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Chiarito M, Lattanzio C, D'Ascanio V, Capalbo D, Cavarzere P, Grandone A, Aiello F, Pepe G, Wasniewska M, Zoller T, Salerno M, Faienza MF. Increased risk of nephrolithiasis: an emerging issue in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocrine 2024; 84:727-734. [PMID: 38536547 PMCID: PMC11076308 DOI: 10.1007/s12020-024-03792-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 03/18/2024] [Indexed: 05/08/2024]
Abstract
PURPOSE To investigate the incidence of nephrolithiasis in a cohort of children with congenital adrenal hyperplasia (CAH), and to study if there is an association with the metabolic control of the disease. METHODS This study was designed as a multicenter 1 year-prospective study involving 52 subjects (35 males) with confirmed molecular diagnosis of CAH due to 21-hydroxylase deficiency (21-OHD). Each patient was evaluated at three different time-points: T0, T1 (+6 months of follow-up), T2 (+12 months of follow up). At each follow up visit, auxological data were collected, and adrenocorticotrophic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), Δ4-androstenedione, dehydroepiandrosterone sulfate (DHEAS) serum levels, and urinary excretion of creatinine, calcium, oxalate and citrate were assayed. Moreover, a renal ultrasound was performed. RESULTS The incidence of nephrolithiasis, assessed by ultrasound was 17.3% at T0, 13.5% at T1 and 11.5% at T2. At T0, one subject showed nephrocalcinosis. In the study population, a statistically significant difference was found for 17-OHP [T0: 11.1 (3.0-25.1) ng/mL; T1: 7.1 (1.8-19.9) ng/mL; T2: 5.9 (2.0-20.0) ng/mL, p < 0.005], and Δ4-androstenedione [T0: 0.9 (0.3-2.5) ng/mL; T1: 0.3 (0.3-1.1) ng/mL; T2: 0.5 (0.3-1.5) ng/mL, p < 0.005] which both decreased over the follow up time. No statistically significant difference among metabolic markers was found in the group of the subjects with nephrolithiasis, even if 17-OHP, DHEAS and Δ4-androstenedione levels showed a tendency towards a reduction from T0 to T2. Principal component analysis (PCA) was performed to study possible hidden patterns of associations/correlations between variables, and to assess the trend of them during the time. PCA revealed a decrease in the amount of the variables 17-OHP, Δ4-androstenedione, and ACTH that occurred during follow-up, which was also observed in subjects showing nephrolithiasis. CONCLUSIONS our data demonstrated that children affected with 21-OHD can be at risk of developing nephrolithiasis. Additional studies are needed to clarify the pathogenesis and other possible risk factors for this condition, and to establish if regular screening of kidney ultrasound in these patients can be indicated.
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Affiliation(s)
- Mariangela Chiarito
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "A. Moro", Bari, Italy
| | - Crescenza Lattanzio
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "A. Moro", Bari, Italy
| | - Vito D'Ascanio
- Institute of Sciences of Food Production (ISPA), Italian National Research Council (CNR), Bari, Italy
| | - Donatella Capalbo
- Pediatric Endocrinology Unit-Department of Translational Medical Sciences, University of Naples Federico II and University Hospital Federico II, Endo-ERN Center for Rare Endocrine Conditions, Naples, Italy
| | - Paolo Cavarzere
- Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy
| | - Anna Grandone
- Department of Woman, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Francesca Aiello
- Department of Woman, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giorgia Pepe
- Department of Human Pathology of adulthood and childhood, University of Messina, Messina, Italy
| | - Malgorzata Wasniewska
- Department of Human Pathology of adulthood and childhood, University of Messina, Messina, Italy
| | - Thomas Zoller
- Pediatric Division, Department of Pediatrics, University Hospital of Verona, Verona, Italy
| | - Mariacarolina Salerno
- Pediatric Endocrinology Unit-Department of Translational Medical Sciences, University of Naples Federico II and University Hospital Federico II, Endo-ERN Center for Rare Endocrine Conditions, Naples, Italy
| | - Maria Felicia Faienza
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "A. Moro", Bari, Italy.
