Publications by authors named "Emmanuel Paul"

27 Publications

  • Page 1 of 1

Carbon Black Nanoparticles Selectively Alter Follicle-Stimulating Hormone Expression and in Female Mice.

Front Neurosci 2021 6;15:780698. Epub 2021 Dec 6.

Université de Paris, BFA, UMR 8251, CNRS, ERL U1133, Inserm, Paris, France.

Toxic effects of nanoparticles on female reproductive health have been documented but the underlying mechanisms still need to be clarified. Here, we investigated the effect of carbon black nanoparticles (CB NPs) on the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are key regulators of gonadal gametogenesis and steroidogenesis. To that purpose, we subjected adult female mice to a weekly non-surgical intratracheal administration of CB NPs at an occupationally relevant dose over 4 weeks. We also analyzed the effects of CB NPs , using both primary cultures of pituitary cells and the LβT2 gonadotrope cell line. We report here that exposure to CB NPs does not disrupt estrous cyclicity but increases both circulating FSH levels and pituitary FSH β-subunit gene () expression in female mice without altering circulating LH levels. Similarly, treatment of anterior pituitary or gonadotrope LβT2 cells with increasing concentrations of CB NPs dose-dependently up-regulates FSH but not LH gene expression or release. Moreover, CB NPs enhance the stimulatory effect of GnRH on expression in LβT2 cells without interfering with LH regulation. We provide evidence that CB NPs are internalized by LβT2 cells and rapidly activate the cAMP/PKA pathway. We further show that pharmacological inhibition of PKA significantly attenuates the stimulatory effect of CB NPs on expression. Altogether, our study demonstrates that exposure to CB NPs alters FSH but not LH expression and may thus lead to gonadotropin imbalance.
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http://dx.doi.org/10.3389/fnins.2021.780698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8685435PMC
December 2021

Summary of the Proceedings of the Basic Science of Uterine Fibroids Meeting: New Developments February 28, 2020.

F S Sci 2021 Feb 7;2(1):88-100. Epub 2020 Nov 7.

Department of Environmental and Occupational Health, George Washington University, Milken School of Public Health.

Scientists from multiple basic disciplines and an international group of physician-scientists from the field of obstetrics and gynecology presented recent studies and discussed new and evolving theories of uterine fibroid etiology, growth and development at The Basic Science of the Uterine Fibroids meeting, sponsored by the Campion Fund and the National Institute of Environmental Health Sciences. The purpose was to share up-to date knowledge and to stimulate new concepts regarding the basic molecular biology and pathophysiology of uterine fibroids, and to promote future collaborations. The meeting was held at the National Institutes of Environmental Health Sciences in North Carolina on February 28, 2020. Speakers reviewed recent advances in cellular and molecular processes that contribute to fibroid growth and new opportunities for treatment. At the conclusion of the conference, attendees identified important new directions for future research.
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http://dx.doi.org/10.1016/j.xfss.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192074PMC
February 2021

Transcriptome Analyses of Myometrium from Fibroid Patients Reveals Phenotypic Differences Compared to Non-Diseased Myometrium.

Int J Mol Sci 2021 Mar 31;22(7). Epub 2021 Mar 31.

Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA.

Uterine fibroid tissues are often compared to their matched myometrium in an effort to understand their pathophysiology, but it is not clear whether the myometria of uterine fibroid patients represent truly non-disease control tissues. We analyzed the transcriptomes of myometrial samples from non-fibroid patients (M) and compared them with fibroid (F) and matched myometrial (MF) samples to determine whether there is a phenotypic difference between fibroid and non-fibroid myometria. Multidimensional scaling plots revealed that M samples clustered separately from both MF and F samples. A total of 1169 differentially expressed genes (DEGs) (false discovery rate < 0.05) were observed in the MF comparison with M. Overrepresented Gene Ontology terms showed a high concordance of upregulated gene sets in MF compared to M, particularly extracellular matrix and structure organization. Gene set enrichment analyses showed that the leading-edge genes from the TGFβ signaling and inflammatory response gene sets were significantly enriched in MF. Overall comparison of the three tissues by three-dimensional principal component analyses showed that M, MF, and F samples clustered separately from each other and that a total of 732 DEGs from F vs. M were not found in the F vs. MF, which are likely understudied in the pathogenesis of uterine fibroids and could be key genes for future investigation. These results suggest that the transcriptome of fibroid-associated myometrium is different from that of non-diseased myometrium and that fibroid studies should consider using both matched myometrium and non-diseased myometrium as controls.
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http://dx.doi.org/10.3390/ijms22073618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036618PMC
March 2021

Chronic, Elevated Maternal Corticosterone During Pregnancy in the Mouse Increases Allergic Airway Inflammation in Offspring.

Front Immunol 2019 21;10:3134. Epub 2020 Jan 21.

Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States.

