DMP1 Mutations: Defects in Odontogenesis

Summary

Principal Investigator: Jian Q Feng
Affiliation: Texas A and M Health Science Center
Country: USA
Abstract: DESCRIPTION (provided by applicant): Tooth development requires the precise spatial and temporal coordination of programs for cell growth, differentiation, and mineralization. In a search for genes required for normal tooth morphogenesis we have studied Dentin matrix protein1 (DMP1), a non- collagenous matrix protein highly expressed in pulp/odontoblast cells, using in vivo loss- and gain-of-function approaches. Dmp1-null mice display profound tooth abnormalities with enlarged pulp chambers, increased width of the predentin zone, hypomineralization, and delayed 3rd molar formation. Realizing that autosomal recessive hypophosphatemic rickets (ARHR) patients manifest phenotypic changes very similar to those observed in Dmp1-KO mice, we recently discovered two DMP1 mutations in these patients. We have concluded that these mutations are causes of the phenotypes resembling those of Dmp1-KO mice, although minor differences exist. In a search for mechanisms by which DMP1 controls odontogenesis, we unexpectedly observed a sharp reduction of osterix in the null pulp/odontoblasts. Osterix is a transcriptional factor that is essential for osteogenesis but its role in odontogenesis is unknown. Targeted re-expression of DMP1 in Dmp1-KO pulp/odontoblast cells restores osterix expression and rescues the defects in tooth formation. Notably, we found similar dentin abnormalities in Dmp1-KO, and osterix (conventional or conditional) KO mice. Therefore, we propose that DMP1 mutations are the cause of dentin defects in ARHR patients, and that DMP1 regulates osterix expression at an early stage of tooth development, which plays a critical role for odontogenesis. To test this hypothesis we will study the molecular genetics and pathophysiology of DMP1 mutations through creation of a mouse model with DMP1 mutations. We will also determine the mechanisms by which DMP1 modulates odontogenesis through Osterix via direct action at the nucleus and/or MAPK pathways. The successful completion of these studies will lead to 1) generation of an animal model mimicking these human mutations;2) understanding the mechanism by which DMP1 controls odontogenesis through osterix via a direct mechanism within the nucleus level and/or MAPK signaling;and 3) identification of bioactive fragment(s) of DMP1 which can ultimately be used in translational applications that will benefit the public by providing therapeutic approaches corresponding to genetic alterations, leading to improved dental/oral health. PUBLIC HEALTH RELEVANCE: Patients with autosomal recessive hypophosphatemic rickets (ARHR) patients manifest phenotypic changes very similar to dentin defects we observed in Dmp1-KO mice. Our discovery of DMP1 mutations in these patients led to the formulation of the current research proposal. Our successful completion of these studies will provide mechanistic details about dentin formation, and will ultimately shed light on the prevention of structural defects in dentin. In addition, the mouse models which to be generated from these studies can be used to correlate individual gene mutations with the appropriate clinical intervention.
Funding Period: 2008-09-30 - 2013-06-30
more information: NIH RePORT

