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Dive into the research topics where Esther Cory is active.

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Featured researches published by Esther Cory.


Journal of Bone and Mineral Research | 2012

Enzyme replacement prevents enamel defects in hypophosphatasia mice

Manisha C. Yadav; Rodrigo Cardoso de Oliveira; Brian L. Foster; Hanson Fong; Esther Cory; Sonoko Narisawa; Robert L. Sah; Martha J. Somerman; Michael P. Whyte; José Luis Millán

Hypophosphatasia (HPP) is the inborn error of metabolism characterized by deficiency of alkaline phosphatase activity, leading to rickets or osteomalacia and to dental defects. HPP occurs from loss‐of‐function mutations within the gene that encodes the tissue‐nonspecific isozyme of alkaline phosphatase (TNAP). TNAP knockout (Alpl−/−, aka Akp2−/−) mice closely phenocopy infantile HPP, including the rickets, vitamin B6‐responsive seizures, improper dentin mineralization, and lack of acellular cementum. Here, we report that lack of TNAP in Alpl−/− mice also causes severe enamel defects, which are preventable by enzyme replacement with mineral‐targeted TNAP (ENB‐0040). Immunohistochemistry was used to map the spatiotemporal expression of TNAP in the tissues of the developing enamel organ of healthy mouse molars and incisors. We found strong, stage‐specific expression of TNAP in ameloblasts. In the Alpl−/− mice, histological, µCT, and scanning electron microscopy analysis showed reduced mineralization and disrupted organization of the rods and inter‐rod structures in enamel of both the molars and incisors. All of these abnormalities were prevented in mice receiving from birth daily subcutaneous injections of mineral‐targeting, human TNAP at 8.2 mg/kg/day for up to 44 days. These data reveal an important role for TNAP in enamel mineralization and demonstrate the efficacy of mineral‐targeted TNAP to prevent enamel defects in HPP.


Bone | 2011

Dose response of bone-targeted enzyme replacement for murine hypophosphatasia

Manisha C. Yadav; Isabelle Lemire; Pierre Leonard; Guy Boileau; Laurent Blond; Martin Beliveau; Esther Cory; Robert L. Sah; Michael P. Whyte; Philippe Crine; José Luis Millán

Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD(10), renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2(-/-)) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2(-/-) mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2mg/kg for 43days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED(80) (the dose that prevents bone defects in 80% of mice) was 3.2, 2.8 and 2.9mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PP(i) concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP in patients, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP to mice. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials.


Journal of Bone and Joint Surgery, American Volume | 2016

Addition of Mesenchymal Stem Cells to Autologous Platelet-enhanced Fibrin Scaffolds in Chondral Defects: Does It Enhance Repair?

Laurie R. Goodrich; Albert C. Chen; Werpy Nm; Ashley Williams; Kisiday Jd; Alvin W. Su; Esther Cory; Morley Ps; McIlwraith Cw; Robert L. Sah; Constance R. Chu

BACKGROUND The chondrogenic potential of culture-expanded bone-marrow-derived mesenchymal stem cells (BMDMSCs) is well described. Numerous studies have also shown enhanced repair when BMDMSCs, scaffolds, and growth factors are placed into chondral defects. Platelets provide a rich milieu of growth factors and, along with fibrin, are readily available for clinical use. The objective of this study was to determine if the addition of BMDMSCs to an autologous platelet-enriched fibrin (APEF) scaffold enhances chondral repair compared with APEF alone. METHODS A 15-mm-diameter full-thickness chondral defect was created on the lateral trochlear ridge of both stifle joints of twelve adult horses. In each animal, one defect was randomly assigned to receive APEF+BMDMSCs and the contralateral defect received APEF alone. Repair tissues were evaluated one year later with arthroscopy, histological examination, magnetic resonance imaging (MRI), micro-computed tomography (micro-CT), and biomechanical testing. RESULTS The arthroscopic findings, MRI T2 map, histological scores, structural stiffness, and material stiffness were similar (p > 0.05) between the APEF and APEF+BMDMSC-treated repairs at one year. Ectopic bone was observed within the repair tissue in four of twelve APEF+BMDMSC-treated defects. Defects repaired with APEF alone had less trabecular bone edema (as seen on MRI) compared with defects repaired with APEF+BMDMSCs. Micro-CT analysis showed thinner repair tissue in defects repaired with APEF+BMDMSCs than in those treated with APEF alone (p < 0.05). CONCLUSIONS APEF alone resulted in thicker repair tissue than was seen with APEF+BMDMSCs. The addition of BMDMSCs to APEF did not enhance cartilage repair and stimulated bone formation in some cartilage defects. CLINICAL RELEVANCE APEF supported repair of critical-size full-thickness chondral defects in horses, which was not improved by the addition of BMDMSCs. This work supports further investigation to determine whether APEF enhances cartilage repair in humans.


