scholarly journals Dentoalveolar Defects in the Hyp Mouse Model of X-linked Hypophosphatemia

2020 ◽  
Vol 99 (4) ◽  
pp. 419-428 ◽  
Author(s):  
H. Zhang ◽  
M.B. Chavez ◽  
T.N. Kolli ◽  
M.H. Tan ◽  
H. Fong ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Alveolar Bone ◽  
Volume Fraction ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Long Bone ◽  
Micro Ct ◽  
Mineral Density ◽  
Dentin Matrix Protein ◽  
Osteocyte Lacunae

Mutations in PHEX cause X-linked hypophosphatemia (XLH), a form of hypophosphatemic rickets. Hyp ( Phex mutant) mice recapitulate the XLH phenotype. Dental disorders are prevalent in individuals with XLH; however, underlying dentoalveolar defects remain incompletely understood. We analyzed Hyp mouse dentoalveolar defects at 42 and 90 d postnatal to comparatively define effects of XLH on dental formation and function. Phex mRNA was expressed by odontoblasts (dentin), osteocytes (bone), and cementocytes (cellular cementum) in wild-type (WT) mice. Enamel density was unaffected, though enamel volume was significantly reduced in Hyp mice. Dentin defects in Hyp molars were indicated histologically by wide predentin, thin dentin, and extensive interglobular dentin, confirming micro–computed tomography (micro-CT) findings of reduced dentin volume and density. Acellular cementum was thin and showed periodontal ligament detachment. Mechanical testing indicated dramatically altered periodontal mechanical properties in Hyp versus WT mice. Hyp mandibles demonstrated expanded alveolar bone with accumulation of osteoid, and micro-CT confirmed decreased bone volume fraction and alveolar bone density. Cellular cementum area was significantly increased in Hyp versus WT molars owing to accumulation of hypomineralized cementoid. Histology, scanning electron microscopy, and nanoindentation revealed hypomineralized “halos” surrounding Hyp cementocyte and osteocyte lacunae. Three-dimensional micro-CT analyses confirmed larger cementocyte/osteocyte lacunae and significantly reduced perilacunar mineral density. While long bone and alveolar bone osteocytes in Hyp mice overexpressed fibroblast growth factor 23 ( Fgf23), its expression in molars was much lower, with cementocyte Fgf23 expression particularly low. Expression and distribution of other selected markers were disturbed in Hyp versus WT long bone, alveolar bone, and cementum, including osteocyte/cementocyte marker dentin matrix protein 1 ( Dmp1). This study reports for the first time a quantitative analysis of the Hyp mouse dentoalveolar phenotype, including all mineralized tissues. Novel insights into cellular cementum provide evidence for a role for cementocytes in perilacunar mineralization and cementum biology.

scholarly journals Periodontal Breakdown in the Dmp1 Null Mouse Model of Hypophosphatemic Rickets

2008 ◽  
Vol 87 (7) ◽  
pp. 624-629 ◽  
Author(s):  
L. Ye ◽  
S. Zhang ◽  
H. Ke ◽  
L. F. Bonewald ◽  
JQ. Feng
Keyword(s):  
Mouse Model ◽  
Matrix Protein ◽  
Alveolar Bone ◽  
Alveolar Bone Loss ◽  
Hypophosphatemic Rickets ◽  
Null Mouse ◽  
Dentin Matrix Protein ◽  
Periodontal Breakdown ◽  
Dentin Matrix ◽  
Increased Susceptibility

Dentin Matrix Protein 1 (DMP1) is highly expressed in alveolar bone and cementum, which are important components of the periodontium. Therefore, we hypothesized that Dmp1 is critical for the integrity of the periodontium, and that deletion may lead to increased susceptibility to disease. An early-onset periodontal defect was observed in the Dmp1 null mouse, a mouse model of hypophosphatemic rickets. The alveolar bone is porous, with increased proteoglycan expression. The cementum is also defective, as characterized by irregular, punctate fluorochrome labeling and elevated proteoglycan. The osteocyte and cementocyte lacuno-canalicular system of both alveolar bone and cementum is abnormal, with irregular lacunar walls and fewer canaliculi. As a consequence, there is significant interproximal alveolar bone loss, combined with detachment between the periodontal ligament (PDL) and cementum. We propose that defective alveolar bone and cementum may account for the periodontal breakdown and increased susceptibility to bacterial infection in Dmp1 null mice.

