Disturbances of cementum formation induced by single injection of 1‐hydroxyethylidene‐1,1‐bisphosphonate (HEBP) in rats: light and scanning electron microscopic studies

Alatli-Kut, Idil; Hultenby, Kjell; Hammarström, Lars

doi:10.1111/j.1600-0722.1994.tb01466.x

Cited by 12 publications

(9 citation statements)

References 15 publications

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“…Intriguingly, the HEBP-treatment studies also report a layer of unmineralized cementum matrix (“hyperplastic cementum”) associated with unmineralized root dentin (47,48,51), identical in appearance to the “cementoid” layer found at later time points in Alpl −/− mouse molar teeth. We speculate this to be a functional response of the periodontal compartment to loss of dentin competence in Alpl −/− mice, and this hypothesis is the subject of ongoing studies.…”

Section: Discussionmentioning

confidence: 92%

Tooth root dentin mineralization defects in a mouse model of hypophosphatasia

Foster

Nagatomo

Tso

et al. 2012

Journal of Bone and Mineral Research

103

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Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in mineralizing tissues and functions to reduce pyrophosphate (PPi), a potent inhibitor of mineralization. Loss of TNAP function causes hypophosphatasia (HPP), a heritable disorder marked by increased PPi, resulting in rickets and osteomalacia. Tooth root cementum defects are well described in both HPP patients and in Alpl−/− mice, a model for infantile HPP. In Alpl−/− mice, dentin mineralization is specifically delayed in the root, however, reports from human HPP patients are variable and inconsistent regarding dentin defects. In the present study, we aimed to define the molecular basis for changes in dentinogenesis observed in Alpl−/− mice. TNAP was found to be highly expressed by mature odontoblasts, and Alpl−/− molar and incisor roots featured defective dentin mineralization, ranging from a mild delay to severely disturbed root dentinogenesis. Lack of mantle dentin mineralization was associated with disordered and dysmorphic odontoblasts having disrupted expression of marker genes osteocalcin and dentin sialophosphoprotein. The formation of, initiation of mineralization within, and rupture of matrix vesicles in Alpl−/− dentin matrix was not affected. Osteopontin (OPN), an inhibitor of mineralization that contributes to the skeletal pathology in Alpl−/− mice, was present in the generally unmineralized Alpl−/− mantle dentin at ruptured mineralizing matrix vesicles, as detected by immunohistochemistry and by immunogold labeling. However, ablating the OPN-encoding Spp1 gene in Alpl−/− mice was insufficient to rescue the dentin mineralization defect. Administration of bioengineered mineral-targeting human TNAP (ENB-0040) to Alpl−/− mice corrected defective dentin mineralization in the molar roots. These studies reveal that TNAP participates in root dentin formation and confirm that reduction of PPi during dentinogenesis is necessary for odontoblast differentiation, dentin matrix secretion, and mineralization. Furthermore, these results elucidate developmental mechanisms underlying dentin pathology in HPP patients, and begin to explain the reported variability in the dentin/pulp complex pathology in these patients.

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Section: Discussionmentioning

confidence: 92%

Tooth root dentin mineralization defects in a mouse model of hypophosphatasia

Foster

Nagatomo

Tso

et al. 2012

Journal of Bone and Mineral Research

103

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“…Secondly, mouse models of hypophosphatemia described to date tend to feature bone, dentin, and cellular cementum disorders, while acellular cementum is less affected [37], [38]. Thirdly, in studies employing a PP i analog, 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP), it was found that HEBP inhibited formation of acellular cementum entirely, while cellular cementum and bone matrices were produced, but remained unmineralized [35], [39], [40]. A parallel pattern emerged when mineralization inhibitor matrix gla protein (MGP) was ectopically expressed in bones and teeth; bone, dentin, and cellular cementum matrices were produced yet remained unmineralized, while AEFC was absent [41]; MGP and PP i may have parallel functions as mineral regulators throughout the body.…”

Section: Discussionmentioning

confidence: 99%

Central Role of Pyrophosphate in Acellular Cementum Formation

et al. 2012

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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.

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“…Based on the effect of single injection of HEBP on rat molar teeth, A latli ‐K ut et al . (16) speculated that inhibition of AEFC by HEBP is caused by lack of an underlying mineralized dentin surface rather than the cell toxicity of HEBP. They noted a lack of AEFC formation on the root dentin surface strictly on the areas of non‐mineralized dentin matrix even in the recovery phase from the influence of circulating HEBP.…”

Section: Discussionmentioning

confidence: 99%

“…In murine teeth, repeated administration of 1‐hydroxyethylidene‐1,1‐bisphosphonate (HEBP), a mineralization inhibitor, totally abolishes the formation of AEFC, whereas deposition of non‐mineralized matrix of bone, dentin, and cellular cementum is not affected significantly under the same conditions (12–15). Inhibition of acellular cementum formation is also reported to occur by single injection of HEBP in rat molars specifically on the portions of root surface where dentin mineralization had been arrested (16). Tissue non‐specific alkaline phosphatase gene‐knockout mice also display poorly developed AEFC, while matrix formation of dentin, enamel, bone, and cellular cementum are seemingly unaffected, associated only with delayed mineralization of the mantle dentin and localized enamel hypoplasia (17).…”

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confidence: 99%

On the origin of intrinsic matrix of acellular extrinsic fiber cementum: Studies on growing cementum pearls of normal and bisphosphonate‐affected guinea pig molars

Jayawardena

Takahashi

Watanabae

et al. 2002

European J Oral Sciences

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Cementum pearls (CPs) belong to a type of acellular extrinsic fiber cementum (AEFC) that form on the maturing enamel of guinea pig molars. This study aimed to elucidate the forming process of intrinsic matrix of AEFC using the CPs of normal and bisphosphonate-affected guinea pig molars as experimental models. A group of guinea pigs were subjected to continuous administration of 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) for 2 wk to inhibit mineralization of growing CPs. Fenestration of the enamel organ and migration of periodontal cells on to the exposed surface of maturing enamel appeared to be unaffected by HEBP, whereas de novo formation as well as growth of pre-existing CPs did not proceed under the same conditions. Immunoreactions for osteopontin were located exclusively on the mineralized matrix of preformed CPs, implying the absence of additional deposition or accumulation of putative intrinsic cementum matrix on the affected CPs, where the propagation of mineral phase had been arrested. In both normal and HEBP-treated groups, distinct enzymatic reactions for alkaline phosphatase appeared on the cells of the periodontal ligament associated closely with the sites of CP formation, and along the mineralization front of CPs. These observations suggest that the mineralization process per se plays a central role in the deposition of AEFC matrix and that alkaline phosphatase of periodontal cells penetrating through the enamel organ to the maturing enamel surface plays a key role in the mineralization process of CPs.

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Disturbances of cementum formation induced by single injection of 1‐hydroxyethylidene‐1,1‐bisphosphonate (HEBP) in rats: light and scanning electron microscopic studies

Cited by 12 publications

References 15 publications

Tooth root dentin mineralization defects in a mouse model of hypophosphatasia

Tooth root dentin mineralization defects in a mouse model of hypophosphatasia

Central Role of Pyrophosphate in Acellular Cementum Formation

On the origin of intrinsic matrix of acellular extrinsic fiber cementum: Studies on growing cementum pearls of normal and bisphosphonate‐affected guinea pig molars

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