Abstract
BackgroundInorganic pyrophosphate (PPi) is a physiologic inhibitor of hydroxyapatite mineral precipitation involved in regulating mineralized tissue development and pathologic calcification. Local levels of PPi are controlled by antagonistic functions of factors that decrease PPi and promote mineralization (tissue-nonspecific alkaline phosphatase, Alpl/TNAP), and those that increase local PPi and restrict mineralization (progressive ankylosis protein, ANK; ectonucleotide pyrophosphatase phosphodiesterase-1, NPP1). The cementum enveloping the tooth root is essential for tooth function by providing attachment to the surrounding bone via the nonmineralized periodontal ligament. At present, the developmental regulation of cementum remains poorly understood, hampering efforts for regeneration. To elucidate the role of PPi in cementum formation, we analyzed root development in knock-out (−/−) mice featuring PPi dysregulation.ResultsExcess PPi in the Alpl−/− mouse inhibited cementum formation, causing root detachment consistent with premature tooth loss in the human condition hypophosphatasia, though cementoblast phenotype was unperturbed. Deficient PPi in both Ank and Enpp1 −/− mice significantly increased cementum apposition and overall thickness more than 12-fold vs. controls, while dentin and cellular cementum were unaltered. Though PPi regulators are widely expressed, cementoblasts selectively expressed greater ANK and NPP1 along the root surface, and dramatically increased ANK or NPP1 in models of reduced PPi output, in compensatory fashion. In vitro mechanistic studies confirmed that under low PPi mineralizing conditions, cementoblasts increased Ank (5-fold) and Enpp1 (20-fold), while increasing PPi inhibited mineralization and associated increases in Ank and Enpp1 mRNA.ConclusionsResults from these studies demonstrate a novel developmental regulation of acellular cementum, wherein cementoblasts tune cementogenesis by modulating local levels of PPi, directing and regulating mineral apposition. These findings underscore developmental differences in acellular versus cellular cementum, and suggest new approaches for cementum regeneration.
Highlights
The mineralized tissues of the teeth and skeleton are subject to homeostasis of inorganic phosphate (Pi) for normal development and maintenance [1]
In order to develop a comprehensive understanding of how PPi regulates tooth root development, we performed a detailed histological study of developing first mandibular molars and incisors of mice harboring homozygous knock-out (2/2) of Alpl, ankylosis gene (Ank), or Enpp1, compared to age-matched homozygous wild-type (+/+) controls
Alpl2/2 molars were marked by disruption of acellular cementum, visible as reduction of the basophilic layer and direct contact of periodontal ligament (PDL) cells and tissues with dentin
Summary
The mineralized tissues of the teeth and skeleton are subject to homeostasis of inorganic phosphate (Pi) for normal development and maintenance [1]. Pyrophosphate (PPi), composed of two molecules of Pi, functions as a pivotal regulator of physiological mineralization and pathologic calcification by acting as a potent inhibitor of HAP crystal precipitation [2,3,4,5]. Though the potential for PPi to inhibit biological mineralization is clear from in vitro experiments, the in vivo role and regulation of PPi has been more difficult to elucidate. As measurement of PPi in vivo at mineralization fronts is not possible, the analysis of cellular proteins that manufacture, transport, or degrade PPi has served to clarify the mechanisms for PPi modulation, in conjunction with in vitro experiments. Inorganic pyrophosphate (PPi) is a physiologic inhibitor of hydroxyapatite mineral precipitation involved in regulating mineralized tissue development and pathologic calcification. To elucidate the role of PPi in cementum formation, we analyzed root development in knock-out (2/2) mice featuring PPi dysregulation
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