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Högler, W., Imel, A., Whyte, P., Munns, C., Anthony, P., Ward, L., . . . Glorieux, F. (2019). BUROSUMAB RESULTED IN GREATER IMPROVEMENT IN PHOSPHATE METABOLISM, RICKETS, GROWTH, AND MOBILITY THAN CONTINUATION WITH CONVENTIONAL THERAPY IN CHILDREN WITH X-LINKED HYPOPHOSPHATEMIA (XLH). Paper presented at World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO), Paris, France, April 4-7, 2019. Osteoporosis International, 30(Suppl. 2), S409-S410
Öppna denna publikation i ny flik eller fönster >>BUROSUMAB RESULTED IN GREATER IMPROVEMENT IN PHOSPHATE METABOLISM, RICKETS, GROWTH, AND MOBILITY THAN CONTINUATION WITH CONVENTIONAL THERAPY IN CHILDREN WITH X-LINKED HYPOPHOSPHATEMIA (XLH)
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2019 (Engelska)Ingår i: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 30, nr Suppl. 2, s. S409-S410Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
Springer, 2019
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:oru:diva-75734 (URN)10.1007/s00198-019-04993-w (DOI)000475685502111 ()
Konferens
World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO), Paris, France, April 4-7, 2019
Tillgänglig från: 2019-08-13 Skapad: 2019-08-13 Senast uppdaterad: 2019-08-13Bibliografiskt granskad
Imel, E. A., Glorieux, F. H., Whyte, M. P., Munns, C. F., Ward, L. M., Nilsson, O., . . . Portale, A. A. (2019). Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. The Lancet, 393(10189), 2416-2427
Öppna denna publikation i ny flik eller fönster >>Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial
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2019 (Engelska)Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 393, nr 10189, s. 2416-2427Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.

Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2.0, fasting serum phosphorus lower than 0.97 mmol/L (3.0 mg/dL), confirmed PHEX (phosphate-regulating endopep-tidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1: 1) to receive either subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.

Findings: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1.9 [SE 0.1] with burosumab vs +0.8 [0.1] with conventional therapy; difference 1.1, 95% CI 0.8-1.5; p<0.0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.

Interpretation: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Ort, förlag, år, upplaga, sidor
Elsevier, 2019
Nationell ämneskategori
Allmänmedicin Pediatrik
Identifikatorer
urn:nbn:se:oru:diva-75226 (URN)10.1016/S0140-6736(19)30654-3 (DOI)000471758200039 ()31104833 (PubMedID)2-s2.0-85067187146 (Scopus ID)
Anmärkning

Funding Agencies:Ultragenyx Pharmaceutical  

Kyowa Kirin International  

Tillgänglig från: 2019-07-26 Skapad: 2019-07-26 Senast uppdaterad: 2019-07-26Bibliografiskt granskad
Beck-Nielsen, S. S., Mughal, Z., Haffner, D., Nilsson, O., Levtchenko, E., Ariceta, G., . . . Mäkitie, O. (2019). FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet Journal of Rare Diseases, 14(1), Article ID 58.
Öppna denna publikation i ny flik eller fönster >>FGF23 and its role in X-linked hypophosphatemia-related morbidity
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2019 (Engelska)Ingår i: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 14, nr 1, artikel-id 58Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood.

METHODS: The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH.

RESULTS: The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations.

CONCLUSIONS: By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.

Ort, förlag, år, upplaga, sidor
BioMed Central, 2019
Nyckelord
X-linked hypophosphatemia (XLH), bone dysplasia, dental abscess, ectopic calcification, fibroblast growth factor 23 (FGF23), hearing impairment, hypophosphatemia, muscle weakness, osteomalacia, phosphate regulating endopeptidase homolog, X-linked (PHEX), rickets, vitamin D deficiency
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:oru:diva-72875 (URN)10.1186/s13023-019-1014-8 (DOI)000459928100004 ()30808384 (PubMedID)2-s2.0-85062456413 (Scopus ID)
Anmärkning