Effects of Active Vitamin D or FGF23 Antibody on Hyp Mice Dentoalveolar Tissues

2021 ◽  
pp. 002203452110110
Author(s):  
E.J. Lira dos Santos ◽  
M.B. Chavez ◽  
M.H. Tan ◽  
F.F. Mohamed ◽  
T.N. Kolli ◽  
...  
Keyword(s):  
Alveolar Bone ◽  
Volume Fraction ◽  
Fibroblast Growth Factor 23 ◽  
Neutralizing Antibody ◽  
Micro Computed Tomography ◽  
Mineral Density ◽  
Bone Volume Fraction ◽  
Treatment Regimens ◽  
New Therapeutic Approaches ◽  
Phex Gene

Mutations in the PHEX gene lead to X-linked hypophosphatemia (XLH), a form of inherited rickets featuring elevated fibroblast growth factor 23 (FGF23), reduced 1,25-dihydroxyvitamin D (1,25D), and hypophosphatemia. Hyp mutant mice replicate the XLH phenotype, including dentin, alveolar bone, and cementum defects. We aimed to compare effects of 1,25D versus FGF23-neutralizing antibody (FGF23Ab) monotherapies on Hyp mouse dentoalveolar mineralization. Male Hyp mice, either injected subcutaneously with daily 1,25D or thrice weekly with FGF23 blocking antibody from 2 to 35 d postnatal, were compared to wild-type (WT) controls and untreated Hyp mice. Mandibles were analyzed by high-resolution micro–computed tomography (micro-CT), histology, and immunohistochemistry. Both interventions maintained normocalcemia, increased serum phosphate levels, and improved dentoalveolar mineralization in treated versus untreated Hyp mice. 1,25D increased crown dentin volume and thickness and root dentin/cementum volume, whereas FGF23Ab effects were limited to crown dentin volume. 1,25D increased bone volume fraction, bone mineral density, and tissue mineral density in Hyp mice, whereas FGF23Ab failed to significantly affect these alveolar bone parameters. Neither treatment fully attenuated dentin and bone defects to WT levels, and pulp volumes remained elevated regardless of treatment. Both treatments reduced predentin thickness and improved periodontal ligament organization, while 1,25D promoted a more profound improvement in acellular cementum thickness. Altered cell densities and lacunocanalicular properties of alveolar and mandibular bone osteocytes and cementocytes in Hyp mice were partially corrected by either treatment. Neither treatment normalized the altered distributions of bone sialoprotein and osteopontin in Hyp mouse alveolar bone. Moderate improvements from both 1,25D and FGF23Ab treatment regimens support further studies and collection of oral health data from subjects receiving a newly approved anti-FGF23 therapy. The inability of either treatment to fully correct Hyp mouse dentin and bone prompts further experiments into underlying pathological mechanisms to identify new therapeutic approaches.

scholarly journals A NovelPHEXMutation in Japanese Patients with X-Linked Hypophosphatemic Rickets

2015 ◽  
Vol 2015 ◽  
pp. 1-5
Author(s):  
Tetsuya Kawahara ◽  
Hiromi Watanabe ◽  
Risa Omae ◽  
Toshiyuki Yamamoto ◽  
Tetsuya Inazu
Keyword(s):  
Female Patient ◽  
Matrix Protein ◽  
Bone Mineralization ◽  
Fibroblast Growth Factor 23 ◽  
Japanese Patients ◽  
Hypophosphatemic Rickets ◽  
Gene Encoding ◽  
Vitamin D Metabolism ◽  
Dentin Matrix Protein ◽  
Disease Associated Genes

X-linked hypophosphatemic rickets (XLH) is a dominant inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. Inactivating mutations in the gene encoding phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) have been found to be associated with XLH. Here, we report a 16-year-old female patient affected by hypophosphatemic rickets. We evaluated her serum fibroblast growth factor 23 (FGF23) levels and conducted sequence analysis of the disease-associated genes of FGF23-related hypophosphatemic rickets:PHEX,FGF23, dentin matrix protein 1, and ectonucleotide pyrophosphatase/phosphodiesterase 1. She was diagnosed with XLH based on her clinical features and family history. Additionally, we observed elevated FGF23 levels and a novelPHEXexon 9 mutation (c.947G>T; p.Gly316Val) inherited from her father. Although bioinformatics showed that the mutation was neutral, Gly316 is perfectly conserved among humans, mice, and rats, and there were no mutations in other FGF23-related rickets genes, suggesting thatin silicoanalysis is limited in determining mutation pathogenicity. In summary, we present a female patient and her father with XLH harboring a novelPHEXmutation that appears to be causative of disease. Measurement of FGF23 for hypophosphatemic patients is therefore useful for the diagnosis of FGF23-dependent hypophosphatemia.