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Fehsel K, Christl J. Comorbidity of osteoporosis and Alzheimer's disease: Is `AKT `-ing on cellular glucose uptake the missing link? Ageing Res Rev 2022; 76:101592. [PMID: 35192961 DOI: 10.1016/j.arr.2022.101592] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 02/08/2023]
Abstract
Osteoporosis and Alzheimer's disease (AD) are both degenerative diseases. Osteoporosis often proceeds cognitive deficits, and multiple studies have revealed common triggers that lead to energy deficits in brain and bone. Risk factors for osteoporosis and AD, such as obesity, type 2 diabetes, aging, chemotherapy, vitamin deficiency, alcohol abuse, and apolipoprotein Eε4 and/or Il-6 gene variants, reduce cellular glucose uptake, and protective factors, such as estrogen, insulin, exercise, mammalian target of rapamycin inhibitors, hydrogen sulfide, and most phytochemicals, increase uptake. Glucose uptake is a fine-tuned process that depends on an abundance of glucose transporters (Gluts) on the cell surface. Gluts are stored in vesicles under the plasma membrane, and protective factors cause these vesicles to fuse with the membrane, resulting in presentation of Gluts on the cell surface. This translocation depends mainly on AKT kinase signaling and can be affected by a range of factors. Reduced AKT kinase signaling results in intracellular glucose deprivation, which causes endoplasmic reticulum stress and iron depletion, leading to activation of HIF-1α, the transcription factor necessary for higher Glut expression. The link between diseases and aging is a topic of growing interest. Here, we show that diseases that affect the same biochemical pathways tend to co-occur, which may explain why osteoporosis and/or diabetes are often associated with AD.
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Zhang Q, Gu S, Yu C, Cao R, Xu Y, Fu L, Wang C. Integrated assessment of endocrine disrupting potential of four novel brominated flame retardants. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 232:113206. [PMID: 35085884 DOI: 10.1016/j.ecoenv.2022.113206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/12/2022] [Accepted: 01/13/2022] [Indexed: 06/14/2023]
Abstract
Novel brominated flame retardants (NBFRs) have emerged as alternatives to the legacy BFRs due to BFRs' persistence, bioaccumulation and evidence of adverse health effects. The increasing production of NBFRs has led to the frequent detection in environmental media and even in organisms. Thus the potential health risks of these novel NBFRs need to be taken into account. Herein, the endocrine disrupting effects of the four NBFRs (α/β-TBCO, PBEB, EHTBB and BEHTBP) were evaluated by constructing an estrogen receptor (ERα), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR) mediated dual-luciferase reporter gene assays on the CHO cells, in combination with steroid experiments on the H295R cells and molecular docking. The results revealed that α/β-TBCO, PBEB and EHTBB induced anti-estrogenic activity at certain concentrations while none of the four NBFRs was agonistic to ERα. For reporter gene assay, only PBEB exhibited GR antagonistic effects. Notably, none of the four NBFRs possess neither agonistic nor antagonistic activity of MR. The molecular docking results were generally consistent with the reporter gene assay, which showed the different binding affinities between NBFRs and the receptors. For steroidogenesis, α/β-TBCO, PBEB, and EHTBB all upregulated genes encoding for steroid synthesis enzymes, including 17βHSD, CYP11B1 and CYP17. Altogether, the data clarified that NBFRs may pose risks of endocrine disruption.
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Affiliation(s)
- Quan Zhang
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China.