Funding Agencies:

Kyowa Kirin Services Ltd  

Medialis Ltd - Kyowa Kirin Services Ltd

Tillgänglig från: 2019-03-04 Skapad: 2019-03-04 Senast uppdaterad: 2019-06-19Bibliografiskt granskad
Nilsson, O., Whyte, M. P., Imel, E. A., Munns, C., Portale, A. A., Ward, L., . . . Glorieux, F. (2018). Burosumab Improved Rickets, Phosphate Metabolism, and Clinical Outcomes Compared to Conventional Therapy in Children with X-Linked Hypophosphatemia (XLH) - A Randomized Controlled Phase 3 Study. Paper presented at 57th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2018), Athens, Greece, September 27-29, 2018. Hormone Research in Paediatrics, 90(Suppl.1), 57-58
Öppna denna publikation i ny flik eller fönster >>Burosumab Improved Rickets, Phosphate Metabolism, and Clinical Outcomes Compared to Conventional Therapy in Children with X-Linked Hypophosphatemia (XLH) - A Randomized Controlled Phase 3 Study
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2018 (Engelska)Ingår i: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, nr Suppl.1, s. 57-58Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Abstract [en]

In children with XLH, high circulating levels of FGF23 cause hypophosphatemia with consequent rickets, skeletal deformities, and growth impairment. Conventional therapy consists of multiple daily doses of oral phosphate and active vitamin D (Pi/D). Burosumab is a fully human monoclonal antibody against FGF23 indicated for the treatment of XLH.

In the active-control study CL301 (NCT02915705), 61 children with XLH (1-12 years old) were randomized (1:1) to receive subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks (Q2W) or Pi/D as prescribed by investigators. Eligibility criteria included a Total Rickets Severity Score (RSS) ≥2.0 and prior receipt of Pi/D. The primary endpoint was healing of rickets at Week 40 assessed by radiologists blinded to treatment using the Radiographic Global Impression of Change (RGI-C).

At Week 40, burosumab significantly improved rickets compared with Pi/D (RGI-C global score least squares [LS] mean ± SE: +1.92 ± 0.11 vs +0.77 ± 0.11; p<0.0001). More subjects in the burosumab group had substantial healing (RGI-C ≥+2.0) at Week 40, compared with the Pi/D group (21/29, 72% vs 2/32, 6%; odds ratio of 39.1, p<0.0001). Additional evidence for improvement of rickets included decreased Total RSS (LS mean ± SE change, burosumab vs Pi/D: -2.04 ± 0.145 vs -0.71 ± 0.138; p<0.0001), decreased alkaline phosphatase (-131 ± 13 vs -35 ± 19; p<0.0001), and improved RGI-C lower limb deformity score (+0.62 ± 0.12 vs +0.21 ± 0.12; p=0.020). At Week 40, increases in serum phosphorous (p<0.0001) and TmP/GFR (p<0.0001) were significantly greater with burosumab compared with Pi/D. Standing height Z-score increased in both treatment groups from baseline to Week 40 with an LS mean change of +0.15 (95% CI: 0.05, 0.25) for burosumab and +0.08 (-0.02, 0.19) for Pi/D. Percent predicted distance walked in six minutes increased with burosumab (Baseline to Week 40: 62% to 72%) and was unchanged with Pi/D (76% to 75%). Pre-defined adverse events (AEs) of interest, including hypersensitivity and injection site reaction, were higher in the burosumab group, but were mild to moderate in severity overall, with no discontinuations. There were 4 serious AEs (3 burosumab, 1 Pi/D); none were treatment-related and all resolved.

In this randomized Phase 3 clinical trial, burosumab Q2W re-sulted in significantly greater improvements in rickets and phosphate metabolism compared with conventional therapy in 1-12 year-old children with XLH.

