title: The nucleocytoplasmic shuttling protein CIZ reduces adult bone mass by inhibiting bone morphogenetic protein-induced bone formation.
abstract: Osteoporosis is a major health problem; however, the mechanisms regulating adult bone mass are poorly understood. Cas-interacting zinc finger protein (CIZ) is a nucleocytoplasmic shuttling protein that localizes at cell adhesion plaques that form where osteoblasts attach to substrate. To investigate the potential role of CIZ in regulating adult bone mass, we examined the bones in CIZ-deficient mice. Bone volume was increased and the rates of bone formation were increased in CIZ-deficient mice, whereas bone resorption was not altered. CIZ deficiency enhanced the levels of mRNA expression of genes encoding proteins related to osteoblastic phenotypes, such as alkaline phosphatase (ALP) as well as osterix mRNA expression in whole long bones. Bone marrow cells obtained from the femora of CIZ-deficient mice revealed higher ALP activity in culture and formed more mineralized nodules than wild-type cells. CIZ deficiency enhanced bone morphogenetic protein (BMP)-induced osteoblastic differentiation in bone marrow cells in cultures, indicating that BMP is the target of CIZ action. CIZ deficiency increased newly formed bone mass after femoral bone marrow ablation in vivo. Finally, BMP-2-induced bone formation on adult mouse calvariae in vivo was enhanced by CIZ deficiency. These results establish that CIZ suppresses the levels of adult bone mass through inhibition of BMP-induced activation of osteoblasts.
authors.affiliation: Department of Molecular Pharmacology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Morinobu
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamoto
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hino
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tsuji
authors.forename: Zhong-Jian
authors.initials: ZJ
authors.lastname: Shen
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakashima
authors.forename: Akira
authors.initials: A
authors.lastname: Nifuji
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hisamaru
authors.initials: H
authors.lastname: Hirai
authors.forename: Masaki
authors.initials: M
authors.lastname: Noda
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis* / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002113:Calcification, Physiologic / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology*; D005260:Female; D005269:Femur / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000076182:Sp7 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000469:Alkaline Phosphatase