Allergic asthma is a chronic pulmonary disorder fundamentally linked to immune dysfunction. Since the immune system begins developing , prenatal exposures can affect immune programming and increase risk for diseases such as allergic asthma. Chronic psychosocial stress during pregnancy is one such risk factor, having been associated with increased risk for atopic diseases including allergic asthma in children. To begin to define the underlying causes of the association between maternal stress and allergic airway inflammation in offspring, we developed a mouse model of chronic heightened stress hormone during pregnancy. Continuous oral administration of corticosterone (CORT) to pregnant mice throughout the second half of pregnancy resulted in an ~2-fold increase in circulating hormone in dams with no concomitant increase in fetal circulation, similar to the human condition. To determine how prolonged heightened stress hormone affected allergic immunity in offspring, we induced allergic asthma with house dust mite (HDM) and examined the airway immune response to allergen. Female mice responded to HDM more frequently and had a more robust immune cell response compared to their male counterparts, irrespective of maternal treatment. Male offspring from CORT-treated dams had a greater number of inflammatory cells in the lung in response to HDM compared to males from control dams, while maternal treatment did not affect immune cell numbers in females. Alternatively, maternal CORT caused enhanced goblet cell hyperplasia in female offspring following HDM, an effect that was not observed in male offspring. In summary, prenatal exposure to mild, prolonged heightened stress hormone had sexually dimorphic effects on allergic inflammation in airways of adult offspring.
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http://dx.doi.org/10.3389/fimmu.2019.03134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985541PMC
November 2020

External Cephalic Version: A Dying Art Worth Reviving.

J Obstet Gynaecol India 2018 Dec 8;68(6):493-497. Epub 2018 Feb 8.

Department of Obstetrics and Gynaecology, Christian Fellowship Hospital, Oddanchatram, Tamil Nadu 624619 India.

Purpose: Breech presentation is the most common abnormal presentation occurring in 3-4% of all deliveries. Incidence of caesarean section for breech presentation has increased markedly in the last few decades. Attempting external cephalic version (ECV) reduces the chance of non-cephalic presentation at term, thus reducing the rate of caesarean sections.

Methods: Prospective study was conducted in secondary healthcare centre, in rural set-up from August 2013 to August 2015. A total of 52 patients were enrolled into the study.

Results: ECV was successful in 32 out of 52 patients with overall success of 61.5%. Out of the 32 successful ECVs, 24 patients delivered vaginally (75%) ( value 0.00), 6 patients delivered by caesarean section, and 2 patients were lost to follow-up. Transverse lie had 100% success rate for ECV ( value 0.005). Gravidity, placental position, gestational age and use of tocolytics did not influence the success rate of ECV. Most common problem observed during the procedure was abdominal discomfort.

Conclusion: ECV is a safe procedure with high percentage of patients delivering vaginally after successful version. Hence, acquiring skills in ECV should be considered mandatory in the postgraduate training of future obstetricians.
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http://dx.doi.org/10.1007/s13224-018-1090-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207544PMC
December 2018

Absence of morningness alleles in non-European populations.

Chronobiol Int 2018 11 7;35(12):1758-1761. Epub 2018 Aug 7.

a Faculty of Health and Medical Sciences , University of Surrey , Guildford , UK.

In spite of suspected circadian differences between different ancestral groups, most human studies have used individuals of European descent. This also applies to three recent genome-wide association studies (GWAS), which pinpointed a number of chronotype loci. We investigated the distribution of these hits in different 1000 Genomes populations. We found 6 out of the 41 alleles previously identified by GWAS in European participants (in the genes RGS16, PER2 and AK5 and between the genes APH1A and CA14) to be absent from some non-European population groups. This highlights the need for ancestral diversity in circadian research and may reflect differences affecting the phenotype of individuals of East Asian ancestry.
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http://dx.doi.org/10.1080/07420528.2018.1506928DOI Listing
November 2018

Multi-scale X-ray computed tomography to detect and localize metal-based nanomaterials in lung tissues of in vivo exposed mice.

Sci Rep 2018 03 13;8(1):4408. Epub 2018 Mar 13.

Aix Marseille Univ, CNRS, IRD, INRA, Coll France, CEREGE, Aix-en-Provence, France.

In this methodological study, we demonstrated the relevance of 3D imaging performed at various scales for the ex vivo detection and location of cerium oxide nanomaterials (CeO-NMs) in mouse lung. X-ray micro-computed tomography (micro-CT) with a voxel size from 14 µm to 1 µm (micro-CT) was combined with X-ray nano-computed tomography with a voxel size of 63 nm (nano-CT). An optimized protocol was proposed to facilitate the sample preparation, to minimize the experimental artifacts and to optimize the contrast of soft tissues exposed to metal-based nanomaterials (NMs). 3D imaging of the NMs biodistribution in lung tissues was consolidated by combining a vast variety of techniques in a correlative approach: histological observations, 2D chemical mapping and speciation analysis were performed for an unambiguous detection of NMs. This original methodological approach was developed following a worst-case scenario of exposure, i.e. high dose of exposure with administration via intra-tracheal instillation. Results highlighted both (i) the non-uniform distribution of CeO-NMs within the entire lung lobe (using large field-of-view micro-CT) and (ii) the detection of CeO-NMs down to the individual cell scale, e.g. macrophage scale (using nano-CT with a voxel size of 63 nm).
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http://dx.doi.org/10.1038/s41598-018-21862-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849692PMC
March 2018

Pulmonary exposure to metallic nanomaterials during pregnancy irreversibly impairs lung development of the offspring.

Nanotoxicology 2017 May 17;11(4):484-495. Epub 2017 Apr 17.

a Inserm U955, Equipe 04 , Créteil , France.