| | - Sijia Gu
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China
| | - Chang Yu
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China
| | - Rui Cao
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China
| | - Yitian Xu
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China
| | - Lili Fu
- Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, China
| | - Cui Wang
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
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Wasniewska MG, Morabito LA, Baronio F, Einaudi S, Salerno M, Bizzarri C, Russo G, Chiarito M, Grandone A, Guazzarotti L, Spinuzza A, Corica D, Ortolano R, Balsamo A, Abrigo E, Baldini Ferroli B, Alibrandi A, Capalbo D, Aversa T, Faienza MF. Growth Trajectory and Adult Height in Children with Nonclassical Congenital Adrenal Hyperplasia. Horm Res Paediatr 2021; 93:173-181. [PMID: 32810858 DOI: 10.1159/000509548] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 06/16/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Children with nonclassical congenital adrenal hyperplasia (NCCAH) often present increased growth velocity secondary to elevation of adrenal androgens that accelerates bone maturation and might compromise adult height (AH). OBJECTIVE The aim of the study was to analyze prognostic factors affecting growth trajectory (GT) and AH in children with NCCAH. METHODS The study was a retrospective, multicentric study. The study population consisted of 192 children with a confirmed molecular diagnosis of NCCAH, followed by pediatric endocrinology centers from diagnosis up to AH. Clinical records were collected and analyzed. AH (standard deviation score; SDS), pubertal growth (PG) (cm), GT from diagnosis to AH (SDS), and AH adjusted to target height (TH) (AH-TH SDS) were evaluated as outcome indicators using stepwise linear regression models. RESULTS The stepwise linear regression analysis showed that AH and AH-TH were significantly related to chronological age (CA) (p = 0.008 and 0.016), bone age (BA)/CA ratio (p = 0.004 and 0.001), height (H) (p < 0.001 for both parameters) at NCCAH diagnosis, and TH (p = 0.013 and <0.001). PG was higher in males than in females (22.59 ± 5.74 vs. 20.72 ± 17.4 cm, p = 0.002), as physiologically observed, and was positively related to height (p = 0.027), negatively to BMI (p = 0.001) and BA/CA ratio (p = 0.001) at NCCAH diagnosis. Gender, genotype, biochemical data, and hydrocortisone treatment did not significantly impair height outcomes of these NCCAH children. CONCLUSIONS The results of this study suggest that AH and GT of NCCAH patients are mainly affected by the severity of phenotype (CA, BA/CA ratio, and H) at the time of diagnosis.
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Affiliation(s)
- Malgorzata Gabriela Wasniewska
- Department of Human Pathology of Adulthood and Childhood Gaetano Barresi, Gaetano Martino University Hospital, University of Messina, Messina, Italy,
| | - Letteria Anna Morabito
- Department of Human Pathology of Adulthood and Childhood Gaetano Barresi, Gaetano Martino University Hospital, University of Messina, Messina, Italy
| | - Federico Baronio
- Department of Women, Children and Urological Diseases, S. Orsola Malpighi University Hospital, University of Bologna, Bologna, Italy
| | - Silvia Einaudi
- Department of Pediatric Endocrinology and Diabetology, Regina Margherita Children Hospital, University of Turin, Turin, Italy
| | - Mariacarolina Salerno
- Pediatric Endocrine Unit, Department of Translational Medical Sciences, Pediatrica Section, Federico II University of Naples, Naples, Italy
| | - Carla Bizzarri
- Endocrinology and Diabetes Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Gianni Russo
- Department of Pediatrics, Endocrine Unit, Scientific Institute San Raffaele, Milan, Italy
| | - Mariangela Chiarito
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University of Bari "A. Moro", Bari, Italy
| | - Anna Grandone
- Department of Woman, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | - Antonietta Spinuzza
- Department of Human Pathology of Adulthood and Childhood Gaetano Barresi, Gaetano Martino University Hospital, University of Messina, Messina, Italy
| | - Domenico Corica
- Department of Human Pathology of Adulthood and Childhood Gaetano Barresi, Gaetano Martino University Hospital, University of Messina, Messina, Italy
| | - Rita Ortolano
- Department of Women, Children and Urological Diseases, S. Orsola Malpighi University Hospital, University of Bologna, Bologna, Italy
| | - Antonio Balsamo
- Department of Women, Children and Urological Diseases, S. Orsola Malpighi University Hospital, University of Bologna, Bologna, Italy
| | - Enrica Abrigo
- Department of Pediatric Endocrinology and Diabetology, Regina Margherita Children Hospital, University of Turin, Turin, Italy
| | | | - Angela Alibrandi
- Department of Economics, Unit of Statistical and Mathematical Sciences, University of Messina, Messina, Italy
| | - Donatella Capalbo
- Pediatric Endocrine Unit, Department of Translational Medical Sciences, Pediatrica Section, Federico II University of Naples, Naples, Italy
| | - Tommaso Aversa
- Department of Human Pathology of Adulthood and Childhood Gaetano Barresi, Gaetano Martino University Hospital, University of Messina, Messina, Italy
| | - Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University of Bari "A. Moro", Bari, Italy
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Ntali G, Charisis S, Kylafi CF, Vogiatzi E, Michala L. The way toward adulthood for females with nonclassic congenital adrenal hyperplasia. Endocrine 2021; 73:16-30. [PMID: 33855677 DOI: 10.1007/s12020-021-02715-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 03/23/2021] [Indexed: 10/21/2022]
Abstract
Females with NC21OHD may present as asymptomatic or develop a wide range of androgen excess expression. Clinical manifestations may become evident in childhood and adolescence and include premature pubarche, precocious puberty, acne, hirsutism, and menstrual disorders or present later in life as oligo-ovulation and infertility. Glucocorticoids have been the mainstay of treatment as they regulate excess androgen expression by dampening ACTH activation. Their use requires a careful dose monitoring to avoid overtreatment and subsequently the risk of obesity, type 2 diabetes, dyslipidemia, hypertension, and osteoporosis. Women with NC21OHD need regular follow up throughout their life in order to overcome the physical and psychological burden of hyperandrogenism.