scholarly journals Update in Osteoporosis and Metabolic Bone Disorders

2007 ◽  
Vol 92 (3) ◽  
pp. 747-753 ◽  
Author(s):  
Dolores Shoback
Keyword(s):  
Bone Loss ◽  
Wnt Signaling ◽  
Matrix Protein ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Causative Role ◽  
Dentin Matrix Protein 1 ◽  
Dentin Matrix Protein ◽  
Sost Gene ◽  
Dentin Matrix

Abstract Considerable progress has been made in the development and testing of agents to treat osteoporosis. Most impressive are reports on new antiresorptive agents—both bisphosphonates (ibandronate and zoledronic acid) and monoclonal antibodies (MAbs) (denosumab) directed against receptor activator of nuclear factor κB-ligand, a key molecule in the control of commitment and activation of osteoclasts. Bisphosphonates promise convenience and potency at slowing bone loss, whereas denosumab offers powerful suppression of resorption and rapid offset of action. Attention is also shifting from the osteoclast as a target for new therapies to the osteoblast and the osteocyte, with its complex network within the depths of bone. Wnt signaling through the frizzled receptor and its coreceptor, the low-density lipoprotein receptor related protein-5, appears from both molecular and in vivo evidence to be a pivotal pathway for modulating osteoblastic activity, bone formation, and bone strength. The recently identified product of the SOST gene or sclerostin has also been shown to block Wnt signaling. Sclerostin is produced by the osteocytes buried in the bone and is a new target to treat bone loss. Clinical trial reports indicate that the calcimimetic cinacalcet can effectively treat PTH hypersecretion due to primary and secondary hyperparathyroidism and parathyroid carcinoma. Lastly, it is now recognized that the matrix protein dentin matrix protein-1 enhances the release of the phosphate-regulating factor fibroblast growth factor 23 and that mutations in dentin matrix protein-1 play a causative role in a form of hypophosphatemic rickets.

Ablation of Pyrophosphate Regulators Promotes Periodontal Regeneration

2020 ◽  
pp. 002203452098185
Author(s):  
A. Nagasaki ◽  
K. Nagasaki ◽  
E.Y. Chu ◽  
B.D. Kear ◽  
W.D. Tadesse ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Alveolar Bone ◽  
Periodontal Regeneration ◽  
Loss Of Function ◽  
Mineral Density ◽  
Inorganic Pyrophosphate ◽  
Dentin Matrix Protein ◽  
Genetic Ablation ◽  
Novel Approach ◽  
Mineralized Tissues

Biomineralization is regulated by inorganic pyrophosphate (PPi), a potent physiological inhibitor of hydroxyapatite crystal growth. Progressive ankylosis protein (ANK) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) act to increase local extracellular levels of PPi, inhibiting mineralization. The periodontal complex includes 2 mineralized tissues, cementum and alveolar bone (AB), both essential for tooth attachment. Previous studies demonstrated that loss of function of ANK or ENPP1 (reducing PPi) resulted in increased cementum formation, suggesting PPi metabolism may be a target for periodontal regenerative therapies. To compare the effects of genetic ablation of Ank, Enpp1, and both factors concurrently on cementum and AB regeneration, mandibular fenestration defects were created in Ank knockout ( Ank KO), Enpp1 mutant ( Enpp1asj/asj), and double KO (dKO) mice. Genetic ablation of Ank, Enpp1, or both factors increased cementum regeneration compared to controls at postoperative days (PODs) 15 and 30 ( Ank KO: 8-fold, 3-fold; Enpp1asj/asj: 7-fold, 3-fold; dKO: 11-fold, 4-fold, respectively) associated with increased fluorochrome labeling and expression of mineralized tissue markers, dentin matrix protein 1 ( Dmp1/DMP1), osteopontin ( Spp1/OPN), and bone sialoprotein ( Ibsp/BSP). Furthermore, dKO mice featured increased cementum thickness compared to single KOs at POD15 and Ank KO at POD30. No differences were noted in AB volume between genotypes, but osteoblast/osteocyte markers were increased in all KOs, partially mineralized osteoid volume was increased in dKO versus controls at POD15 (3-fold), and mineral density was decreased in Enpp1asj/asj and dKOs at POD30 (6% and 9%, respectively). Increased numbers of osteoclasts were present in regenerated AB of all KOs versus controls. These preclinical studies suggest PPi modulation as a potential and novel approach for cementum regeneration, particularly targeting ENPP1 and/or ANK. Differences in cementum and AB regeneration in response to reduced PPi conditions highlight the need to consider tissue-specific responses in strategies targeting regeneration of the entire periodontal complex.