Due to the growing commercial applications of manufactured nanoparticles (NPs), toxicological studies on NPs, especially during the critical window of development, are of major importance. The aim of the study was to assess the impact of respiratory exposure to metallic and metal oxide NPs during pregnancy on lung development of the offspring and to determine the key parameters involved in lung alterations. Pregnant mice were exposed to weekly doses of 100 μg (total dose 300 μg) of titanium dioxide (TiO), cerium oxide (CeO), silver (Ag) NPs or saline solution by nonsurgical intratracheal instillation. The offspring lungs were analyzed at different stages of lung development: fetal stage (gestational day 17.5), pulmonary alveolarization (post-delivery day 14.5) and lung maturity (post-delivery day 49.5). Regardless of the type of NP, maternal exposure during gestation induced long-lasting impairment of lung development of the offspring. This effect was accompanied by: i) decreased placental efficiency together with the presence of NPs in placenta, ii) no increase of inflammatory mediators present in amniotic fluid, placenta or offspring lungs and iii) decreased pulmonary expression of vascular endothelial growth factor-α (VEGF-α) and matrix metalloproteinase 9 (MMP-9) at the fetal stage, and fibroblast growth factor-18 (FGF-18) at the alveolarization stage. Respiratory exposure to metallic NPs during pregnancy induces stereotyped impairment of lung development with a lasting effect in adult mice, independently of the chemical nature of the NP.
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http://dx.doi.org/10.1080/17435390.2017.1311381DOI Listing
May 2017

Construct damage and loosening around glenoid implants: A longitudinal micro-CT study of five cadaver specimens.

J Orthop Res 2016 06 28;34(6):1053-60. Epub 2015 Dec 28.

Department of Orthopaedics and Rehabilitation, Penn State College of Medicine and M.S. Hershey Medical Center, 500 University Drive, Mail Code H089, Hershey, Pennsylvania, 17033.

The evolution of failure of bone and cement leading to loosening of glenoid components following shoulder arthroplasty is not well understood. The purpose of this study was to identify and visualize potential mechanisms of mechanical failure within cadavers, cemented with two types of components, and subject to cyclic loading. Five glenoid cadaver bones were implanted with either a three-pegged polyethylene component, or prototype posteriorly augmented component which addresses posterior bone loss. Specimens were loaded by constant glenohumeral compression combined with cyclic anterior-posterior displacement of the humeral head relative to the glenoid. At six time points across 100,000 cycles, implant loosening micromotions were optically measured, and specimens were imaged by micro-computed tomography. Scans were 3D registered and inspected for crack initiation and progression, and micro-CT based time-lapse movies were created. Cement cracking initiated at stress concentrations and progressed with additional cyclic loading. Failure planes within trabecular bone and the bone-cement interface were identified in four of the five specimens. Implant subsidence increased to greater than 1.0 mm in two specimens. Cemented glenoid structural failure can occur within the cement, along planes of trabecular bone, or at the bone cement interface. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1053-1060, 2016.
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http://dx.doi.org/10.1002/jor.23119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800522PMC
June 2016

Maternal and fetal outcome in pre-eclampsia in a secondary care hospital in South India.

J Family Med Prim Care 2015 Apr-Jun;4(2):257-60

Department of Community Health, Christian Medical College, Vellore, Tamil Nadu, India.

Background: Hypertensive disorders in pregnancy are one of the common causes for perinatal and maternal morbidity and mortality in developing countries. Pre-eclampsia is a condition which typically occurs after 20 weeks of gestation and has high blood pressure as the main contributing factor. The aim was to study the effects of pre-eclampsia on the mother and the fetus in rural South Indian population.

Materials And Methods: This was a descriptive study conducted in a secondary level hospital in rural South India. A total of 1900 antenatal women were screened for pre-eclampsia during the period August 2010 to July 2011 to study the effects on the mother and fetus.

Results: Of the 1900 women screened 93 were detected with pre-eclampsia in the study. Among these, 46.23% were primigravida, 30.1% belonged to socio-economic class 4 and 48.8% were among those with BMI 26-30. The incidence of severe pre-eclampsia was higher in the unregistered women. The most common maternal complication was antepartum hemorrhage (13.9%) and the most common neonatal complication was prematurity (23.65%).

Conclusions: Treating anemia and improving socioeconomic status will improve maternal and neonatal outcome in pre-eclampsia. Antenatal care and educating women on significance of symptoms will markedly improve perinatal morbidity and mortality. Prematurity, growth restriction and low birth weight are neonatal complications to be anticipated and dealt with when the mother has pre-eclampsia. A good neonatal intensive care unit will help improve neonatal outcomes.
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http://dx.doi.org/10.4103/2249-4863.154669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408711PMC
May 2015

The roles of P2Y2 purinergic receptors in osteoblasts and mechanotransduction.

PLoS One 2014 30;9(9):e108417. Epub 2014 Sep 30.

Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America.