Bone | 2013

Fifteen days of microgravity causes growth in calvaria of mice

Bing Zhang; Esther Cory; Roshmi Bhattacharya; Robert L. Sah; Alan R. Hargens

Bone growth may occur in spaceflight as a response to skeletal unloading and head-ward fluid shifts. While unloading causes significant loss of bone mass and density in legs of animals exposed to microgravity, increased blood and interstitial fluid flows accompanying microgravity-induced fluid redistribution may elicit an opposite effect in the head. Seven 23-week-old, adult female wild-type C57BL/6 mice were randomly chosen for exposure to 15 days of microgravity on the STS-131 mission, while eight female littermates served as ground controls. Upon mission completion, all 15 murine calvariae were imaged on a micro-computed tomography scanner. A standardized rectangular volume was placed on the parietal bones of each calvaria for analyses, and three parameters were determined to measure increased parietal bone volume: bone volume (BV), average cortical thickness (Ct.Th), and tissue mineral density (TMD). Microgravity exposure caused a statistically significant increase in BV of the spaceflight (SF) group compared to that of the ground control (GC) group, the mean BV±SD for the SF group was 1.904±0.842 mm3, compared to 1.758±0.122 mm3 for the GC group (p<0.05). Ct.Th demonstrated a trend of increase from 0.099±0.006 mm in the GC group to 0.104±0.005 mm in the SF group (p=0.12). TMD was similar between the two groups with 0.878±0.029 g/cm3 for the GC group and 0.893±0.028 g/cm3 for the SF group (p=0.31). Our results indicate that microgravity causes responsive changes in calvarial bones that do not normally bear weight. These findings suggest that fluid shifts alone accompanying microgravity may initiate bone adaptation independent of skeletal loading by tissue.


Science Translational Medicine | 2015

Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy

Karen M. Doody; Stephanie M. Stanford; Cristiano Sacchetti; Mattias N. D. Svensson; Charlotte H. Coles; Nikolaos Mitakidis; William B. Kiosses; Beatrix Bartok; Camille Fos; Esther Cory; Robert L. Sah; Ru Liu-Bryan; David L. Boyle; Heather A. Arnett; Tomas Mustelin; Maripat Corr; Jeffrey D. Esko; Michel L. Tremblay; Gary S. Firestein; A. Radu Aricescu; Nunzio Bottini

Targeting joint-lining fibroblast-like synoviocytes reduces the severity of arthritis. Switching off arthritis In patients with rheumatoid arthritis (RA), joint-lining cells—fibroblast-like synoviocytes (FLS)—become activated and contribute to inflammation as well as cartilage and bone destruction. FLS express RPTPσ, which, in neurons, can be regulated by a proteoglycan switch. Doody et al. now find that FLS can also be regulated by this proteoglycan switch, and that an RPTPσ decoy protein can block this switch and decrease FLS invasiveness and severity of arthritis in human cells and a mouse model of RA. If these data hold true in humans, targeting this proteoglycan switch may add another option when treating patients with RA. Despite the availability of several therapies for rheumatoid arthritis (RA) that target the immune system, a large number of RA patients fail to achieve remission. Joint-lining cells, called fibroblast-like synoviocytes (FLS), become activated during RA and mediate joint inflammation and destruction of cartilage and bone. We identify RPTPσ, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy. RPTPσ is reciprocally regulated by interactions with chondroitin sulfate or heparan sulfate containing extracellular proteoglycans in a mechanism called the proteoglycan switch. We show that the proteoglycan switch regulates FLS function. Incubation of FLS with a proteoglycan-binding RPTPσ decoy protein inhibited cell invasiveness and attachment to cartilage by disrupting a constitutive interaction between RPTPσ and the heparan sulfate proteoglycan syndecan-4. RPTPσ mediated the effect of proteoglycans on FLS signaling by regulating the phosphorylation and cytoskeletal localization of ezrin. Furthermore, administration of the RPTPσ decoy protein ameliorated in vivo human FLS invasiveness and arthritis severity in the K/BxN serum transfer model of RA. Our data demonstrate that FLS are regulated by an RPTPσ-dependent proteoglycan switch in vivo, which can be targeted for RA therapy. We envision that therapies targeting the proteoglycan switch or its intracellular pathway in FLS could be effective as a monotherapy or in combination with currently available immune-targeted agents to improve control of disease activity in RA patients.