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Affiliation(s)
- Georgia Ntali
- Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece.
| | - Sokratis Charisis
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece
| | - Christo F Kylafi
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece
| | | | - Lina Michala
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Alexandra Hospital, Athens, Greece
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Gao Y, Wang O, Guan W, Wu X, Mao J, Wang X, Yu W, Nie M. Bone mineral density and trabecular bone score in patients with 21-hydroxylase deficiency after glucocorticoid treatment. Clin Endocrinol (Oxf) 2021; 94:765-773. [PMID: 33301636 DOI: 10.1111/cen.14391] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/28/2020] [Accepted: 12/02/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Patients with 21-hydroxylase deficiency (21-OHD) are at risk of reduced bone mineral density (BMD) and fracture due to long-term glucocorticoid treatment. Trabecular bone score (TBS) is complementary to conventional BMD as a marker for bone quality in patients with glucocorticoid-induced osteoporosis. The purpose of this study is to evaluate the BMD and TBS in a cohort of patients with 21-OHD and analyse factors related to TBS. DESIGN An observational study. PATIENTS A total of 46 21-OHD adult patients treated with glucocorticoid for over 10 years who visited Peking Union Medical College Hospital between 2015 and 2019 were recruited. Eight male patients included in this study were all under 50 years old, and 38 female patients were all premenopausal. MEASUREMENTS Diagnosis was confirmed by multiplex ligation-dependent probe amplification combined with sequencing. Data were collected on physical characteristics, serum hormones and glucocorticoid treatment. Skeletal quality was evaluated by BMD and TBS, and factors related to TBS were analysed. RESULTS Among the 46 patients, 2 (4.3%) had low BMD (Z-score ≤ -2), while 11 (23.9%) patients had low TBS (degraded or partially degraded microarchitecture). The proportion of bone abnormality evaluated by TBS was higher than that by BMD (p < .001). Patients with lower TBS had significantly higher daily hydrocortisone dosage (p = .009 for males; p = .019 for females). TBS value was negatively correlated with daily hydrocortisone dosage (r = -.317, p = .026), and positively correlated with BMI in female patients (r = .345, p = .034). And there was a negative correlation between TBS value and the current age in male patients (r = -.741, p = .036). The distribution of genotypes (p = 1.000 for male; p = .567 for female) or phenotypes (p = .486 for male; p = .075 for female) had no statistical difference in patients with normal or abnormal TBS. CONCLUSIONS Approximately 24% of patients with 21-OHD had abnormal microarchitecture of their bone in our study, and TBS score was negatively correlated with daily glucocorticoid dosage in patients. TBS may be used alongside conventional BMD as a complementary marker for bone evaluation in 21-OHD patients.
