The Progressive Ankylosis Protein Regulates Cementum Apposition and Extracellular Matrix Composition

Foster, Brian L.; Nagatomo, Kanako J.; Bamashmous, Shatha; Tompkins, Kevin; Fong, Hanson; Dunn, Douglas; Chu, Emily Y.; Guenther, Catherine; Kingsley, David M.; Rutherford, R. Bruce; Somerman, Martha J.

doi:10.1159/000323457

Cited by 38 publications

(82 citation statements)

References 176 publications

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“…Intramembranous bone forms as a two-step process whereby osteoblasts secrete the ECM (osteoid), and then in a second step, the matrix becomes mineralized in a regulated process. In contrast, acellular cementum formation involves a directed mineralization of the collagen fringe fibers at the tooth root surface (Bosshardt and Schroeder, 1991), a process that we and others have found to be heavily reliant on the physicochemical process of mineralization (Beertsen et al, 1985; Beertsen et al, 1999; Foster et al, 2011; Foster et al, 2012; Jayawardena et al, 2002; Kaipatur et al, 2008; McKee et al, 2011; Nociti et al, 2002; Zweifler et al, 2014). With lack of BSP, craniofacial intramembranous bone is delayed in the conversion from osteoid to mineralized bone.…”

Section: Discussionmentioning

confidence: 86%

Mineralization defects in cementum and craniofacial bone from loss of bone sialoprotein

Foster¹,

Ao²,

Willoughby³

et al. 2015

Bone

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Bone sialoprotein (BSP) is a multifunctional extracellular matrix protein found in mineralized tissues, including bone, cartilage, tooth root cementum (both acellular and cellular types), and dentin. In order to define the role BSP plays in the process of biomineralization of these tissues, we analyzed cementogenesis, dentinogenesis, and osteogenesis (intramembranous and endochondral) in craniofacial bone in Bsp null mice and wild-type (WT) controls over a developmental period (1-60 days post natal; dpn) by histology, immunohistochemistry, undecalcified histochemistry, microcomputed tomography (microCT), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and quantitative PCR (qPCR). Regions of intramembranous ossification in the alveolus, mandible, and calvaria presented delayed mineralization and osteoid accumulation, assessed by von Kossa and Goldner's trichrome stains at 1 and 14 dpn. Moreover, Bsp−/− mice featured increased cranial suture size at the early time point, 1 dpn. Immunostaining and PCR demonstrated that osteoblast markers, osterix, alkaline phosphatase, and osteopontin were unchanged in Bsp null mandibles compared to WT. Bsp−/− mouse molars featured a lack of functional acellular cementum formation by histology, SEM, and TEM, and subsequent loss of Sharpey's collagen fiber insertion into the tooth root structure. Bsp−/− mouse alveolar and mandibular bone featured equivalent or fewer osteoclasts at early ages (1 and 14 dpn), however, increased RANKL immunostaining and mRNA, and significantly increased number of osteoclast-like cells (2-5 fold) were found at later ages (26 and 60 dpn), corresponding to periodontal breakdown and severe alveolar bone resorption observed following molar teeth entering occlusion. Dentin formation was unperturbed in Bsp−/− mouse molars, with no delay in mineralization, no alteration in dentin dimensions, and no differences in odontoblast markers analyzed. No defects were identified in endochondral ossification in the cranial base, and craniofacial morphology was unaffected in Bsp−/− mice. These analyses confirm a critical role for BSP in processes of cementogenesis and intramembranous ossification of craniofacial bone, whereas endochondral ossification in the cranial base was minimally affected and dentinogenesis was normal in Bsp−/− molar teeth. Dissimilar effects of loss of BSP on mineralization of dental and craniofacial tissues suggest local differences in the role of BSP and/or yet to be defined interactions with site-specific factors.

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Section: Discussionmentioning

confidence: 86%

Mineralization defects in cementum and craniofacial bone from loss of bone sialoprotein

Foster¹,

Ao²,

Willoughby³

et al. 2015

Bone

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“…Alpl -/-mice harbor increased levels of the mineral inhibitor pyrophosphate (PP i ) and serve as a model of hypophosphatasia (HPP), where lack of acellular cementum predisposes to tooth loss (van den Bos et al, 2005). We have demonstrated that reduction of PP i , in turn, promotes increased acellular cementum formation (Foster et al, 2011, and hypothesized that acellular cementum represents a tissue strongly regulated at the physicochemical level of mineralization, i.e., hydroxyapatite nucleation and growth. Cellular cementum size was undiminished by the loss of BSP, though mineralization was delayed at earlier ages; functional consequences of this are under study.…”