Top Publications

  1. pmc Steroid-associated hip joint collapse in bipedal emus
    Li Zhen Zheng
    Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
    PLoS ONE 8:e76797. 2013
  2. pmc BMP receptor 1A determines the cell fate of the postnatal growth plate
    Junjun Jing
    1 State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, China 2 Department of Biomedical Sciences, Texas A and M Baylor College of Dentistry, Dallas, TX, USA
    Int J Biol Sci 9:895-906. 2013
  3. pmc Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia
    Jian Q Feng
    Department of Biomedical Sciences, Baylor College of Dentistry, Texas A and M Health Science Center, Dallas, TX 75246, USA
    Bone 54:213-21. 2013
  4. pmc GEP, a local growth factor, is critical for odontogenesis and amelogenesis
    Zhengguo Cao
    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 430079, China
    Int J Biol Sci 6:719-29. 2010
  5. pmc Dentin matrix protein 1 and phosphate homeostasis are critical for postnatal pulp, dentin and enamel formation
    Afsaneh Rangiani
    Biomedical Sciences, Baylor College of Dentistry, Texas A and M Health Science Center, Dallas, TX 75246, USA
    Int J Oral Sci 4:189-95. 2012
  6. pmc Hexa-D-arginine treatment increases 7B2•PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype
    Baozhi Yuan
    Department of Medicine, University of Wisconsin Madison and Geriatric Research and Education Center, William S Middleton Memorial Veterans Hospital, Madison, WI, USA
    J Bone Miner Res 28:56-72. 2013
  7. pmc Protective roles of DMP1 in high phosphate homeostasis
    Afsaneh Rangiani
    Biomedical Sciences, Baylor College of Dentistry, Texas A and M Health Science Center, Dallas, Texas, United States of America
    PLoS ONE 7:e42329. 2012
  8. pmc Genetic evidence for the vital function of Osterix in cementogenesis
    Zhengguo Cao
    The State Key Laboratory Breeding Base of Basic Science of Stomatology Hubei MOST, Ministry of Education, Department of Periodontology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
    J Bone Miner Res 27:1080-92. 2012
  9. pmc Post-natal effect of overexpressed DKK1 on mandibular molar formation
    X L Han
    Baylor College of Dentistry, Department of Biomedical Sciences, Texas A and M Health Science Center, 3302 Gaston Avenue, Dallas, TX 75246, USA
    J Dent Res 90:1312-7. 2011
  10. pmc Unique roles of phosphorus in endochondral bone formation and osteocyte maturation
    Rong Zhang
    Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, Xi an, People s Republic of China
    J Bone Miner Res 26:1047-56. 2011

Scientific Experts

  • Jian Q Feng
  • Yongbo Lu
  • Zhengguo Cao
  • Baozhi Yuan
  • Ying Liu
  • Afsaneh Rangiani
  • Chunlin Qin
  • Marc K Drezner
  • Tian Gao
  • Rong Zhang
  • Yixia Xie
  • Junjun Jing
  • Li Zhen Zheng
  • Yinshi Ren
  • Yao Sun
  • Xianglong Han
  • X L Han
  • Lynda F Bonewald
  • Dedong Ma
  • De Ming Xiao
  • STEPHEN BOWMAN
  • Xin Hui Xie
  • Zhaowen Zong
  • Yi Xin He
  • Daniel Tik Pui Fong
  • Robert D Blank
  • Ge Zhang
  • Yuji Mishina
  • Nobuhiro Kamiya
  • Iris Lindberg
  • Ling Qin
  • Xin Luan Wang
  • Zhong Liu
  • Jiang Peng
  • Xuedong Zhou
  • Le Huang
  • Da Ping Wang
  • Chi Wai Man
  • Chuanju Liu
  • Yang Chen
  • Ming Lei
  • Hua Zhang
  • Yong Jiang
  • Anika Voisey Rodgers
  • Benoit de Crombrugghe
  • Xin Zhou
  • Anika Rodgers
  • Chun lin Qin
  • Yin Xiao
  • Zheng guo Cao
  • Martha J Somerman
  • Makoto Kuro-o
  • Naoto Haruyama
  • P Dechow
  • P Kurimoto
  • Ling Ye
  • Shibin Yu
  • L Tefera
  • Marc D McKee
  • A Voisey
  • M Liu
  • Hector F Rios
  • Sarah L Dallas
  • Ashok B Kulkarni
  • T Gao
  • Y S Ren
  • H Z Ke
  • Chuan Ju Liu
  • Baichun Jiang