We previously demonstrated, using osteoblastic MC3T3-E1 cells, that P2Y2 purinergic receptors are involved in osteoblast mechanotransduction. In this study, our objective was to further investigate, using a knockout mouse model, the roles of P2Y2 receptors in bone mechanobiology. We first examined bone structure with micro-CT and measured bone mechanical properties with three point bending experiments in both wild type mice and P2Y2 knockout mice. We found that bones from P2Y2 knockout mice have significantly decreased bone volume, bone thickness, bone stiffness and bone ultimate breaking force at 17 week old age. In order to elucidate the mechanisms by which P2Y2 receptors contribute to bone biology, we examined differentiation and mineralization of bone marrow cells from wild type and P2Y2 knockout mice. We found that P2Y2 receptor deficiency reduces the differentiation and mineralization of bone marrow cells. Next, we compared the response of primary osteoblasts, from both wild type and P2Y2 knockout mice, to ATP and mechanical stimulation (oscillatory fluid flow), and found that osteoblasts from wild type mice have a stronger response, in terms of ERK1/2 phosphorylation, to both ATP and fluid flow, relative to P2Y2 knockout mice. However, we did not detect any difference in ATP release in response to fluid flow between wild type and P2Y2 knock out osteoblasts. Our findings suggest that P2Y2 receptors play important roles in bone marrow cell differentiation and mineralization as well as in bone cell mechanotransduction, leading to an osteopenic phenotype in P2Y2 knockout mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108417PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182465PMC
June 2015

Patients' response toward an automated orthopedic osteoporosis intervention program.

Geriatr Orthop Surg Rehabil 2013 Sep;4(3):89-98

Department of Orthopaedics and Rehabilitation, Penn State Hershey Medical Center, Hershey, PA, USA.

Osteoporosis is overshadowed in an era of chronic illnesses, and a care gap exists between physicians and patients. The aim of this study was to determine the effectiveness of implementing an automated system for identifying and sending a letter to patients at high risk for osteoporosis. Patients 50 years of age and older were tagged with an International Classification of Diseases, Ninth Revision, diagnostic code upon initial visit to the emergency department (ED), identifying potential fragility fractures. Automatically generated letters were sent via our osteoporosis database system to each patient 3 months after the initial visit to the ED. The letter indicated that he or she was at risk for osteoporosis and suggested that the patient schedule a follow-up appointment with a physician. Patients were subsequently telephoned 3 months after receiving the letter and asked about their current plan for follow-up. The control group did not receive a letter after departure from the ED. In the control group, 84 (85.71%) individuals of the total 98 did not have any follow-up but the remaining 14 (14.29%) sought a follow-up. In the intervention group, 62 (60.19%) individuals of 103 did schedule a follow-up, while the remaining 41 (39.81%) did not seek a follow-up. Thus, the patient follow-up response rate after fracture treatment improved with intervention (P < .0001). Current literature has demonstrated the low rate of follow-up care addressing osteoporosis in patients experiencing fragility fractures (1%-25% without intervention). Research has shown the effectiveness of various types of intervention programs for improving the continuum of care for these high-risk patients. Nonautomated intervention programs can have a multitude of human-related system failures in identifying these patients. Our study successfully implements an automated system that is able to be applied to most hospitals with minimal cost and resources.
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http://dx.doi.org/10.1177/2151458513502039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848331PMC
September 2013

Endodermal sinus tumor of the vagina in a child.

J Obstet Gynaecol India 2012 Dec 14;62(Suppl 1):81-2. Epub 2013 Mar 14.

Department of Obstetrics and Gynecology, Christian Fellowship Hospital, Oddanchatram, India.

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http://dx.doi.org/10.1007/s13224-013-0383-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632709PMC
December 2012

Inhibition of GSK-3β rescues the impairments in bone formation and mechanical properties associated with fracture healing in osteoblast selective connexin 43 deficient mice.

PLoS One 2013 8;8(11):e81399. Epub 2013 Nov 8.

Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.

Connexin 43 (Cx43) is the most abundant gap junction protein in bone and is required for osteoblastic differentiation and bone homeostasis. During fracture healing, Cx43 is abundantly expressed in osteoblasts and osteocytes, while Cx43 deficiency impairs bone formation and healing. In the present study we selectively deleted Cx43 in the osteoblastic lineage from immature osteoblasts through osteocytes and tested the hypothesis that Cx43 deficiency results in delayed osteoblastic differentiation and impaired restoration of biomechanical properties due to attenuated β-catenin expression relative to wild type littermates. Here we show that Cx43 deficiency results in alterations in the mineralization and remodeling phases of healing. In Cx43 deficient fractures the mineralization phase is marked by delayed expression of osteogenic genes. Additionally, the decrease in the RankL/Opg ratio, osteoclast number and osteoclast size suggest decreased osteoclast bone resorption and remodeling. These changes in healing result in functional deficits as shown by a decrease in ultimate torque at failure. Consistent with these impairments in healing, β-catenin expression is attenuated in Cx43 deficient fractures at 14 and 21 days, while Sclerostin (Sost) expression, a negative regulator of bone formation is increased in Cx43cKO fractures at 21 days, as is GSK-3β, a key component of the β-catenin proteasomal degradation complex. Furthermore, we show that alterations in healing in Cx43 deficient fractures can be rescued by inhibiting GSK-3β activity using Lithium Chloride (LiCl). Treatment of Cx43 deficient mice with LiCl restores both normal bone formation and mechanical properties relative to LiCl treated WT fractures. This study suggests that Cx43 is a potential therapeutic target to enhance fracture healing and identifies a previously unknown role for Cx43 in regulating β-catenin expression and thus bone formation during fracture repair.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832658PMC
June 2014

Interdependence of muscle atrophy and bone loss induced by mechanical unloading.

J Bone Miner Res 2014 ;29(5):1118-30

Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, PA, USA.