Ort, förlag, år, upplaga, sidor
S. Karger, 2018
Nationell ämneskategori
Endokrinologi och diabetes Pediatrik
Identifikatorer
urn:nbn:se:oru:diva-69558 (URN)000445204100114 ()
Konferens
57th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2018), Athens, Greece, September 27-29, 2018
Tillgänglig från: 2018-10-17 Skapad: 2018-10-17 Senast uppdaterad: 2018-10-17Bibliografiskt granskad
Gkourogianni, A., Segerlund, E., Hallgrimsdottir, S., Nilsson, O. & Stattin, E.-L. (2018). Clinical and Radiological Manifestations in a Large Swedish Family with a Pathogenic Heterozygous ACAN Variant. Paper presented at 57th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2018), Athens, Greece, September 27-29, 2018. Hormone Research in Paediatrics, 90(Suppl.1), 424-424
Öppna denna publikation i ny flik eller fönster >>Clinical and Radiological Manifestations in a Large Swedish Family with a Pathogenic Heterozygous ACAN Variant
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2018 (Engelska)Ingår i: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, nr Suppl.1, s. 424-424Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Abstract [en]

Objectives: Heterozygous mutations in the aggrecan gene (ACAN) are associated with idiopathic short stature, with or without advanced bone age (BA), osteochondritis dissecans (OCD) and early onset of severe osteoarthritis (OA). Variable features also include midface hypoplasia, brachydactyly, short thumbs and intervertebral disc degenerative disease.

Methods: We reviewed 173 radiographs in 22 individuals (8F:14M), (3shoulders, 10hands, 10wrists, 17spines, 10pelvis, 31hips, 79knees, 5 lower-legs, 4ankles, 4feet).Furthermore 2 computed tomography scans (1hip; 1knee), and 5 magnetic resonance scans (2hips; 3knees). All included individuals belong to a five generation Swedish family with short stature, OCD, and early onset OA (MIM#165800), caused by a pathogenic sequence variant, p.V2303M, in the C-type lectin domain of ACAN.

Results: In the group of children (n=6; age ≤15yo; 3F:3M), six had moderately advanced BA (range:6-17.5months). There was no clear sign of a metaphyseal or epiphyseal dysplasia, but subtle defects of the distal radial growth plate were present in four children. There were 3 males with OCD in the knees and one of them also present-ed OCD of the hip, scoliosis and schmorl’s nodes of intervertebral discs. Actually he went through a derotation osteotomy in both hips and later a proximal tibia osteotomy and distal fibula osteotomy.Among 16 adult patients (5F:11M), 16 had OCD (7elbows,4 hips,13 knees, 5 patellas), 13 developed early onset (>40y) OA, (1shoulder, 5elbows, 3 spines, 1 metatarsophalangeal joint, 6 hips, 12 knees, 1 patella). Radiological manifestations of the spine were detected in 4 patients and included 1 scoliosis, 1 spina bifida occulta, 1 platyspondyly, 1 schmorl’s nodes, and 3 with lowering of the intervertebral discs.Moreover 8 adult patients (3F:5M) have been operated, 4 pa-tients had hip replacement (1F:3M;3bilateral;1unilateral) and 5 knee arthroplasties (2F:3M; 3bilateral;2unilateral) in particular 5 patients had tibia osteotomy of which one had combined tibia and fibula osteotomy. We measured all phalanges of eight adult hand x-rays and found no brachydactyly.

Conclusions: The pathogenic heterozygous p.V2303M variant in the ACAN gene causes mildly disproportionate short stature with early-onset OA and intervertebral disc degeneration often requiring multiple orthopedic interventions. Radiologic findings, included moderately advanced BA, OCD in knees, hips, and elbows as well as OA in 13 individuals. Further studies are needed to identify preventive measures that may slow the progression of OA and intervertebral disc disease and to determine the role of rhGH to improve final height