scholarly journals Effects of different force magnitudes on corticotomy-assisted orthodontic tooth movement in rats

2018 ◽  
Vol 88 (5) ◽  
pp. 632-637 ◽  
Author(s):  
Kriangkrai Kraiwattanapong ◽  
Bancha Samruajbenjakun
Keyword(s):  
Alveolar Bone ◽  
Tooth Movement ◽  
Root Resorption ◽  
Volume Fraction ◽  
Micro Ct ◽  
Histomorphometric Analysis ◽  
Bone Volume Fraction ◽  
Bone Response ◽  
Significant Difference ◽  
Light Force

ABSTRACT Objectives: To investigate the effects of light and heavy forces with corticotomy on tooth movement rate, alveolar bone response, and root resorption in a rat model. Materials and Methods: The right and left sides of 40 male Wistar rats were randomly assigned using the split-mouth design to two groups: light force with corticotomy (LF) and heavy force with corticotomy (HF). Tooth movement was performed on the maxillary first molars using a nickel-titanium closed-coil spring delivering either 10 g (light force) or 50 g (heavy force). Tooth movement and alveolar bone response were assessed by micro–computed tomography (micro-CT) at day 0 as the baseline and on days 7, 14, 21, and 28. Root resorption was examined by histomorphometric analysis at day 28. Results: Micro-CT analysis showed a significantly greater tooth movement in the HF group at days 7 and 14 but no difference in bone volume fraction at any of the observed periods. Histomorphometric analysis found no significant difference in root resorption between the LF and HF groups at day 28. Conclusions: Heavy force with corticotomy increased tooth movement at days 7 and 14 but did not show any difference in alveolar bone change or root resorption.

scholarly journals Promoting effect of 1,25(OH) 2 vitamin D 3 in osteogenic differentiation from induced pluripotent stem cells to osteocyte-like cells

Open Biology ◽  
2015 ◽  
Vol 5 (2) ◽  
pp. 140201 ◽  
Author(s):  
Hiroshi Kato ◽  
Hiromi Ochiai-Shino ◽  
Shoko Onodera ◽  
Akiko Saito ◽  
Takahiko Shibahara ◽  
...  
Keyword(s):  
Vitamin D ◽  
Matrix Protein ◽  
Fibroblast Growth Factor 23 ◽  
Late Phase ◽  
Promoting Effect ◽  
Process Step ◽  
Dentin Matrix Protein ◽  
Related Transcription Factor ◽  
Vitamin D 3 ◽  
Induced Pluripotent

We recently reported a new method to purify the induced pluripotent stem (iPS)-derived osteoprogenitors (iPSop). In this paper, we optimized the procedure and characterized cells at each process step. We observed that 10 days of treatment with FGF-2, IGF-1 and TGF-β (FIT) resulted in early-phase osteoblasts and 14 days of treatment resulted in late-phase osteoblasts. We found that treatment with 1,25(OH) 2 vitamin D 3 increased expression of osteocalcin and decreased expression of tissue-non-specific alkaline phosphatase and runt-related transcription factor 2 (RUNX2) in iPSop-day14 cells (cells treated with FIT for 14 days). Therefore, iPSop-day14 cells were promoted to mature osteoblasts by 1,25(OH) 2 vitamin D 3 treatment. In addition, we found that 1,25(OH) 2 vitamin D 3 treatment for 14 days enhanced not only mineralization but also expression of osteocyte markers, including dentin matrix protein-1 and fibroblast growth factor-23, in iPSop cells. Therefore, 1,25(OH) 2 vitamin D 3 is a potent promoter of osteoblast–osteocyte transition. The results of this study suggest that it is possible to evaluate both early- and late-phase osteoblasts and to apply cells to drug screening for anabolic drugs that stimulate bone formation.

