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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
7R01DE018486-05
Application #
8291108
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Scholnick, Steven
Project Start
2008-09-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$333,834
Indirect Cost
$105,961
Name
Texas A&M University
Department
Other Basic Sciences
Type
Schools of Dentistry
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Lin, Shuxian; Zhang, Qi; Cao, Zhengguo et al. (2014) Constitutive nuclear expression of dentin matrix protein 1 fails to rescue the Dmp1-null phenotype. J Biol Chem 289:21533-43
Ren, Y; Lin, S; Jing, Y et al. (2014) A novel way to statistically analyze morphologic changes in Dmp1-null osteocytes. Connect Tissue Res 55 Suppl 1:129-33
Jing, J; Hinton, R J; Jing, Y et al. (2014) Osterix couples chondrogenesis and osteogenesis in post-natal condylar growth. J Dent Res 93:1014-21
Jing, Junjun; Hinton, Robert J; Mishina, Yuji et al. (2014) Critical role of Bmpr1a in mandibular condyle growth. Connect Tissue Res 55 Suppl 1:73-8
Lin, Shu-Xian; Zhang, Qi; Zhang, Hua et al. (2014) Nucleus-targeted Dmp1 transgene fails to rescue dental defects in Dmp1 null mice. Int J Oral Sci 6:133-41
Jing, Junjun; Ren, Yinshi; Zong, Zhaowen et al. (2013) BMP receptor 1A determines the cell fate of the postnatal growth plate. Int J Biol Sci 9:895-906
Yuan, Baozhi; Feng, Jian Q; Bowman, Stephen et al. (2013) Hexa-D-arginine treatment increases 7B2•PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype. J Bone Miner Res 28:56-72
Feng, Jian Q; Clinkenbeard, Erica L; Yuan, Baozhi et al. (2013) Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 54:213-21
Cao, Zhengguo; Zhang, Hua; Zhou, Xin et al. (2012) Genetic evidence for the vital function of Osterix in cementogenesis. J Bone Miner Res 27:1080-92
Zhang, Rong; Lu, Yongbo; Ye, Ling et al. (2011) Unique roles of phosphorus in endochondral bone formation and osteocyte maturation. J Bone Miner Res 26:1047-56

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