Mechanical unloading induces muscle atrophy and bone loss; however, the time course and interdependence of these effects is not well defined. We subjected 4-month-old C57BL/6J mice to hindlimb suspension (HLS) for 3 weeks, euthanizing 12 to 16 mice on day (D) 0, 7, 14, and 21. Lean mass was 7% to 9% lower for HLS versus control from D7-21. Absolute mass of the gastrocnemius (gastroc) decreased 8% by D7, and was maximally decreased 16% by D14 of HLS. mRNA levels of Atrogin-1 in the gastroc and quadriceps (quad) were increased 99% and 122%, respectively, at D7 of HLS. Similar increases in MuRF1 mRNA levels occurred at D7. Both atrogenes returned to baseline by D14. Protein synthesis in gastroc and quad was reduced 30% from D7-14 of HLS, returning to baseline by D21. HLS decreased phosphorylation of SK61, a substrate of mammalian target of rapamycin (mTOR), on D7-21, whereas 4E-BP1 was not lower until D21. Cortical thickness of the femur and tibia did not decrease until D14 of HLS. Cortical bone of controls did not change over time. HLS mice had lower distal femur bone volume fraction (-22%) by D14; however, the effects of HLS were eliminated by D21 because of the decline of trabecular bone mass of controls. Femur strength was decreased approximately 13% by D14 of HLS, with no change in tibia mechanical properties at any time point. This investigation reveals that muscle atrophy precedes bone loss during unloading and may contribute to subsequent skeletal deficits. Countermeasures that preserve muscle may reduce bone loss induced by mechanical unloading or prolonged disuse. Trabecular bone loss with age, similar to that which occurs in mature astronauts, is superimposed on unloading. Preservation of muscle mass, cortical structure, and bone strength during the experiment suggests muscle may have a greater effect on cortical than trabecular bone.
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http://dx.doi.org/10.1002/jbmr.2113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074925PMC
December 2014

Specific biomimetic hydroxyapatite nanotopographies enhance osteoblastic differentiation and bone graft osteointegration.

Tissue Eng Part A 2013 Aug 25;19(15-16):1704-12. Epub 2013 Apr 25.

Division of Musculoskeletal Sciences, College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, USA.

Impaired healing of cortical bone grafts represents a significant clinical problem. Cadaveric bone grafts undergo extensive chemical processing to decrease the risk of disease transmission; however, these processing techniques alter the bone surface and decrease the osteogenic potential of cells at the healing site. Extensive work has been done to optimize the surface of bone grafts, and hydroxyapatite (HAP) and nanotopography both increase osteoblastic differentiation. HAP is the main mineral component of bone and can enhance osteoblastic differentiation and bone implant healing in vivo, while nanotopography can enhance osteoblastic differentiation, adhesion, and proliferation. This is the first study to test the combined effects of HAP and nanotopographies on bone graft healing. With the goal of identifying the optimized surface features to improve bone graft healing, we tested the hypothesis that HAP-based nanotopographic resurfacing of bone grafts improves integration of cortical bone grafts by enhancing osteoblastic differentiation. Here we show that osteoblastic cells cultured on processed bones coated with specific-scale (50-60 nm) HAP nanotopographies display increased osteoblastic differentiation compared to cells on uncoated bone, bones coated with poly-l-lactic acid nanotopographies, or other HAP nanotopographies. Further, bone grafts coated with 50-60-nm HAP exhibited increased formation of new bone and improved healing, with mechanical properties equivalent to live autografts. These data indicate the potential for specific HAP nanotopographies to not only increase osteoblastic differentiation but also improve bone graft incorporation, which could significantly increase patient quality of life after traumatic bone injuries or resection of an osteosarcoma.
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http://dx.doi.org/10.1089/ten.TEA.2012.0560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700012PMC
August 2013

Osteoblast and osteocyte-specific loss of Connexin43 results in delayed bone formation and healing during murine fracture healing.

J Orthop Res 2013 Jan 20;31(1):147-54. Epub 2012 Jun 20.

Division of Musculoskeletal Sciences, College of Medicine, Pennsylvania State University, 500 University Dr., Mail Code H089, Hershey, Pennsylvania 17033, USA.

Connexin43 (Cx43) plays an important role in osteoblastic differentiation in vitro, and bone formation in vivo. Mice with osteoblast/osteocyte-specific loss of Cx43 display decreased gap junctional intercellular communication (GJIC), bone density, and cortical thickness. To determine the role of Cx43 in fracture healing, a closed femur fracture was induced in Osteocalcin-Cre+; Cx43(flox/flox) (Cx43cKO) and Cre-; Cx43(flox/flox) (WT) mice. We tested the hypothesis that loss of Cx43 results in decreased bone formation and impaired healing following fracture. Here, we show that osteoblast and osteocyte-specific deletion of Cx43 results in decreased bone formation, bone remodeling, and mechanical properties during fracture healing. Cx43cKO mice display decreased bone volume, total volume, and fewer TRAP+ osteoclasts. Furthermore, loss of Cx43 in mature osteoblasts and osteocytes results in a significant decrease in torsional rigidity between 21 and 35 days post-fracture, compared to WT mice. These studies identify a novel role for the gap junction protein Cx43 during fracture healing, suggesting that loss of Cx43 can result in both decreased bone formation and bone resorption. Therefore, enhancing Cx43 expression or GJIC may provide a novel means to enhance bone formation during fracture healing.
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http://dx.doi.org/10.1002/jor.22178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640531PMC
January 2013

Connexin 43 deficiency attenuates loss of trabecular bone and prevents suppression of cortical bone formation during unloading.

