Bone Impairment in Phenylketonuria Is Characterized by Circulating Osteoclast Precursors and Activated T Cell Increase
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{"title"=>"Bone impairment in phenylketonuria is characterized by circulating osteoclast precursors and activated T cell increase", "type"=>"journal", "authors"=>[{"first_name"=>"Ilaria", "last_name"=>"Roato", "scopus_author_id"=>"23019670400"}, {"first_name"=>"Francesco", "last_name"=>"Porta", "scopus_author_id"=>"24402992200"}, {"first_name"=>"Alessandro", "last_name"=>"Mussa", "scopus_author_id"=>"23988917700"}, {"first_name"=>"Lucia", "last_name"=>"D'Amico", "scopus_author_id"=>"26429051500"}, {"first_name"=>"Ludovica", "last_name"=>"Fiore", "scopus_author_id"=>"36436967400"}, {"first_name"=>"Davide", "last_name"=>"Garelli", "scopus_author_id"=>"36660792600"}, {"first_name"=>"Marco", "last_name"=>"Spada", "scopus_author_id"=>"35617706200"}, {"first_name"=>"Riccardo", "last_name"=>"Ferracini", "scopus_author_id"=>"36960580300"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"360095038", "doi"=>"10.1371/journal.pone.0014167", "sgr"=>"78649765384", "pmid"=>"21152388", "scopus"=>"2-s2.0-78649765384"}, "id"=>"a1b7b08a-b557-355f-b0c9-593eb2b7cc0c", "abstract"=>"BACKGROUND: Phenylketonuria (PKU) is a rare inborn error of metabolism often complicated by a progressive bone impairment of uncertain etiology, as documented by both ionizing and non- ionizing techniques.\\n\\nMETHODOLOGY: Peripheral blood mononuclear cell (PBMC) cultures were performed to study osteoclastogenesis, in the presence or absence of recombinant human monocyte-colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). Flow cytometry was utilized to analyze osteoclast precursors (OCPs) and T cell phenotype. Tumour necrosis factor α (TNF-α), RANKL and osteoprotegerin (OPG) were quantified in cell culture supernatants by ELISA. The effects of RANKFc and anti-TNF-α antibodies were also investigated to determine their ability to inhibit osteoclastogenesis. In addition, bone conditions and phenylalanine levels in PKU patients were clinically evaluated.\\n\\nPRINCIPAL FINDINGS: Several in vitro studies in PKU patients' cells identified a potential mechanism of bone formation inhibition commonly associated with this disorder. First, PKU patients disclosed an increased osteoclastogenesis compared to healthy controls, both in unstimulated and M-CSF/RANKL stimulated PBMC cultures. OCPs and the measured RANKL/OPG ratio were higher in PKU patients compared to healthy controls. The addition of specific antagonist RANKFc caused osteoclastogenesis inhibition, whereas anti-TNF-α failed to have this effect. Among PBMCs isolated from PKU patients, activated T cells, expressing CD69, CD25 and RANKL were identified. Confirmatory in vivo studies support this proposed model. These in vivo studies included the analysis of osteoclastogenesis in PKU patients, which demonstrated an inverse relation to bone condition assessed by phalangeal Quantitative Ultrasound (QUS). This was also directly related to non-compliance to therapeutic diet reflected by hyperphenylalaninemia.\\n\\nCONCLUSIONS: Our results indicate that PKU spontaneous osteoclastogenesis depends on the circulating OCP increase and the activation of T cells. Osteoclastogenesis correlates with clinical parameters, suggesting its value as a diagnostic tool for an early assessment of an increased bone resorption in PKU patients.", "link"=>"http://www.mendeley.com/research/bone-impairment-phenylketonuria-characterized-circulating-osteoclast-precursors-activated-t-cell-inc", "reader_count"=>25, "reader_count_by_academic_status"=>{"Student > Doctoral Student"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>4, "Other"=>4, "Student > Master"=>6, "Student > Bachelor"=>3, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Student > Doctoral Student"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>4, "Other"=>4, "Student > Master"=>6, "Student > Bachelor"=>3, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>9, "Agricultural and Biological Sciences"=>9, "Neuroscience"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>3}}, "group_count"=>4}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/815411"], "description"=>"<p>Representative dot plots of CD14+CD16+ OCPs (A, B). The analysis of the expression of OCPs markers on CD14+ cells show CD11b+CD51/61+ (C, D) and CD16+CD51/61+ (E, F) increase in PKU compared to controls.</p>", "links"=>[], "tags"=>["ocps", "peripheral", "pku"], "article_id"=>485773, "categories"=>["Immunology", "Cell Biology", "Medicine"], "users"=>["Ilaria Roato", "Francesco Porta", "Alessandro Mussa", "Lucia D'Amico", "Ludovica Fiore", "Davide Garelli", "Marco Spada", "Riccardo Ferracini"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0014167.g002", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Circulating_OCPs_are_increase_in_peripheral_blood_of_PKU_patients_/485773", "title"=>"Circulating OCPs are increase in peripheral blood of PKU patients.