Ort, förlag, år, upplaga, sidor
S. Karger, 2018
Nationell ämneskategori
Endokrinologi och diabetes Pediatrik
Identifikatorer
urn:nbn:se:oru:diva-69560 (URN)000445204103093 ()
Konferens
57th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2018), Athens, Greece, September 27-29, 2018
Tillgänglig från: 2018-10-16 Skapad: 2018-10-16 Senast uppdaterad: 2018-10-16Bibliografiskt granskad
Lui, J. C., Barnes, K. M., Dong, L., Yue, S., Graber, E., Rapaport, R., . . . Baron, J. (2018). Ezh2 mutations found in the Weaver overgrowth syndrome cause a partial loss of H3K27 histone methyltransferase activity. Journal of Clinical Endocrinology and Metabolism, 103(4), 1470-1478
Öppna denna publikation i ny flik eller fönster >>Ezh2 mutations found in the Weaver overgrowth syndrome cause a partial loss of H3K27 histone methyltransferase activity
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2018 (Engelska)Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, nr 4, s. 1470-1478Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in EZH2, a histone methyltransferase responsible for H3K27 trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome.

Objective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome either cause a gain of function or a partial loss of function.

Design: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos.

Results: A de novo missense EZH2 mutation (c.1876G>A (p.Val626Met)) was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality while heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation.

Conclusion: We generated a mouse model with the same mutation as our patient and found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.

Ort, förlag, år, upplaga, sidor
Cary, NC, United States: Oxford University Press, 2018
Nationell ämneskategori
Medicinsk genetik Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:oru:diva-63399 (URN)10.1210/jc.2017-01948 (DOI)000429442000027 ()29244146 (PubMedID)2-s2.0-85045423542 (Scopus ID)
Anmärkning

Funding Agency:

Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH)

Tillgänglig från: 2018-01-08 Skapad: 2018-01-08 Senast uppdaterad: 2018-08-13Bibliografiskt granskad
Nilsson, O. (2018). Growth and growth disorders in 2017: Genetic and epigenetic regulation of childhood growth. Nature Reviews Endocrinology, 14(2), 71-72
Öppna denna publikation i ny flik eller fönster >>Growth and growth disorders in 2017: Genetic and epigenetic regulation of childhood growth
2018 (Engelska)Ingår i: Nature Reviews Endocrinology, ISSN 1759-5029, E-ISSN 1759-5037, Vol. 14, nr 2, s. 71-72Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Studies of rare growth disorders taken together with large-scale genetic studies of adult height variability have uncovered a large genetic network regulating childhood growth. Advances in technology and experimental model systems will help decipher the molecular mechanisms of this complex network and lead to novel treatment approaches for growth disorders.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2018
Nationell ämneskategori
Genetik Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:oru:diva-64007 (URN)10.1038/nrendo.2017.178 (DOI)000419855300011 ()29286042 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, K2015-54X-22 736-01-4 2015-02227VINNOVA, 2014-01438Marianne och Marcus Wallenbergs StiftelseSvenska läkaresällskapetNovo Nordisk
Anmärkning

Funding Agencies:

Stockholm County Council  

Byggmästare Olle Engkvist Stiftelse 

Erik och Edith Fernstrom Foundation for Medical Research  

HKH Kronprinsessan Lovisas förening för barnasjukvård  

Sällskapet Barnavård  

Stiftelsen Frimurare Barnhuset i Stockholm  

Karolinska Institutet, Stockholm, Sweden  

Örebro University, Örebro, Sweden 

Tillgänglig från: 2018-01-11 Skapad: 2018-01-11 Senast uppdaterad: 2018-01-25Bibliografiskt granskad
Nilsson, O. (2018). It Is Not Just the Growth Hormone-IGF-I Axis. Paper presented at 57th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2018), Athens, Greece, September 27-29, 2018. Hormone Research in Paediatrics, 90(Suppl.1), 12-13
Öppna denna publikation i ny flik eller fönster >>It Is Not Just the Growth Hormone-IGF-I Axis
2018 (Engelska)Ingår i: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, nr Suppl.1, s. 12-13Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Abstract [en]

