title: Constitutive nuclear expression of dentin matrix protein 1 fails to rescue the Dmp1-null phenotype.
abstract: Dentin matrix protein 1 (DMP1) plays multiple roles in bone, tooth, phosphate homeostasis, kidney, salivary gland, reproductive cycles, and the development of cancer. In vitro studies have indicated two different biological mechanisms: 1) as a matrix protein, DMP1 interacts with αvβ3 integrin and activates MAP kinase signaling; and 2) DMP1 serves as a transcription co-factor. In vivo studies have demonstrated its key role in osteocytes. This study attempted to determine whether DMP1 functions as a transcription co-factor and regulates osteoblast functions. For gene expression comparisons using adenovirus constructs, we targeted the expression of DMP1 either to the nucleus only by replacing the endogenous signal peptide with a nuclear localization signal (NLS) sequence (referred to as (NLS)DMP1) or to the extracellular matrix as the WT type (referred to as (SP)DMP1) in MC3T3 osteoblasts. High levels of DMP1 in either form greatly increased osteogenic gene expression in an identical manner. However, the targeted (NLS)DMP1 transgene driven by a 3.6-kb rat Col 1α1 promoter in the nucleus of osteoblasts and osteocytes failed to rescue the phenotyope of Dmp1-null mice, whereas the (SP)DMP1 transgene rescued the rickets defect. These studies support the notion that DMP1 functions as an extracellular matrix protein, rather than as a transcription co-factor in vivo. We also show that DMP1 continues its expression in osteoblasts during postnatal development and that the deletion of Dmp1 leads to an increase in osteoblast proliferation. However, poor mineralization in the metaphysis indicates a critical role for DMP1 in both osteoblasts and osteocytes.
authors.affiliation: From the Department of Biomedical Sciences, Texas A&M University, Baylor College of Dentistry, Dallas, Texas 75246, The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430072, Hubei, China.
authors.forename: Shuxian
authors.initials: S
authors.lastname: Lin
authors.affiliation: Laboratory of Oral Biomedical Science and Translational Medicine, Department of Endodontics, School of Stomatology, Tongji University, Shanghai 200092, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430072, Hubei, China.
authors.forename: Zhengguo
authors.initials: Z
authors.lastname: Cao
authors.affiliation: From the Department of Biomedical Sciences, Texas A&M University, Baylor College of Dentistry, Dallas, Texas 75246.
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Lu
authors.affiliation: From the Department of Biomedical Sciences, Texas A&M University, Baylor College of Dentistry, Dallas, Texas 75246.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: the Department of Biological Sciences, Columbia University, New York, New York 10027, and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Yan
authors.affiliation: From the Department of Biomedical Sciences, Texas A&M University, Baylor College of Dentistry, Dallas, Texas 75246.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: the Faculty of Dentistry, and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0G4, Canada.
authors.forename: Marc D
authors.initials: MD
authors.lastname: McKee
authors.affiliation: From the Department of Biomedical Sciences, Texas A&M University, Baylor College of Dentistry, Dallas, Texas 75246.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Qin
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430072, Hubei, China, zhichen@whu.edu.cn.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: From the Department of Biomedical Sciences, Texas A&M University, Baylor College of Dentistry, Dallas, Texas 75246, jfeng@bcd.tamhsc.edu.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism*; D017931:DNA Primers; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D019076:Transgenes
chemical_list: D017931:DNA Primers; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins
keywords: Autosomal Recessive Hypophosphatemic Rickets; Biomineralization; Bone; Dentin Matrix Protein 1; Development; Osteoblast; Osteocyte; Osteogenesis; Osteomalacia