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Affiliation(s)
- Yinjie Gao
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Ou Wang
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Wenmin Guan
- Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xueyan Wu
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiangfeng Mao
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xi Wang
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Yu
- Department of Radiology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Min Nie
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Oliveira NMD, Langer RD, Lemos-Marini SHVD, Guerra-Júnior G, Gonçalves EM. Bioelectrical Impedance Phase Angle and Its Determinants in Patients with Classic Congenital Adrenal Hyperplasia. J Am Coll Nutr 2021; 41:407-414. [PMID: 33764276 DOI: 10.1080/07315724.2021.1895902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH21OHD) have increased fat mass and metabolic alterations. The bioelectrical impedance phase angle (PhA) is an indicator of cellular integrity in several diseases. This study aimed to determine the influence of adiposity levels, sex, CAH21OHD, pubertal development, body composition, and treatment on the PhA of patients with CAH21OHD. METHODS Forty girls and 30 boys with CAH21OHD aged 15.3 ± 5.8 years were evaluated. Sexual maturation was assessed by a pediatrician. The PhA was assessed using bioelectrical impedance, percentage of fat mass (% FM), and lean soft tissue (LST) with dual-energy X-ray absorptiometry. Adiposity levels were compared using % FM tertiles and body mass index (BMI). Glucocorticoid dosage was converted using hydrocortisone dose equivalent (HDE). RESULTS No differences were found in the PhA values among the clinical form (p = 0.103), BMI (p = 0.498), and % FM (p = 0.654) groups. High PhA values were observed in boys (p = 0.011) and postpubertal (p < 0.001) patients. LST, HDE, and height in girls (r2 = 0.68, p < 0.001) and age, HDE, and FM in boys (r2 = 0.82, p < 0.001) determined the PhA variations. BMI explained 14% (p = 0.032) of the PhA variations, whereas LST, height, HDE, and FM (kg) explained 66% (p < 0.001) in the prepubertal, pubertal, and postpubertal groups, respectively. CONCLUSION LST determined the PhA variations in girls and the postpubertal group. Age and BMI were determinants in boys and the pre- and pubertal groups, respectively.
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Affiliation(s)
- Núbia Maria de Oliveira
- Laboratory of Growth and Development (LabCreD) - Center for Investigation in Pediatrics (CIPED) - School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Raquel David Langer
- Laboratory of Growth and Development (LabCreD) - Center for Investigation in Pediatrics (CIPED) - School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Sofia Helena Valente de Lemos-Marini
- Laboratory of Growth and Development (LabCreD) - Center for Investigation in Pediatrics (CIPED) - School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Gil Guerra-Júnior
- Laboratory of Growth and Development (LabCreD) - Center for Investigation in Pediatrics (CIPED) - School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Ezequiel Moreira Gonçalves
- Laboratory of Growth and Development (LabCreD) - Center for Investigation in Pediatrics (CIPED) - School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
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Li P, Mao W, Zhang S, Zhang L, Chen Z, Lu Z. MicroRNA-22 contributes to dexamethasone-induced osteoblast differentiation inhibition and dysfunction through targeting caveolin-3 expression in osteoblastic cells. Exp Ther Med 2021; 21:336. [PMID: 33732309 PMCID: PMC7903452 DOI: 10.3892/etm.2021.9767] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 10/30/2020] [Indexed: 12/14/2022] Open
Abstract
Osteoporosis is a common complication of long-term use of glucocorticoids (GCs) characterized by the loss of bone mass and damage of the microarchitecture as well as osteoblast dysfunction. Previous studies have demonstrated that microRNA-22 (miR-22) is the negative modulator of osteogenesis that may target caveolin-3 (CAV3), which has been reported to enhance bone formation and inhibit the progression of osteoporosis as well as apoptosis. The present study aimed to investigate whether miR-22 may be involved in dexamethasone (DEX)-induced inhibition of osteoblast differentiation and dysfunction by regulating CAV3 expression. Reverse transcription-quantitative PCR (RT-qPCR) was performed to measure the expression of miR-22 and western blotting was performed to determine protein levels. The results demonstrated that miR-22 expression was upregulated in DEX-treated osteoblastic cells compared with the control group. In addition, miR-22 mimic aggravated, whereas miR-22 inhibitor mitigated DEX-induced damage in osteoblastic cells compared with the control groups. Additionally, CAV3 was identified as the target of miR-22 in osteoblasts using RT-qPCR, western blotting and dual-luciferase reporter gene assay analysis. The results also demonstrated that silencing of CAV3 blocked the beneficial effects of miR-22 inhibitor against DEX-induced cell damage and apoptosis in osteoblasts, as evidenced by the increased expression levels of cleaved caspase-3, Bax and alkaline phosphatase activity as well as decreased cell viability and Bcl-2 levels. Collectively, these results indicate a novel molecular mechanism by which miR-22 contributes to DEX-induced osteoblast dysfunction and apoptosis via the miR-22/CAV3 pathway.