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-30 01:36:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/815627"], "description"=>"<p>The RANKFc addition to unstimulated PBMC culture from PKU patients caused a dose-dependent inhibition of OC formation (A), whereas anti-TNF-α failed to inhibit osteoclastogenesis (B). The <i>p</i> value indicated was calculated by unpaired T-test.</p>", "links"=>[], "tags"=>["osteoclastogenesis"], "article_id"=>485992, "categories"=>["Immunology", "Cell Biology", "Medicine"], "users"=>["Ilaria Roato", "Francesco Porta", "Alessandro Mussa", "Lucia D'Amico", "Ludovica Fiore", "Davide Garelli", "Marco Spada", "Riccardo Ferracini"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0014167.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PKU_osteoclastogenesis_is_RANKL_dependent_/485992", "title"=>"PKU osteoclastogenesis is RANKL-dependent.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-30 01:39:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/815864"], "description"=>"<p>Spontaneous osteoclastogenesis in PKU patients shows a significant correlation with age (•, continuous line) and blood phenylalanine concentration, dosed in the last year before the study (○, dotted line). PKU patients showed a significant negative correlation between spontaneous osteoclastogenesis and bone condition assessed by QUS parameters, Amplitude-Dependent Speed of Sound (AD-SoS) (○, dotted line) and Bone Transmission Time (BTT) (•, continuous line). Correlations were evaluated by Pearson's coefficients.</p>", "links"=>[], "tags"=>["osteoclastogenesis", "correlates"], "article_id"=>486228, "categories"=>["Immunology", "Cell Biology", "Medicine"], "users"=>["Ilaria Roato", "Francesco Porta", "Alessandro Mussa", "Lucia D'Amico", "Ludovica Fiore", "Davide Garelli", "Marco Spada", "Riccardo Ferracini"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0014167.g006", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PKU_osteoclastogenesis_correlates_with_clinical_parameters_/486228", "title"=>"PKU osteoclastogenesis correlates with clinical parameters.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-30 01:43:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/406603"], "description"=>"<div><h3>Background</h3><p>Phenylketonuria (PKU) is a rare inborn error of metabolism often complicated by a progressive bone impairment of uncertain etiology, as documented by both ionizing and non- ionizing techniques.</p><h3>Methodology</h3><p>Peripheral blood mononuclear cell (PBMC) cultures were performed to study osteoclastogenesis, in the presence or absence of recombinant human monocyte-colony stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). Flow cytometry was utilized to analyze osteoclast precursors (OCPs) and T cell phenotype. Tumour necrosis factor α (TNF-α), RANKL and osteoprotegerin (OPG) were quantified in cell culture supernatants by ELISA. The effects of RANKFc and anti-TNF-α antibodies were also investigated to determine their ability to inhibit osteoclastogenesis. In addition, bone conditions and phenylalanine levels in PKU patients were clinically evaluated.</p><h3>Principal Findings</h3><p>Several <em>in vitro</em> studies in PKU patients' cells identified a potential mechanism of bone formation inhibition commonly associated with this disorder. First, PKU patients disclosed an increased osteoclastogenesis compared to healthy controls, both in unstimulated and M-CSF/RANKL stimulated PBMC cultures. OCPs and the measured RANKL/OPG ratio were higher in PKU patients compared to healthy controls. The addition of specific antagonist RANKFc caused osteoclastogenesis inhibition, whereas anti-TNF-α failed to have this effect. Among PBMCs isolated from PKU patients, activated T cells, expressing CD69, CD25 and RANKL were identified. Confirmatory <em>in vivo</em> studies support this proposed model. These <em>in vivo</em> studies included the analysis of osteoclastogenesis in PKU patients, which demonstrated an inverse relation to bone condition assessed by phalangeal Quantitative Ultrasound (QUS). This was also directly related to non-compliance to therapeutic diet reflected by hyperphenylalaninemia.</p><h3>Conclusions</h3><p>Our results indicate that PKU spontaneous osteoclastogenesis depends on the circulating OCP increase and the activation of T cells. Osteoclastogenesis correlates with clinical parameters, suggesting its value as a diagnostic tool for an early assessment of an increased bone resorption in PKU patients.