For decades, the dominant conceptual framework for understanding short and tall stature was centered on the GH-IGF-I axis. However, recent findings in basic molecular and cellular biology and in clinical genetics have uncovered a vast array of other regulatory systems that control skeletal growth and an accompanying vast array of genetic defects outside the GH-IGF-I axis that can cause disorders of linear growth. As a result, the traditional view of short or tall stature that is centered on the GH-IGF-I axis is now far too narrow to encompass the ever-growing number of defects that cause abnormal linear growth. A much broader conceptual framework can be based on the simple concept that linear growth disorders are necessarily due to dysfunction of the growth plate, the structure responsible for bone elongation and therefore overall body size. Consequently, short stature can more generally be conceptualized as a primary or secondary disorder of the growth plate chondrocytes. The wide array of genetic defects, many newly-discovered, that affect growth plate chondrocyte function and thereby cause childhood growth disorders will be reviewed. A novel concept that has emerged from recent findings is that sequence variants in a single gene can produce a phenotypic spectrum that ranges from a severe skeletal dysplasia to disproportionate or proportionate short stature, to normal variation in height, to tall stat-ure. The recent advances reviewed in this paper are steadily dimin-ishing the number of children who receive the unhelpful diagnoses of severe idiopathic short stature or tall stature.

Ort, förlag, år, upplaga, sidor
S. Karger, 2018
Nationell ämneskategori
Endokrinologi och diabetes Pediatrik
Identifikatorer
urn:nbn:se:oru:diva-69556 (URN)000445204100031 ()
Konferens
57th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2018), Athens, Greece, September 27-29, 2018
Tillgänglig från: 2018-10-17 Skapad: 2018-10-17 Senast uppdaterad: 2018-10-17Bibliografiskt granskad
Jee, Y. H., Wang, J., Yue, S., Jennings, M., Clokie, S. J. H., Nilsson, O., . . . Baron, J. (2018). Mir-374-5p, mir-379-5p, and mir-503-5p regulate proliferation and hypertrophic differentiation of growth plate chondrocytes in male rats. Endocrinology, 159(3), 1469-1478
Öppna denna publikation i ny flik eller fönster >>Mir-374-5p, mir-379-5p, and mir-503-5p regulate proliferation and hypertrophic differentiation of growth plate chondrocytes in male rats
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2018 (Engelska)Ingår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 159, nr 3, s. 1469-1478Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Growth plate chondrocytes undergo sequential differentiation to form the resting (RZ), proliferative (PZ), and hypertrophic zones (HZ). The important role of microRNAs (miRNAs) in the growth plate was previously revealed by cartilage-specific ablation of Dicer, an enzyme essential for biogenesis of many miRNAs. To identify specific miRNAs that regulate differentiation of PZ chondrocytes to HZ chondrocytes, we microdissected individual growth plate zones from juvenile rats and performed miRNA profiling using a solution hybridization method and also miRNA-seq. Thirty-four miRNAs were differentially expressed between PZ and HZ and we hypothesized that some of the miRNAs that are preferentially expressed in PZ may serve to promote proliferation and inhibit hypertrophic differentiation. Consistent with this hypothesis, transfection of inhibitors for four of these miRNAs (mir-369-3p, mir-374-5p, mir-379-5p, mir-503-5p) decreased proliferation in primary epiphyseal chondrocytes. The inhibitors for three of these miRNAs (mir-374-5p, mir-379-5p, mir-503-5p) also increased expression of multiple genes that are associated with chondrocyte hypertrophic differentiation. We next hypothesized that preferential expression of these miRNAs in PZ is driven by the PTHrP concentration gradient across the growth plate. Consistent with this hypothesis, treatment of primary chondrocytes with a PTH/PTHrP receptor agonist, PTH1-34, increased expression of mir-374-5p, mir-379-5p, and mir-503-5p. Taken together, our findings suggest that the PTHrP concentration gradient across the growth plate induces differential expression of mir-374-5p, mir-379-5p and mir-503-5p between PZ and HZ. In PZ, the higher expression levels of these miRNAs promote proliferation and inhibit hypertrophic differentiation. In HZ, downregulation of these miRNAs inhibits proliferation and promotes hypertrophic differentiation.