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Affiliation(s)
- Peng Li
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Weiwei Mao
- Clinical Skill Center of Yinchuan First People's Hospital, Yinchuan, Ningxia 750001, P.R. China
| | - Shuai Zhang
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Liang Zhang
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Zhirong Chen
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
| | - Zhidong Lu
- Department of Orthopedics, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China
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Li P, Mao WW, Zhang S, Zhang L, Chen ZR, Lu ZD. Sodium hydrosulfide alleviates dexamethasone-induced cell senescence and dysfunction through targeting the miR-22/sirt1 pathway in osteoblastic MC3T3-E1 cells. Exp Ther Med 2021; 21:238. [PMID: 33603846 PMCID: PMC7851607 DOI: 10.3892/etm.2021.9669] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 09/15/2020] [Indexed: 01/30/2023] Open
Abstract
Glucocorticoid-induced osteoporosis is characterized by osteoblastic cell and microarchitecture dysfunction, as well as a loss of bone mass. Cell senescence contributes to the pathological process of osteoporosis and sodium hydrosulfide (NaHS) regulates the potent protective effects through delaying cell senescence. The aim of the present study was to investigate whether senescence could contribute to dexamethasone (Dex)-induced osteoblast impairment and to examine the effect of NaHS on Dex-induced cell senescence and damage. It was found that the levels of the senescence-associated markers, p53 and p21, were markedly increased in osteoblasts exposed to Dex. A p53 inhibitor reversed Dex-induced osteoblast injury, a process that was mitigated by NaHS administration through alleviating osteoblastic cell senescence. MicroRNA (miR)-22 blocked the impact of NaHS on Dex-induced osteoblast damage and senescence through targeting the regulation of Sirtuin 1 (sirt1) expression, as shown by the decreased cell viability and alkaline phosphatase activity, as well as an increased expression of p53 and p21. It was revealed that the sirt1 gene was the target of miR-22 in osteoblastic MC3T3-E1 cells through combining the results of dual luciferase reporter assays and reverse transcription-quantitative PCR, as well as western blot analyses. Silencing of sirt1 abolished the protective effect of NaHS against Dex-associated osteoblast senescence and injury. Taken together, the present study showed that NaHS prevents Dex-induced cell senescence and damage through targeting the miR-22/sirt1 pathway in osteoblastic MC3T3-E1 cells.
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Affiliation(s)
- Peng Li
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Wei-Wei Mao
- Clinical Skill Center of Yinchuan First People's Hospital, Yinchuan, Ningxia 750001, P.R. China
| | - Shuai Zhang
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Liang Zhang
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Zhi-Rong Chen
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
| | - Zhi-Dong Lu
- Department of Orthopedics, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia 750004, P.R. China
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Chiarito M, Brunetti G, D'Amato G, Faienza MF. Monitoring and maintaining bone health in patients with Turner syndrome. Expert Rev Endocrinol Metab 2020; 15:431-438. [PMID: 33074770 DOI: 10.1080/17446651.2020.1834846] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/07/2020] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Subjects affected with Turner Syndrome (TS) suffer low bone mineral density and high risk of fracture from a young age. Estrogen deficiency is considered the main risk factor but other factors, such as intrinsic bone abnormalities, enhanced osteoclastogenesis, vitamin D deficiency and other comorbidities may contribute to the exalted bone fragility. AREAS COVERED The authors performed a literature search in PubMed and EMBASE, using selected key words. They focused their search on pathogenetic mechanisms of osteoporosis in TS and updated the diagnosis, prevention and therapeutic interventions. EXPERT OPINION Bone health is a concern in subjects with TS, and strategies to prevent osteoporosis and fractures should be considered from childhood. Advice on how to live a healthy lifestyle, including physical activity and correct nutrition, should be given during childhood in order to prevent bone impairment later in life. The screening for vitamin D deficiency should be performed between the ages of 9 and 11, and every 2-3 years thereafter. Early initiation of estrogen replacement therapy (ERT) between 11-12 years of age, prompt titration to the adult dose after 2 years, and long-term follow-up to guarantee compliance with ERT, are the key points of osteoporosis prevention in women with TS.
