmp4/CIZ) in mice extends the PTH bone-forming capacity. Nmp4 was discovered during our search for nuclear matrix transcription factors that couple this hormone's impact on osteoblast cytoskeletal and nuclear organization with its anabolic capacity. CIZ was independently discovered as a protein that associates with the focal adhesion-associated mechanosensor p130Cas. The Nmp4/CIZ-knockout (KO) skeletal phenotype exhibits a modestly enhanced bone mineral density but manifests an exaggerated response to both PTH and to BMP2 and is resistant to disuse-induced bone loss. The cellular basis of the global Nmp4/CIZ-KO skeletal phenotype remains to be elucidated but may involve an expansion of the bone marrow osteoprogenitor population along with modestly enhanced osteoblast and osteoclast activities supporting anabolic bone turnover. As a shuttling Cys2His2 zinc finger protein, Nmp4/CIZ acts as a repressive transcription factor perhaps associated with epigenetic remodeling complexes, but the functional significance of its interaction with p130Cas is not known. Despite numerous remaining questions, Nmp4/CIZ provides insights into how the anabolic window is regulated, and itself may provide an adjuvant therapy target for the treatment of osteoporosis by extending PTH anabolic efficacy.


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