J Bone Miner Res 2012 Nov;27(11):2359-72

Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, PA 17033, USA.

Connexin 43 (Cx43) is the most abundant gap junction protein in bone and has been demonstrated as an integral component of skeletal homeostasis. In the present study, we sought to further refine the role of Cx43 in the response to mechanical unloading by subjecting skeletally mature mice with a bone-specific deletion of Cx43 (cKO) to 3 weeks of mechanical unloading via hindlimb suspension (HLS). The HLS model was selected to recapitulate the effects of skeletal unloading due to prolonged bed rest, reduced activity associated with aging, and spaceflight microgravity. At baseline, the cortical bone of cKO mice displayed an osteopenic phenotype, with expanded cortices, decreased cortical thickness, decreased bone mineral density, and increased porosity. There was no baseline trabecular phenotype. After 3 weeks of HLS, wild-type (WT) mice experienced a substantial decline in trabecular bone volume fraction, connectivity density, trabecular thickness, and trabecular tissue mineral density. These deleterious effects were attenuated in cKO mice. Conversely, there was a similar and significant amount of cortical bone loss in both WT and cKO. Interestingly, mechanical testing revealed a greater loss of strength and rigidity for cKO during HLS. Analysis of double-label quantitative histomorphometry data demonstrated a substantial decrease in bone formation rate, mineralizing surface, and mineral apposition rate at both the periosteal and endocortical surfaces of the femur after unloading of WT mice. This suppression of bone formation was not observed in cKO mice, in which parameters were maintained at baseline levels. Taken together, the results of the present study indicate that Cx43 deficiency desensitizes bone to the effects of mechanical unloading, and that this may be due to an inability of mechanosensing osteocytes to effectively communicate the unloading state to osteoblasts to suppress bone formation. Cx43 may represent a novel therapeutic target for investigation as a countermeasure for age-related and unloading-induced bone loss.
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http://dx.doi.org/10.1002/jbmr.1687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683470PMC
November 2012

Enhanced osteoclastic resorption and responsiveness to mechanical load in gap junction deficient bone.

PLoS One 2011 29;6(8):e23516. Epub 2011 Aug 29.

Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.

Emerging evidence suggests that connexin mediated gap junctional intercellular communication contributes to many aspects of bone biology including bone development, maintenance of bone homeostasis and responsiveness of bone cells to diverse extracellular signals. Deletion of connexin 43, the predominant gap junction protein in bone, is embryonic lethal making it challenging to examine the role of connexin 43 in bone in vivo. However, transgenic murine models in which only osteocytes and osteoblasts are deficient in connexin 43, and which are fully viable, have recently been developed. Unfortunately, the bone phenotype of different connexin 43 deficient models has been variable. To address this issue, we used an osteocalcin driven Cre-lox system to create osteoblast and osteocyte specific connexin 43 deficient mice. These mice displayed bone loss as a result of increased bone resorption and osteoclastogenesis. The mechanism underlying this increased osteoclastogenesis included increases in the osteocytic, but not osteoblastic, RANKL/OPG ratio. Previous in vitro studies suggest that connexin 43 deficient bone cells are less responsive to biomechanical signals. Interestingly, and in contrast to in vitro studies, we found that connexin 43 deficient mice displayed an enhanced anabolic response to mechanical load. Our results suggest that transient inhibition of connexin 43 expression and gap junctional intercellular communication may prove a potentially powerful means of enhancing the anabolic response of bone to mechanical loading.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023516PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163577PMC
December 2011

Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase.

Inflammopharmacology 2011 Apr 11;19(2):75-87. Epub 2010 Oct 11.

Department of Pharmacology, Penn State College of Medicine, Hershey, Hummelstown, PA 17036, USA.

Unlabelled: Pro-inflammatory cytokines like TNF-α activate sphingosine kinase (SK). Therefore, inhibition of SK is a potential molecular target for the treatment of rheumatoid arthritis.

Aims: The primary goal of this study was to assess the efficacy of ABC249640 (a selective SK-2 inhibitor) in two models of rodent arthritis. A secondary goal was to evaluate the pharmacological profile of ABC294640, when given in combination with methotrexate.

Methods: The efficacy of ABC294640 was determined by paw diameter/volume measurements, histological evaluations, and micro-CT analyses.

Results: ABC294640 attenuated both collagen-induced arthritis in mice, as well as adjuvant-induced arthritis in rats. With the adjuvant arthritis model, the prophylactic efficacy profile of ABC294640 was similar to indomethacin. Of note, ABC294640 reduced the bone and cartilage degradation, associated with adjuvant-induced arthritis. Rats treated with a suboptimal dose of MTX (50 μg/kg/day) in combination with ABC249640 (100 mg/kg/day) had better anti-arthritis effects in the adjuvant model, than treatment with either agent alone.

Conclusion: Our results suggest that ABC249640 is an orally available drug candidate with a good pre-clinical efficacy profile for the prevention and/or treatment of RA.
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http://dx.doi.org/10.1007/s10787-010-0060-6DOI Listing
April 2011

Short-term intermittent PTH 1-34 administration enhances bone formation in SCID/Beige mice.

Endocr J 2010 6;57(5):373-82. Epub 2010 Feb 6.