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Affiliation(s)
- Mariangela Chiarito
- Department of Biomedical Sciences and Human Oncology, University "A.Moro" , Bari, Italy
| | - Giacomina Brunetti
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" , Bari, Italy
| | - Gabriele D'Amato
- Department of Women's and Children's Health, ASL Bari, Neonatal Intensive Care Unit, Di Venere Hospital , Bari, Italy
| | - Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, University "A.Moro" , Bari, Italy
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Auer MK, Paizoni L, Hofbauer LC, Rauner M, Chen Y, Schmidt H, Huebner A, Bidlingmaier M, Reisch N. Effects of androgen excess and glucocorticoid exposure on bone health in adult patients with 21-hydroxylase deficiency. J Steroid Biochem Mol Biol 2020; 204:105734. [PMID: 32784048 DOI: 10.1016/j.jsbmb.2020.105734] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 07/05/2020] [Accepted: 07/27/2020] [Indexed: 01/08/2023]
Abstract
CONTEXT This study aimed to determine the role of modifiable predictors on bone health in congenital adrenal hyperplasia (CAH). DESIGN Cross-sectional, single center study, including 97 patients (N = 42 men) with classic CAH due to 21-hydroxylase deficiency (N = 65 salt wasting, N = 32 simple virilizing). MAIN OUTCOME MEASURES Treatment-related predictors of bone health. RESULTS Average T scores (-0.9 ± 1.4 vs. -0.4 ± 1.4; p = 0.036) as well as Z scores (-1.0 ± 1.3 vs. -0.1 ± 1.4; p = 0.012) at the spine in patients with CAH were significantly lower in men than women. While osteoporosis was rare in women, it was documented in 9.1% of men with CAH. There was a significant positive correlation of Z scores at the spine with advancing age in women with CAH (R² = 0.178; p = 0.003). In multivariate analysis, the intake of conventional hydrocortisone (HC) instead of synthetic glucocorticoids was independently associated with a higher bone mineral density (BMD) at the hip region in both sexes. In women, there was a positive association with vitamin D concentrations. Interestingly, higher sodium levels were associated with a lower BMD independent of renin levels and fludrocortisone dosage. Neither in men nor in women, markers of androgen control were predictive for BMD at any site. Markers of bone turnover indicated low bone turnover. No pathological fractures were documented. CONCLUSIONS Men with CAH are particularly prone to low bone density, while women seem to be relatively protected by androgen excess compared to the general female population. The use of HC instead of synthetic GCs for hormone replacement may translate into better bone health.
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Affiliation(s)
- Matthias K Auer
- Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Luisa Paizoni
- Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Lorenz C Hofbauer
- Division of Endocrinology and Diabetes, Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Division of Endocrinology and Diabetes, Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Yiqing Chen
- Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Heinrich Schmidt
- Department of Pediatric Endocrinology, Dr. von Haunersches Children's Hospital, Klinikum der Universität München, LMU München, Munich, Germany
| | - Angela Huebner
- Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden, Germany
| | - Martin Bidlingmaier
- Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany
| | - Nicole Reisch
- Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany.
