Counter-regulatory phosphatases TNAP and NPP1 temporally regulate tooth root cementogenesis

Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate (Pi) to mineral inhibitor pyrophosphate (PPi), where local Pi and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1). The focus of this study was to define the roles of these phosphatases in cementogenesis. TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enpp1 null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enpp1 gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected. The timing and site of action of two key enzymes help regulate the formation of cementum, one of the mineralized substances of teeth. An international team led by Brian Foster from the US National Institute of Arthritis and Musculoskeletal and Skin Diseases considered the roles of two enzymes — tissue non-specific phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) — in cementum development. They showed in mice that early TNAP expression created a particular environment in teeth with low levels of pyrophosphate, a mineral inhibitor. This promoted the creation of a type of cementum that does not incorporate cells into its structure. Later on in development, the expression of NPP1 boosted levels of pyrophosphate, which restricted this type of cementum. These enzymes had little effect on cementum containing cells. The researchers confirmed these patterns in extracted human teeth.