scholarly journals Degradation of MEPE, DMP1, and Release of SIBLING ASARM-Peptides (Minhibins): ASARM-Peptide(s) Are Directly Responsible for Defective Mineralization in HYP

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1757-1772 ◽  
Author(s):  
Aline Martin ◽  
Valentin David ◽  
Jennifer S. Laurence ◽  
Patricia M. Schwarz ◽  
Eileen M. Lafer ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Matrix Protein ◽  
Specific Binding ◽  
Osteoclast Differentiation ◽  
Hypophosphatemic Rickets ◽  
Western Blots ◽  
Dentin Matrix Protein ◽  
Coculture Model ◽  
Mineralization Defect ◽  
Asarm Peptide

Mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) and DMP1 (dentin matrix protein 1) result in X-linked hypophosphatemic rickets (HYP) and autosomal-recessive hypophosphatemic-rickets (ARHR), respectively. Specific binding of PHEX to matrix extracellular phosphoglycoprotein (MEPE) regulates the release of small protease-resistant MEPE peptides [acidic serine- and aspartate-rich MEPE-associated motif (ASARM) peptides]. ASARM peptides are potent inhibitors of mineralization (minhibins) that also occur in DMP1 [MEPE-related small integrin-binding ligand, N-linked glycoprotein (SIBLING) protein]. It is not known whether these peptides are directly responsible for the mineralization defect. We therefore used a bone marrow stromal cell (BMSC) coculture model, ASARM peptides, anti-ASARM antibodies, and a small synthetic PHEX peptide (SPR4; 4.2 kDa) to examine this. Surface plasmon resonance (SPR) and two-dimensional 1H/15N nuclear magnetic resonance demonstrated specific binding of SPR4 peptide to ASARM peptide. When cultured individually for 21 d, HYP BMSCs displayed reduced mineralization compared with wild type (WT) (−87%, P < 0.05). When cocultured, both HYP and WT cells failed to mineralize. However, cocultures (HYP and WT) or monocultures of HYP BMSCs treated with SPR4 peptide or anti-ASARM neutralizing antibodies mineralized normally. WT BMSCs treated with ASARM peptide also failed to mineralize properly without SPR4 peptide or anti-ASARM neutralizing antibodies. ASARM peptide treatment decreased PHEX mRNA and protein (−80%, P < 0.05) and SPR4 peptide cotreatment reversed this by binding ASARM peptide. SPR4 peptide also reversed ASARM peptide-mediated changes in expression of key osteoclast and osteoblast differentiation genes. Western blots of HYP calvariae and BMSCs revealed massive degradation of both MEPE and DMP1 protein compared with the WT. We conclude that degradation of MEPE and DMP-1 and release of ASARM peptides are chiefly responsible for the HYP mineralization defect and changes in osteoblast-osteoclast differentiation.

scholarly journals A Novel Method to Quantify Longitudinal Orthodontic Bone Changes with In Vivo Micro-CT Data

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Chao Wang ◽  
Li Cao ◽  
Chongshi Yang ◽  
Yubo Fan
Keyword(s):  
Alveolar Bone ◽  
Tooth Movement ◽  
Orthodontic Tooth Movement ◽  
Bone Modeling ◽  
Micro Ct ◽  
Sprague Dawley ◽  
Mineral Density ◽  
Bone Changes ◽  
Novel Method

Orthodontic tooth movement (OTM) is the result of region-specific bone modeling under a load. Quantification of this change in the alveolar bone around a tooth is a basic requirement to understand the mechanism of orthodontics. The purpose of this study was to quantify subregional alveolar bone changes during orthodontic tooth movement with a novel method. In this study, 12 Sprague-Dawley (SD) rats were used as an orthodontic model, and one side of the first upper molar was used to simulate OTM. The alveolar bone around the mesial root was reconstructed from in vivo micro-CT images and separated from other parts of the alveolar bone with two semicylinder filters. The amount and rate of OTM, bone mineral density (BMD), and bone volume (BV) around the root were calculated and compared at 5 time points. The results showed that the amount of tooth movement, BMD, and BV can be evaluated dynamically with this method. The molar moved fastest during the first 3 days, and the rate decreased after day 14. BMD decreased from day 0 to day 14 and returned from day 14 to day 28. BV deceased from day 0 to day 7 and from day 14 to day 28. The method created in this study can be used to accurately quantify dynamic alveolar bone changes during OTM.

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