Penn State College of Medicine, Department of Orthopaedics and Rehabilitation, Hershey, PA 17033-0850, USA.

The anabolic effect of intermittent PTH on bone is variable depending on the species studied, duration/mode of administration, and location of skeletal response investigated. We tested the hypothesis low dose, short term, intermittent PTH 1-34 administration is sufficient to enhance bone formation without altering bone resorption. To test our hypothesis, mice were treated intermittently with one of three concentrations of PTH 1-34 (1 microg/kg; low, 10 microg/kg, or 20 microg/kg; high) for three weeks. The skeletal response was identified by quantifying: serum markers of bone turnover, cancellous bone parameters in distal femur, proximal tibia, and lumbar vertebrae by microCT, and number of osteoblasts and osteoclasts in distal femur. Mice receiving 20 microg/kg of PTH 1-34 demonstrated a 30% increase in serum osteocalcin, but no differences in serum calcium, type I collagen teleopeptides, or TRACP 5b. For all bones, microCT analysis suggested mice receiving 20 microg/kg of PTH 1-34 had increased cancellous bone mineral density, trabecular thickness and spacing, but decreased trabecular number. A 60% increase in the number of alkaline phosphatase positive osteoblasts in the distal femur was also observed in tissue sections; however, the number of TRAP positive osteoclasts was not different between test and control groups. While animals administered 10 microg/kg demonstrated similar trends for all bone turnover indices, such alterations were not observed in animals administered PTH 1-34 at 1 microg/kg per day. Thus, PTH 1-34, administered intermittently for three weeks at 20 microg/kg is sufficient to enhance bone formation without enhancing resorption.
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http://dx.doi.org/10.1507/endocrj.k09e-349DOI Listing
September 2010

Osteosclerotic prostate cancer metastasis to murine bone are enhanced with increased bone formation.

Clin Exp Metastasis 2009 7;26(7):641-51. Epub 2009 May 7.

Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, PA 17033, USA.

Spontaneous development of osteoblastic lesions of prostate cancer (PCa) in mice is modeled by orthotopic (intraprostatic) deposition of neoplastic cells followed by an extremely long latency associated with low incidence of spontaneous bone metastasis. Intracardial injection results in overt bone metastases only with osteoclastic PCa cells (i.e., PC-3). Herein, we report that androgen independent osteoblastic PCa cells readily colonize bone when in a high remodeling state. SCID/Beige mice were subjected to periods of intermittent human parathyroid hormone 1-34 (hPTH) exposure, followed by an intracardiac infusion of osteoblastic C4-2 PCa cells. At the time of PCa infusion, analysis of bone turnover markers from mice treated with hPTH revealed significant increases in osteocalcin (55.06 +/- 7.5 vs. 74.01 +/- 18.5 ng/ml) and TRAcP-5b (3.3 +/- 0.6 vs. 4.81 +/- 0.8 U/l), but no change in type I collagen C-terminal teleopeptide levels relative to control mice. Analysis of femoral cancellous bone architecture revealed significant increases in bone mineral density, trabecular thickness (0.056 +/- 0.002 vs. 0.062 +/- 0.001 mm) and porosity, but significant decreases in connectivity density and trabecular number in hPTH treated mice relative to controls. By 8 weeks post-infusion, 70% of mice pre-treated with hPTH demonstrated detectable serum prostate specific antigen (PSAs) ranging between 2 and 18.8 ng/ml. Immuno-histochemical labeling of femurs for PSA and pan-Cytokeratin revealed the presence of significant tumor cell nests in marrow and trabecular spaces. These results suggest that: (1) local bone physiology is an important factor for developing osteoblastic/sclerotic PCa bone metastases in murine hosts; (2) the establishment of osteosclerotic PCa bone metastases in mice is enhanced by alterations that drive bone formation.
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http://dx.doi.org/10.1007/s10585-009-9263-xDOI Listing
November 2009

Bone and soft connective tissue alterations result from loss of fibrillin-2 expression.

Matrix Biol 2008 Oct 22;27(8):661-6. Epub 2008 Sep 22.

Division of Musculoskeletal Sciences, Department of Orthopedics, H089, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033-0850, United States.

Fibrillins 1, 2 and 3 make up a family of genes that encode large, cysteine-rich extracellular matrix glycoproteins found in connective tissues, lung, blood vessels and other extensible tissues. Fibrillins 1 and 2 have both overlapping as well as separate distributions in human embryonic and adult tissues. Fibrillin-containing microfibrils are known to modulate morphogenetic events by proper targeting of growth factors to the extracellular matrix. Mutation of the fibrillin-2 gene causes a genetic disorder, congenital contractural arachnodactyly (CCA), that results in flexion contractures. Previously, we have shown a distinct fibrillin-2 distribution in the pericellular matrix of interior tenocytes and later demonstrated a unique fibrillin-2 containing structure that runs along the tendon cell arrays in the canine flexor tendon. We hypothesized that loss of these fibrillin-2 containing structures might affect normal tendon development. To test our hypothesis, connective tissues from mice null for fibrillin-2 gene expression were studied. Murine flexor digitorum longus tendons were evaluated for total collagen content, and the intermolecular collagen cross-links hydroxylysyl and lysyl pyridinoline. The results show decreased collagen cross-links in fibrillin-2 null mice, however total collagen content remained the same when compared to wild type. Bone morphology was studied using micro computed tomography (CT). Fibrillin-2 null mice display a focal area of decreased bone length in the extremities as compared to wild type mice. Together, these results demonstrate a role for fibrillin-2 in bone and soft connective tissue morphological and biochemical processes.
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http://dx.doi.org/10.1016/j.matbio.2008.09.579DOI Listing
October 2008

Ovarian adenosarcoma with extensive deciduoid morphology arising in endometriosis: a case report.

