Regulatory Effects of Pyrophosphate Metabolism on Cementogenesis

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Abstract

Cementum that envelops the tooth root provides an interface between the tooth proper and the supporting periodontal tissues. Evidence suggests cementum is uniquely sensitive to modulation of inorganic phosphate (Pᵢ), a component of hydroxyapatite, and pyrophosphate (PPᵢ), an inhibitor of hydroxyapatite precipitation. Modulation of PPᵢ concentration at sites of bone and tooth mineralization is important in guiding proper hard tissue formation. Factors increasing PPj include progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1), while tissue nonspecific alkaline phosphatase (TNAP) reduces PPᵢ by hydrolysis. To elucidate mechanisms by which root development is shaped by Pᵢ/PPᵢ homeostasis, studies were designed employing in vivo and in vitro approaches. In mice where the gene for TNAP (Akp2) was ablated, increased PP, caused aplasia or severe hypoplasia of the acellular extrinsic fiber cementum (AEFC). Expression of a key cementoblast gene bone sialoprotein (Bsp) was unaltered, suggesting the mechanism was physical-chemical inhibition of HAP rather than directed effects on cementoblasts. Conversely, in both Ank and Enppl KO mice, AEFC increased more than 10-fold versus controls, while other dentoalveolar tissues, including cellular intrinsic fiber cementum (CIFC), were unaltered. In both Ank and Enpp1 KO, AEFC featured a cellular cementum-like phenotype of dispersed BSP, and increased osteopontin (OPN) and dentin matrix protein 1 (DMP1) expression. Notably, Ank KO triggered markedly increased cementoblast NPP1 expression, suggesting attempted compensation for PP: dysregulation. In vitro studies provided a mechanistic platform for probing the association of Ank, Enppl, Opn, and Dmp1 with cementoblast mineralization. Under mineralizing conditions, OCCM.30 cementoblasts exhibited an increase in Ank and Enpp1, as well as Opn and Dmp1, and induction coincided with mineral nodule formation, suggesting these genes are functionally coupled to cementoblast mineralization. While low PPᵢ presided over robust mineralization and induction of PPr and mineral-associated genes, establishment of high PPᵢ conditions was sufficient to inhibit both mineralization and associated gene induction. Thus, PPᵢ is capable of governing both mineral apposition and cementoblast gene expression, and PPᵢ regulation is revealed as a major determinant defining acellular cementum formation. These results underscore the concept that PPᵢ modulation has potential as a novel approach to promote cementum regeneration.

Cited Works (13)

Year	Entry
2001	Toyosawa S, Shintani S, Fujiwara T, Ooshima T, Sato A, Ijuhin N, Komori T. Dentin matrix protein 1 is predominantly expressed in chicken and rat osteocytes but not in osteoblasts. J Bone Miner Res. November 2001;16(11):2017-2026.
2007	Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone. June 2007;40(6):1434-1446.
2009	Paic F, Igwe JC, Nori R, Kronenberg MS, Franceschetti T, Harrington P, Kuo L, Shin D-G, Rowe DW, Harris SE, Kalajzic I. Identification of differentially expressed genes between osteoblasts and osteocytes. Bone. October 2009;45(4):682-692.
1979	Junqueira LCU, Bignolas G, Brentani RR. Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histchem J. 1979;11:447-455.
1990	Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, Koga T, Martin TJ, Suda T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci USA. September 1, 1990;87(18):7260-7264.
2003	Gluhak-Heinrich J, Ye L, Bonewald LF, Feng JQ, MacDougall M, Harris SE, Pavlin D. Mechanical loading stimulates dentin matrix protein 1 (DMP1) expression in osteocytes in vivo. J Bone Miner Res. May 2003;18(5):807-817.
2001	Li J, Mashiba T, Burr DB. Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Calcif Tiss Int. November 2001;69(5):281-286.
2000	Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res. April 2000;15(4):613-620.
2007	Fantner GE, Adams J, Turner P, Thurner PJ, Fisher LW, Hansma PK. Nanoscale ion mediated networks in bone: osteopontin can repeatedly dissipate large amounts of energy. Nano Lett. August 2007;7(8):2491-2498.
2004	Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. May 2004;62(5):527-534.
2002	Boskey AL, Spevak L, Paschalis E, Doty SB, McKee MD. Osteopontin deficiency increases mineral content and mineral crystallinity in mouse bone. Calcif Tiss Int. August 2002;71(2):145-154.
2006	Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, Yu X, Rauch F, Davis SI, Zhang S, Rios H, Drezner MK, Quarles LD, Bonewald LF, White KE. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. November 2006;38(11):1310-1315.
2001	Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone. May 2001;28(5):524-531.