Cartilage | 2014

Development of a Comprehensive Osteochondral Allograft MRI Scoring System (OCAMRISS) with Histopathologic, Micro-Computed Tomography, and Biomechanical Validation.

Eric Y. Chang; Andrea L. Pallante-Kichura; Won C. Bae; Jiang Du; Sheronda Statum; Tanya Wolfson; Anthony Gamst; Esther Cory; David Amiel; William D. Bugbee; Robert L. Sah; Christine B. Chung

Objective: To describe and apply a semiquantitative MRI scoring system for multifeature analysis of cartilage defect repair in the knee by osteochondral allografts and to correlate this scoring system with histopathologic, micro–computed tomography (µCT), and biomechanical reference standards using a goat repair model. Design: Fourteen adult goats had 2 osteochondral allografts implanted into each knee: one in the medial femoral condyle and one in the lateral trochlea. At 12 months, goats were euthanized and MRI was performed. Two blinded radiologists independently rated 9 primary features for each graft, including cartilage signal, fill, edge integration, surface congruity, calcified cartilage integrity, subchondral bone plate congruity, subchondral bone marrow signal, osseous integration, and presence of cystic changes. Four ancillary features of the joint were also evaluated, including opposing cartilage, meniscal tears, synovitis, and fat-pad scarring. Comparison was made with histologic and µCT reference standards as well as biomechanical measures. Interobserver agreement and agreement with reference standards was assessed. Cohen’s κ, Spearman’s correlation, and Kruskal-Wallis tests were used as appropriate. Results: There was substantial agreement (κ > 0.6, P < 0.001) for each MRI feature and with comparison against reference standards, except for cartilage edge integration (κ = 0.6). There was a strong positive correlation between MRI and reference standard scores (ρ = 0.86, P < 0.01). Osteochondral allograft MRI scoring system was sensitive to differences in outcomes between the types of allografts. Conclusions: We have described a comprehensive MRI scoring system for osteochondral allografts and have validated this scoring system with histopathologic and µCT reference standards as well as biomechanical indentation testing.


Journal of Bone and Mineral Research | 2016

Skeletal Mineralization Deficits and Impaired Biogenesis and Function of Chondrocyte‐Derived Matrix Vesicles in Phospho1–/– and Phospho1/Pit1 Double‐Knockout Mice

Manisha C. Yadav; Massimo Bottini; Esther Cory; Kunal Bhattacharya; Pia Kuss; Sonoko Narisawa; Robert L. Sah; Laurent Beck; Bengt Fadeel; Colin Farquharson; José Luis Millán