</p></div>", "links"=>[], "tags"=>["impairment", "phenylketonuria", "characterized", "circulating", "osteoclast", "precursors", "activated"], "article_id"=>140331, "categories"=>["Immunology", "Cell Biology", "Medicine"], "users"=>["Ilaria Roato", "Francesco Porta", "Alessandro Mussa", "Lucia D'Amico", "Ludovica Fiore", "Davide Garelli", "Marco Spada", "Riccardo Ferracini"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0014167", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Bone_Impairment_in_Phenylketonuria_Is_Characterized_by_Circulating_Osteoclast_Precursors_and_Activated_T_Cell_Increase/140331", "title"=>"Bone Impairment in Phenylketonuria Is Characterized by Circulating Osteoclast Precursors and Activated T Cell Increase", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-30 00:05:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/815228"], "description"=>"<p>Numerous, multinucleated (<3 nuclei/cell), TRAP+ OCs (black arrows) were obtained from unstimulated PBMCs of PKU patients (A), while few OCs were observed in healthy control cultures (B). After addition of M-CSF and RANKL, a significant increase in osteoclastogenesis was observed both in PKU patient and in healthy control PBMC cultures (C, D, respectively). The OC number in PBMC cultures was quantified, resulting higher in PKU patients than in healthy controls (E). OCs were normally distributed, hence PKU patients and healthy controls were compared by means of unpaired T-test. OCs from PKU patients' PBMC cultures expressed vitronectin receptor (F).</p>", "links"=>[], "tags"=>["pku", "patients"], "article_id"=>485596, "categories"=>["Immunology", "Cell Biology", "Medicine"], "users"=>["Ilaria Roato", "Francesco Porta", "Alessandro Mussa", "Lucia D'Amico", "Ludovica Fiore", "Davide Garelli", "Marco Spada", "Riccardo Ferracini"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0014167.g001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Osteoclastogenesis_in_PKU_patients_and_healthy_controls_/485596", "title"=>"Osteoclastogenesis in PKU patients and healthy controls.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-30 01:33:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/815540"], "description"=>"<p>Box and whisker plots showed cytokines dosed in the PBMCs supernatants. Each Box represents the 25<sup>th</sup> to 75<sup>th</sup> percentiles. Lines outside the boxes represent the minimum and maximum values. Lines inside the boxes represent the medians calculated for all the data set. The <i>p</i> value indicated was calculated with the Mann-Whitney U test after correction for age. In PKU patients TNF-α was higher than in healthy controls (A). RANKL resulted significantly higher in PKU than in controls at day 10 (B), whereas OPG did not differ between patients and controls (C). The RANKL to OPG ratio was in favour of RANKL in PKU patients compared to healthy controls (D).</p>", "links"=>[], "tags"=>["cytokines"], "article_id"=>485911, "categories"=>["Immunology", "Cell Biology", "Medicine"], "users"=>["Ilaria Roato", "Francesco Porta", "Alessandro Mussa", "Lucia D'Amico", "Ludovica Fiore", "Davide Garelli", "Marco Spada", "Riccardo Ferracini"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0014167.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Osteoclastogenic_cytokines_in_culture_media_/485911", "title"=>"Osteoclastogenic cytokines in culture media.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-30 01:38:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/815744"], "description"=>"<p>Representative dot plots of CD4+ T cells expressing both CD69 and CD25 in PKU patient (A) and healthy controls (B).</p>", "links"=>[], "tags"=>["patients", "activated", "cells", "peripheral"], "article_id"=>486102, "categories"=>["Immunology", "Cell Biology", "Medicine"], "users"=>["Ilaria Roato", "Francesco Porta", "Alessandro Mussa", "Lucia D'Amico", "Ludovica Fiore", "Davide Garelli", "Marco Spada", "Riccardo Ferracini"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0014167.g005", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PKU_patients_have_activated_T_cells_in_peripheral_blood_/486102", "title"=>"PKU patients have activated T cells in peripheral blood.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-11-30 01:41:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/815963"], "description"=>"<p>Clinical features of patients with phenylketonuria (PKU) compared to healthy controls.</p>", "links"=>[], "tags"=>["patients", "phenylketonuria", "compared"], "article_id"=>486326, "categories"=>["Immunology", "Cell Biology", "Medicine"], "users"=>["Ilaria Roato", "Francesco Porta", "Alessandro Mussa", "Lucia D'Amico", "Ludovica Fiore", "Davide Garelli", "Marco Spada", "Riccardo Ferracini"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0014167.t001", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clinical_features_of_patients_with_phenylketonuria_PKU_compared_to_healthy_controls_/486326", "title"=>"Clinical features of patients with phenylketonuria (PKU) compared to healthy controls.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-11-30 01:45:26"}

PMC Usage Stats | Further Information

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Relative Metric

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