104 Concerted regulation of cementum by pyrophosphate regulatory agents

Thursday, March 22, 2012: 8 a.m. - 9:30 a.m.
Presentation Type: Oral Session
B. FOSTER1, F. NOCITI2, A. TRAN2, K.J. NAGATOMO1, D. MATSA-DUNN1, J. WADE1, W. WANG3, J.L. MILLAN3, and M. SOMERMAN2, 1Periodontics, University of Washington, Seattle, WA, 2National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, 3Sanford-Burnham Medical Research Institute, La Jolla, CA
Objectives: Levels of the mineralization inhibitor pyrophosphate (PPi) are controlled by antagonistic functions of factors that increase local PPi (progressive ankylosis protein, ANK; ectonucleotide pyrophosphatase/phosphodiesterase-1, NPP1) and those that decrease PPi (tissue-nonspecific alkaline phosphatase, Akp2/TNAP).  Transgenic mouse models have demonstrated tooth root acellular cementum is affected by PPi dysregulation, but it remains unclear how regulatory factors work in concert to affect PPi homeostasis and ultimately cementogenesis. 

Methods: Single and compound KO mouse models for Akp2, Ank, and Enpp1 were analyzed to determine the role of PPi in controlling cementogenesis.  Periodontal development in KO vs. control mice was analyzed by microCT, histology, histomorphometry, and immunohistochemistry.     

Results: Excess PPi during development (Akp2 KO) inhibited cementogenesis, while conversely, deficient PPi (Ank or Enpp1 KO) encouraged increased cementum apposition to more than 10-fold WT.  Low PPi and increased cementum conditions were associated with increased cementoblast expression of osteopontin (OPN), dentin matrix protein-1 (DMP1), and ANK or NPP1, all reflecting occurrence of excess mineralization.  Compound Akp2/Ank double KO (dKO) mice were prepared to determine effect on cementum when PPi levels were relatively normalized by ablation of both ANK and TNAP.  Presence of cementum in dKO mice indicated that TNAP is not absolutely necessary for cementogenesis, but that PPi removal is likely critical.  Regions of hypercementosis in the dKO (more than 5-fold WT) suggested reduced PPi from loss of ANK was not sufficiently corrected by removing TNAP.  Increased OPN, DMP1, and NPP1 linked to increased dKO cementum showed that PPi tunes not only cementum thickness, but also matrix properties.

Conclusions: PPi is a central regulator of acellular cementum formation, and physiologic PPi levels are carefully balanced by TNAP, ANK, and NPP1 in order to properly direct cementogenesis. The sensitivity of cementum to PPi may provide an advantageous strategy for cementum regeneration via PPi modulation.

This abstract is based on research that was funded entirely or partially by an outside source: NIH R01DE15109, NIH R01AR47908

Keywords: Cementum, Extracellular matrix molecules, Mineralization, Periodontics and Root