We have previously shown that ablation of either the Phospho1 or Alpl gene, encoding PHOSPHO1 and tissue‐nonspecific alkaline phosphatase (TNAP) respectively, lead to hyperosteoidosis, but that their chondrocyte‐derived and osteoblast‐derived matrix vesicles (MVs) are able to initiate mineralization. In contrast, the double ablation of Phospho1 and Alpl completely abolish initiation and progression of skeletal mineralization. We argued that MVs initiate mineralization by a dual mechanism: PHOSPHO1‐mediated intravesicular generation of inorganic phosphate (Pi) and phosphate transporter‐mediated influx of Pi. To test this hypothesis, we generated mice with col2a1‐driven Cre‐mediated ablation of Slc20a1, hereafter referred to as Pit1, alone or in combination with a Phospho1 gene deletion. Pit1col2/col2 mice did not show any major phenotypic abnormalities, whereas severe skeletal deformities were observed in the [Phospho1–/–; Pit1col2/col2] double knockout mice that were more pronounced than those observed in the Phospho1–/– mice. Histological analysis of [Phospho1–/–; Pit1col2/col2] bones showed growth plate abnormalities with a shorter hypertrophic chondrocyte zone and extensive hyperosteoidosis. The [Phospho1–/–; Pit1col2/col2] skeleton displayed significant decreases in BV/TV%, trabecular number, and bone mineral density, as well as decreased stiffness, decreased strength, and increased postyield deflection compared to Phospho1–/– mice. Using atomic force microscopy we found that ∼80% of [Phospho1–/–; Pit1col2/col2] MVs were devoid of mineral in comparison to ∼50% for the Phospho1–/– MVs and ∼25% for the WT and Pit1col2/col2 MVs. We also found a significant decrease in the number of MVs produced by both Phospho1–/– and [Phospho1–/–; Pit1col2/col2] chondrocytes. These data support the involvement of phosphate transporter 1, hereafter referred to as PiT‐1, in the initiation of skeletal mineralization and provide compelling evidence that PHOSPHO1 function is involved in MV biogenesis.


Journal of Dental Research | 2015

Periodontal Defects in the A116T Knock-in Murine Model of Odontohypophosphatasia

Brian L. Foster; C.R. Sheen; Nan E. Hatch; J. Liu; Esther Cory; Sonoko Narisawa; Tina Kiffer-Moreira; Robert L. Sah; Michael P. Whyte; Martha J. Somerman; José Luis Millán

Mutations in ALPL result in hypophosphatasia (HPP), a disease causing defective skeletal mineralization. ALPL encodes tissue nonspecific alkaline phosphatase (ALP), an enzyme that promotes mineralization by reducing inorganic pyrophosphate, a mineralization inhibitor. In addition to skeletal defects, HPP causes dental defects, and a mild clinical form of HPP, odontohypophosphatasia, features only a dental phenotype. The Alpl knockout (Alpl-/-) mouse phenocopies severe infantile HPP, including profound skeletal and dental defects. However, the severity of disease in Alpl-/- mice prevents analysis at advanced ages, including studies to target rescue of dental tissues. We aimed to generate a knock-in mouse model of odontohypophosphatasia with a primarily dental phenotype, based on a mutation (c.346G>A) identified in a human kindred with autosomal dominant odontohypophosphatasia. Biochemical, skeletal, and dental analyses were performed on the resulting Alpl+/A116T mice to validate this model. Alpl+/A116T mice featured 50% reduction in plasma ALP activity compared with wild-type controls. No differences in litter size, survival, or body weight were observed in Alpl+/A116T versus wild-type mice. The postcranial skeleton of Alpl+/A116T mice was normal by radiography, with no differences in femur length, cortical/trabecular structure or mineral density, or mechanical properties. Parietal bone trabecular compartment was mildly altered. Alpl+/A116T mice featured alterations in the alveolar bone, including radiolucencies and resorptive lesions, osteoid accumulation on the alveolar bone crest, and significant differences in several bone properties measured by micro–computed tomography. Nonsignificant changes in acellular cementum did not appear to affect periodontal attachment or function, although circulating ALP activity was correlated significantly with incisor cementum thickness. The Alpl+/A116T mouse is the first model of odontohypophosphatasia, providing insights on dentoalveolar development and function under reduced ALP, bringing attention to direct effects of HPP on alveolar bone, and offering a new model for testing potential dental-targeted therapies in future studies.