Int J Gynecol Pathol 2008 Jul;27(3):398-401

Department of General Pathology, Christian Medical College, Vellore-632004, Tamil Nadu, India.

A case of müllerian adenosarcoma arising in ovarian endometriosis is reported in which the whole of the mesenchymal component exhibited striking deciduoid morphology, a phenomenon that has not been previously described. The patient was not taking hormonal preparations. We discuss the differential diagnosis and the possible pathogenesis of the deciduoid stromal alteration.
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http://dx.doi.org/10.1097/PGP.0b013e318165e2d0DOI Listing
July 2008

Validation of three-dimensional models of in situ scapulae.

J Shoulder Elbow Surg 2008 Sep-Oct;17(5):825-32. Epub 2008 May 19.

Department of Orthopaedics & Rehabilitation, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA.

A principal challenge in creating accurate models of in situ scapulae is delineating bone from surrounding soft tissues. Computed tomography scans were obtained of both shoulders of 20 embalmed cadavers. Each shoulder was rescanned after repositioning of the cadavers to test for rescan reliability. After scans were complete, all scapulae were excised and stripped of all soft tissue. Thresholding, region growing, and manual processing were used to create computer-generated 3-dimensional (3D) models. Seven anatomic measurements were performed on each scapula and 3D model. Mean differences between corresponding measurements of specimen and model were small (<3 mm). Intraobserver and interobserver reliability for cadaveric measurements and rescan and interobserver reliability for model measurements were all excellent (R(2) = 0.99). Patient positioning was not a significant source of error in obtaining measurements from 3D models. Results from this work verify that accurate and reproducible 3D models can be created from in situ scapulae by use of effective segmentation.
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http://dx.doi.org/10.1016/j.jse.2008.01.141DOI Listing
February 2009

Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice.

J Clin Invest 2008 May;118(5):1858-66

Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Osteoclastogenesis is a tightly regulated biological process, and deregulation can lead to severe bone disorders such as osteoporosis. The regulation of osteoclastic signaling is incompletely understood, but ubiquitination of TNF receptor-associated factor 6 (TRAF6) has recently been shown to be important in mediating this process. We therefore investigated the role of the recently identified deubiquitinating enzyme CYLD in osteoclastogenesis and found that mice with a genetic deficiency of CYLD had aberrant osteoclast differentiation and developed severe osteoporosis. Cultured osteoclast precursors derived from CYLD-deficient mice were hyperresponsive to RANKL-induced differentiation and produced more and larger osteoclasts than did controls upon stimulation. We assessed the expression pattern of CYLD and found that it was drastically upregulated during RANKL-induced differentiation of preosteoclasts. Furthermore, CYLD negatively regulated RANK signaling by inhibiting TRAF6 ubiquitination and activation of downstream signaling events. Interestingly, we found that CYLD interacted physically with the signaling adaptor p62 and thereby was recruited to TRAF6. These findings establish CYLD as a crucial negative regulator of osteoclastogenesis and suggest its involvement in the p62/TRAF6 signaling axis.
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http://dx.doi.org/10.1172/JCI34257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2276399PMC
May 2008

Complete mineralisation of dimethylformamide by Ochrobactrum sp. DGVK1 isolated from the soil samples collected from the coalmine leftovers.

Appl Microbiol Biotechnol 2006 Jul 7;71(3):369-75. Epub 2005 Oct 7.

Department of Biochemistry, Gulbarga University, Karnataka, India.

A bacterial strain DGVK1 capable of using N,N-dimethylformamide (DMF) as sole source of carbon and nitrogen was isolated from the soil samples collected from the coalmine leftovers. The molecular phylogram generated using the complete sequence of 16S rDNA of the strain DGVK1 showed close links to the bacteria grouped under Brucellaceae family that belongs to alphaproteobacteria class. Specifically, the 16S rDNA sequence of strain DGVK1 has shown 97% similarity to Ochrobactrum anthropi LMG 3331 (D12794). This bacterium has also shown impressive growth on dimethylamine, methylamine, formaldehyde and formate that are considered to be the prominent catabolic intermediates of DMF. DMF degradation has led to the accumulation of ammonia and dimethylamine contributing to the increase of pH of the medium. The DMF-grown resting cells of Ochrobactrum sp. DGVK1 have also contributed for the release of ammonia when resting cell suspension was added to phosphate buffer containing DMF. Similar experiments done with the glucose-grown cultures have not produced ammonia and thus indicating the inducible nature of DMF-degrading enzymes in Ochrobactrum sp. DGVK1. Further, dimethylformamidase, dimethylamine dehydrogenase and methylamine dehydrogenase, the key enzymes involved in the degradation of DMF, were assayed, and the activities of these enzymes were found only in DMF-grown cultures further confirming the inducible nature of the DMF degradation. Based on these results, DMF degradation pathway found in Ochrobactrum sp. DGVK1 has been proposed.
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http://dx.doi.org/10.1007/s00253-005-0157-9DOI Listing
July 2006
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