Detail Information

Publications14

  1. pmc Steroid-associated hip joint collapse in bipedal emus
    Li Zhen Zheng
    Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China
    PLoS ONE 8:e76797. 2013
    ..In conclusion, bipedal emus could be used as an effective preclinical experimental model to evaluate potential treatment protocols to be developed for prevention of ON-induced hip joint collapse in patients...
  2. pmc BMP receptor 1A determines the cell fate of the postnatal growth plate
    Junjun Jing
    1 State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, China 2 Department of Biomedical Sciences, Texas A and M Baylor College of Dentistry, Dallas, TX, USA
    Int J Biol Sci 9:895-906. 2013
    ..A working hypothesis is proposed to explain the vital role of BMPR1A in postnatal chondrogenesis. ..
  3. pmc Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia
    Jian Q Feng
    Department of Biomedical Sciences, Baylor College of Dentistry, Texas A and M Health Science Center, Dallas, TX 75246, USA
    Bone 54:213-21. 2013
    ....
  4. pmc GEP, a local growth factor, is critical for odontogenesis and amelogenesis
    Zhengguo Cao
    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 430079, China
    Int J Biol Sci 6:719-29. 2010
    ..In conclusion, both the in vivo and the in vivo data support an important role of GEP in tooth formation during postnatal development...
  5. pmc Dentin matrix protein 1 and phosphate homeostasis are critical for postnatal pulp, dentin and enamel formation
    Afsaneh Rangiani
    Biomedical Sciences, Baylor College of Dentistry, Texas A and M Health Science Center, Dallas, TX 75246, USA
    Int J Oral Sci 4:189-95. 2012
    ..Based on the above findings, we conclude that DMP1 has a protective role for odontoblasts and ameloblasts in a pro-apoptotic environment (a high Pi level)...
  6. pmc Hexa-D-arginine treatment increases 7B2•PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype
    Baozhi Yuan
    Department of Medicine, University of Wisconsin Madison and Geriatric Research and Education Center, William S Middleton Memorial Veterans Hospital, Madison, WI, USA
    J Bone Miner Res 28:56-72. 2013
    ..These data suggest that decreased PHEX-dependent 7B2•PC2 activity is central to the pathogenesis of XLH...
  7. pmc Protective roles of DMP1 in high phosphate homeostasis
    Afsaneh Rangiani
    Biomedical Sciences, Baylor College of Dentistry, Texas A and M Health Science Center, Dallas, Texas, United States of America
    PLoS ONE 7:e42329. 2012
    ..To determine the role of DMP1 in both a hyperphosphatemic environment and within the ectopic calcifications, we created Dmp1/Klotho compound deficient (Dmp1(-/-)kl/kl) mice...
  8. pmc Genetic evidence for the vital function of Osterix in cementogenesis
    Zhengguo Cao
    The State Key Laboratory Breeding Base of Basic Science of Stomatology Hubei MOST, Ministry of Education, Department of Periodontology, School and Hospital of Stomatology, Wuhan University, Wuhan, China
    J Bone Miner Res 27:1080-92. 2012
    ....
  9. pmc Post-natal effect of overexpressed DKK1 on mandibular molar formation
    X L Han
    Baylor College of Dentistry, Department of Biomedical Sciences, Texas A and M Health Science Center, 3302 Gaston Avenue, Dallas, TX 75246, USA
    J Dent Res 90:1312-7. 2011
    ....
  10. pmc Unique roles of phosphorus in endochondral bone formation and osteocyte maturation
    Rong Zhang
    Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, Xi an, People s Republic of China
    J Bone Miner Res 26:1047-56. 2011
    ..Finally, a working hypothesis is proposed to explain how phosphate and DMP1 control osteocyte maturation...
  11. pmc FGF23 in skeletal modeling and remodeling
    Yongbo Lu
    Department of Biomedical Sciences, Baylor College of Dentistry Texas A and M University Health Science Center, 3302 Gaston Avenue, Dallas, TX 75246, USA
    Curr Osteoporos Rep 9:103-8. 2011
    ....
  12. pmc A novel role of periostin in postnatal tooth formation and mineralization
    Dedong Ma
    Department of Respiratory Medicine, Qilu Hospital, Shandong University, Jinan 250012, China
    J Biol Chem 286:4302-9. 2011
    ..In conclusion, periostin plays a novel direct role in controlling postnatal tooth formation, which is required for the integrity of both enamel and dentin...
  13. pmc The biological function of DMP-1 in osteocyte maturation is mediated by its 57-kDa C-terminal fragment
    Yongbo Lu
    Department of Biomedical Sciences, Baylor College of Dentistry, Texas A and M Health Science Center, Dallas, TX 75246, USA
    J Bone Miner Res 26:331-40. 2011
    ..These results show that the 57-kDa C-terminal fragment is the functional domain of DMP-1 that controls osteocyte maturation and phosphate metabolism...
  14. pmc Granulin epithelin precursor: a bone morphogenic protein 2-inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis
    Jian Q Feng
    Department of Biomedical Sciences, Baylor College of Dentistry, Texas A and M University System Health Science Center, Dallas, Texas, USA
    FASEB J 24:1879-92. 2010
    ..Collectively, these findings reveal a novel critical role of GEP growth factor in chondrocyte differentiation and the molecular events both in vivo and in vitro...