Endocrinology | 2014

Soluble Guanylate Cyclase as a Novel Treatment Target for Osteoporosis

Jisha Joshua; Gerburg K. Schwaerzer; Hema Kalyanaraman; Esther Cory; Robert L. Sah; Mofei Li; Florin Vaida; Gerry R. Boss; Renate B. Pilz

Osteoporosis is a major health problem leading to fractures that cause substantial morbidity and mortality. Current osteoporosis therapies have significant drawbacks, creating a need for novel bone-anabolic agents. We previously showed that the nitric oxide/cyclic GMP (cGMP)/protein kinase G pathway mediates some of the anabolic effects of estrogens and mechanical stimulation in osteoblasts and osteocytes, leading us to hypothesize that cGMP-elevating agents may have bone-protective effects. We tested cinaciguat, a prototype of a novel class of soluble guanylate cyclase activators, in a mouse model of estrogen deficiency-induced osteoporosis. Compared with sham-operated mice, ovariectomized mice had lower serum cGMP concentrations, which were largely restored to normal by treatment with cinaciguat or low-dose 17β-estradiol. Microcomputed tomography of tibiae showed that cinaciguat significantly improved trabecular bone microarchitecture in ovariectomized animals, with effect sizes similar to those obtained with estrogen replacement therapy. Cinaciguat reversed ovariectomy-induced osteocyte apoptosis as efficiently as estradiol and enhanced bone formation parameters in vivo, consistent with in vitro effects on osteoblast proliferation, differentiation, and survival. Compared with 17β-estradiol, which completely reversed the ovariectomy-induced increase in osteoclast number, cinaciguat had little effect on osteoclasts. Direct guanylate cyclase stimulators have been extremely well tolerated in clinical trials of cardiovascular diseases, and our findings provide proof-of-concept for this new class of drugs as a novel, anabolic treatment strategy for postmenopausal osteoporosis, confirming an important role of nitric oxide/cGMP/protein kinase G signaling in bone.


Journal of Bone and Mineral Research | 2017

A Novel, Direct NO Donor Regulates Osteoblast and Osteoclast Functions and Increases Bone Mass in Ovariectomized Mice

Hema Kalyanaraman; Ghania Ramdani; Jisha Joshua; Nadine Schall; Gerry R. Boss; Esther Cory; Robert L. Sah; Darren E. Casteel; Renate B. Pilz

Most US Food and Drug Administration (FDA)‐approved treatments for osteoporosis target osteoclastic bone resorption. Only PTH derivatives improve bone formation, but they have drawbacks, and novel bone‐anabolic agents are needed. Nitrates, which generate NO, improved BMD in estrogen‐deficient rats and may improve bone formation markers and BMD in postmenopausal women. However, nitrates are limited by induction of oxidative stress and development of tolerance, and may increase cardiovascular mortality after long‐term use. Here we studied nitrosyl‐cobinamide (NO‐Cbi), a novel, direct NO‐releasing agent, in a mouse model of estrogen deficiency–induced osteoporosis. In murine primary osteoblasts, NO‐Cbi increased intracellular cGMP, Wnt/β‐catenin signaling, proliferation, and osteoblastic gene expression, and protected cells from apoptosis. Correspondingly, in intact and ovariectomized (OVX) female C57Bl/6 mice, NO‐Cbi increased serum cGMP concentrations, bone formation, and osteoblastic gene expression, and in OVX mice, it prevented osteocyte apoptosis. NO‐Cbi reduced osteoclasts in intact mice and prevented the known increase in osteoclasts in OVX mice, partially through a reduction in the RANKL/osteoprotegerin gene expression ratio, which regulates osteoclast differentiation, and partially through direct inhibition of osteoclast differentiation, observed in vitro in the presence of excess RANKL. The positive NO effects in osteoblasts were mediated by cGMP/protein kinase G (PKG), but some of the osteoclast‐inhibitory effects appeared to be cGMP‐independent. NO‐Cbi increased trabecular bone mass in both intact and OVX mice, consistent with its in vitro effects on osteoblasts and osteoclasts. NO‐Cbi is a novel direct NO‐releasing agent that, in contrast to nitrates, does not generate oxygen radicals, and combines anabolic and antiresorptive effects in bone, making it an excellent candidate for treating osteoporosis.

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Robert L. Sah

University of California

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Albert C. Chen

University of California

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Martha J. Somerman

National Institutes of Health

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Michael P. Whyte

Washington University in St. Louis

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Dominique P. Pioletti

École Polytechnique Fédérale de Lausanne

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