Section: Acellular Cementum As a Mineralization-sensitive Tissuementioning

confidence: 99%

Deficiency in Acellular Cementum and Periodontal Attachment in Bsp Null Mice

et al. 2012

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A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. ABSTRACTBone sialoprotein (BSP) is an extracellular matrix protein found in mineralized tissues of the skeleton and dentition. BSP is multifunctional, affecting cell attachment and signaling through an RGD integrin-binding region, and acting as a positive regulator for mineral precipitation by nucleating hydroxyapatite crystals. BSP is present in cementum, the hard tissue covering the tooth root that anchors periodontal ligament (PDL) attachment. To test our hypothesis that BSP plays an important role in cementogenesis, we analyzed tooth development in a Bsp null ( -/-) mouse model. Developmental analysis by histology, histochemistry, and SEM revealed a significant reduction in acellular cementum formation on Bsp -/-mouse molar and incisor roots, and the cementum deposited appeared hypomineralized. Structural defects in cementum-PDL interfaces in Bsp -/-mice caused PDL detachment, likely contributing to the high incidence of incisor malocclusion. Loss of BSP caused progressively disorganized PDL and significantly increased epithelial down-growth with aging. Bsp -/-mice displayed extensive root and alveolar bone resorption, mediated by increased RANKL and the presence of osteoclasts. Results collected here suggest that BSP plays a non-redundant role in acellular cementum formation, likely involved in initiating mineralization on the root surface. Through its importance to cementum integrity, BSP is essential for periodontal function.KEY WORDS: bone sialoprotein, cementum, periodontal ligament, bone, alkaline phosphatase, extracellular matrix.

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“…Cementum and bone share regulatory pathways and key developmental influences as evidenced by mouse genetic studies and human disease phenotypes [2–4]. However, accumulated evidence over the past two decades has revealed that acellular cementum is hypersensitive to regulators of mineralization, apparently more so than other hard tissues of the dentition and skeleton [5–7]. …”

Section: Introductionmentioning

confidence: 99%

“…Mice lacking either ANK or ENPP1 activity ( Ank −/− and Enpp1 −/− mice, respectively) feature decreased extracellular PP i production/secretion and are predisposed to ectopic calcification [17, 19, 22, 23]. In the absence of ANK or ENPP1, acellular cementum is dramatically increased, pointing to PP i as a central regulator tuning cementum growth and mineralization [5–7]. Additional examples of the sensitivity of acellular cementum to disturbances in mineralization come from studies of endocrine disorders like X-linked hypophosphatemia (XLH; OMIM 307800) [24, 25] and autosomal recessive hypophosphatemic rickets (ARHR; OMIM 241520) [26], transgenic mouse models over-expressing mineralization inhibitors like matrix gla protein [27], or administration of pharmacologic agents such as etidronate, a synthetic PP i analog [28–30], where acellular cementum formation and function are negatively affected.…”

Section: Introductionmentioning

confidence: 99%

Overlapping functions of bone sialoprotein and pyrophosphate regulators in directing cementogenesis

Chavez

Chu

et al. 2017

Bone

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Although acellular cementum is essential for tooth attachment, factors directing its development and regeneration remain poorly understood. Inorganic pyrophosphate (PPi), a mineralization inhibitor, is a key regulator of cementum formation: tissue-nonspecific alkaline phosphatase (Alpl/TNAP) null mice (increased PPi) feature deficient cementum, while progressive ankylosis protein (Ank/ANK) null mice (decreased PPi) feature increased cementum. Bone sialoprotein (Bsp/BSP) and osteopontin (Spp1/OPN) are multifunctional extracellular matrix components of cementum proposed to have direct and indirect effects on cell activities and mineralization. Studies on dentoalveolar development of Bsp knockout (Bsp−/−) mice revealed severely reduced acellular cementum, however underlying mechanisms remain unclear. The similarity in defective cementum phenotypes between Bsp−/− mice and Alpl−/− mice (the latter featuring elevated PPi and OPN), prompted us to examine whether BSP is operating by modulating PPi-associated genes. Genetic ablation of Bsp caused a 2-fold increase in circulating PPi, altered mRNA expression of Alpl, Spp1, and Ank, and increased OPN protein in the periodontia. Generation of a Bsp knock-out (KO) cementoblast cell line revealed significantly decreased mineralization capacity, 50% increased PPi in culture media, and increased Spp1 and Ank mRNA expression. While addition of 2 μg/ml recombinant BSP altered Spp1, Ank, and Enpp1 expression in cementoblasts, changes resulting from this dose were not dependent on the integrin-binding RGD motif or by genetic ablation of Ank on the Bsp−/− MAPK/ERK signaling pathway. Decreasing PPi mouse background reestablished cementum formation, allowing more than 3-fold increased acellular cementum volume compared to WT. However, deleting Ank did not fully compensate for the absence of BSP. Bsp−/−;Ank−/− double-deficient mice exhibited mean 20–27% reduced cementum thickness and volume compared to Ank−/− mice. From these data, we conclude that the perturbations in PPi metabolism are not solely driving the cementum pathology in Bsp−/− mice, and that PPi is more potent than BSP as a cementum regulator, as shown by the ability to override loss of BSP by lowering PPi. We propose that BSP and PPi work in concert to direct mineralization in cementum and likely other mineralized tissues.

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The Progressive Ankylosis Protein Regulates Cementum Apposition and Extracellular Matrix Composition

Cited by 38 publications

References 176 publications

Mineralization defects in cementum and craniofacial bone from loss of bone sialoprotein

Mineralization defects in cementum and craniofacial bone from loss of bone sialoprotein

Deficiency in Acellular Cementum and Periodontal Attachment in Bsp Null Mice

Overlapping functions of bone sialoprotein and pyrophosphate regulators in directing cementogenesis

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