Ort, förlag, år, upplaga, sidor
Cary, NC, USA: Oxford University Press, 2018
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:oru:diva-64843 (URN)10.1210/en.2017-00780 (DOI)000430710400019 ()29390136 (PubMedID)2-s2.0-85042671241 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, K2015-54X-22 736-01-4 2015-02227VINNOVA, 2014-01438Marianne och Marcus Wallenbergs StiftelseNovo Nordisk
Anmärkning

Funding Agencies:

Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development  

Intramural Research Program of the National Human Genome Research Institute  

Common Fund of the National Institutes of Health

Stockholm County Council  

Byggmästare Olle Engkvist Stiftelse 

Sallskapet Barnavard  

Stiftelsen Frimurare Barnhuset i Stockholm  

Karolinska Institutet, Stockholm, Sweden  

Örebro University, Örebro, Sweden 

Tillgänglig från: 2018-02-07 Skapad: 2018-02-07 Senast uppdaterad: 2018-09-04Bibliografiskt granskad
Jee, Y. H., Baron, J. & Nilsson, O. (2018). New developments in the genetic diagnosis of short stature. Current opinion in pediatrics, 30(4), 541-547
Öppna denna publikation i ny flik eller fönster >>New developments in the genetic diagnosis of short stature
2018 (Engelska)Ingår i: Current opinion in pediatrics, ISSN 1040-8703, E-ISSN 1531-698X, Vol. 30, nr 4, s. 541-547Artikel, forskningsöversikt (Refereegranskat) Published
Abstract [en]

Purpose of review: Genome-wide approaches including genome-wide association studies as well as exome and genome sequencing represent powerful new approaches that have improved our ability to identify genetic causes of human disorders. The purpose of this review is to describe recent advances in the genetic causes of short stature.

Recent findings: In addition to SHOX deficiency which is one of the most common causes of isolated short stature, PAPPA2, ACAN, NPPC, NPR2, PTPN11 (and other rasopathies), FBN1, IHH and BMP2 have been identified in isolated growth disorders with or without other mild skeletal findings. In addition, novel genetic causes of syndromic short stature have been discovered, including pathogenic variants in BRCA1, DONSON, AMMECR1, NFIX, SLC25A24, and FN1.

Summary: Isolated growth disorders are often monogenic. Specific genetic causes typically have specific biochemical and/or phenotype characteristics which are diagnostically helpful. Identification of additional subjects with a specific genetic cause of short stature often leads to a broadening of the known clinical spectrum for that condition. The identification of novel genetic causes of short stature has provided important insights into the underlying molecular mechanisms of growth failure.

Ort, förlag, år, upplaga, sidor
Lippincott Williams & Wilkins, 2018
Nyckelord
exome sequencing, genetic cause, genome-wide association study, short stature
Nationell ämneskategori
Pediatrik
Identifikatorer
urn:nbn:se:oru:diva-68775 (URN)10.1097/MOP.0000000000000653 (DOI)000442247700016 ()29787394 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, K2015-54X-22736-01-4 2015-02227VINNOVA, 201401438Marianne och Marcus Wallenbergs StiftelseStockholms läns landstingSvenska läkaresällskapetNovo Nordisk, NNF16OC0021508
Anmärkning

Funding Agencies:

Byggmästare Olle Engkvist Stiftelse

Erik och Edith Fernstrom Foundation for Medical Research  

HKH Kronprinsessan Lovisas förening for barnasjukvård  

Sällskapet Barnavård  

Stiftelsen Frimurare Barnhuset i Stockholm  

Karolinska Institutet, Stockholm, Sweden  

Örebro University, Örebro, Sweden  

Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 

Tillgänglig från: 2018-09-06 Skapad: 2018-09-06 Senast uppdaterad: 2018-09-06Bibliografiskt granskad
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-9986-8138

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