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Brunetti G, Mori G, Faienza MF. Editorial: Special Issue on "Molecular Mechanisms Regulating Osteoclastogenesis". Int J Mol Sci 2020; 21:ijms21207643. [PMID: 33076553 PMCID: PMC7589872 DOI: 10.3390/ijms21207643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 10/13/2020] [Indexed: 11/24/2022] Open
Affiliation(s)
- Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, 70124 Bari, Italy
- Correspondence: ; Tel.: +39-080-0547-8306
| | - Giorgio Mori
- Department of Clinical and Experimental Medicine, University of Foggia Medical School, 71122 Foggia, Italy;
| | - Maria Felicia Faienza
- Department of Biomedical Science and Human Oncology, Paediatric Unit, University of Bari, 70100 Bari, Italy;
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Eskandarynasab M, Doustimotlagh AH, Takzaree N, Etemad-Moghadam S, Alaeddini M, Dehpour AR, Goudarzi R, Partoazar A. Phosphatidylserine nanoliposomes inhibit glucocorticoid-induced osteoporosis: A potential combination therapy with alendronate. Life Sci 2020; 257:118033. [DOI: 10.1016/j.lfs.2020.118033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/20/2020] [Accepted: 06/28/2020] [Indexed: 02/07/2023]
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Riehl G, Reisch N, Roehle R, Claahsen van der Grinten H, Falhammar H, Quinkler M. Bone mineral density and fractures in congenital adrenal hyperplasia: Findings from the dsd-LIFE study. Clin Endocrinol (Oxf) 2020; 92:284-294. [PMID: 31886890 DOI: 10.1111/cen.14149] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/26/2019] [Accepted: 12/28/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND In patients with congenital adrenal hyperplasia (CAH) type and doses of glucocorticoids used as well as sex hormone secretion during puberty have important actions on bone mineral density (BMD) in adulthood. AIM To evaluate BMD in adult CAH patients depending on current glucocorticoid therapy and on androgen levels in adulthood and at age 16 years. METHODS We included 244 CAH patients from the dsd-LIFE cohort (women n = 147, men n = 97; salt-wasting n = 148, simple-virilizing n = 71, nonclassical n = 25) in which BMD and bloods were available. Clinical and hormonal data at age 16years were retrieved from patients' files. RESULTS Simple-virilizing women showed lower BMD compared to salt-wasting women at trochanter (0.65 ± 0.12 vs 0.75 ± 0.15 g/cm2 ; P < .050), whole femur T-score (-0.87 ± 1.08 vs -0.16 ± 1.24; P < .05) and lumbar T-score (-0.81 ± 1.34 vs 0.09 ± 1.3; P < .050). Fracture prevalence did not differ significantly between the CAH groups. Prednisolone vs. hydrocortisone only therapy caused worse trochanter Z-score (-1.38 ± 1.46 vs -0.47 ± 1.16; P < .050). In women lumbar spine, BMD correlated negatively with hydrocortisone-equivalent dose per body surface (r2 = 0.695, P < .001). Furthermore, BMI at age 16years correlated positively with lumbar spine T-score (r2 = 0.439, P = .003) and BMD (r2 = 0.420, P = .002) in women. The androstenedione/testosterone ratio at age 16years correlated positively with lumbar spine Z-score in women (r2 = 0.284, P = .024) and trochanter Z-score in men (r2 = 0.600, P = .025). CONCLUSION Higher glucocorticoid doses seemed to cause lower BMD especially in women. Prednisolone appeared to have more detrimental effects on BMD than hydrocortisone. Higher glucocorticoid doses (lower androstenedione/testosterone ratio) during adolescence may cause lower BMD in adulthood.
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Affiliation(s)
| | - Nicole Reisch
- Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany
| | - Robert Roehle
- Charité Universitätsmedizin Berlin, Coordinating Center for Clinical Studies, Berlin, Germany
- Institute of Biometry and Clinical Epidemiology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Hedi Claahsen van der Grinten
- Department of Pediatric Endocrinology, Amalia Children's Hospital, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Henrik Falhammar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
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How Physical Activity across the Lifespan Can Reduce the Impact of Bone Ageing: A Literature Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17061862. [PMID: 32183049 PMCID: PMC7143872 DOI: 10.3390/ijerph17061862] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/05/2020] [Accepted: 03/10/2020] [Indexed: 02/07/2023]
Abstract
Bone remodeling is a lifelong process, due to the balanced activity of the osteoblasts (OBs), the bone-forming cells, and osteoclasts (OCs), the bone-resorbing cells. This equilibrium is mainly regulated by the WNT-ß-cathenin pathway and the RANK-RANKL/OPG system, respectively. Bone ageing is a process which normally occurs during life due to the imbalance between bone formation and bone resorption, potentially leading to osteoporosis. Bone loss associated with bone ageing is determined by oxidative stress, the result of the increasing production of reactive oxygen species (ROS). The promotion of physical exercise during growth increases the chances of accruing bone and delaying the onset of osteoporosis. Several studies demonstrate that physical exercise is associated with higher bone mineral density and lower fracture incidence, and the resulting bone mineral gain is maintained with ageing, despite a reduction of physical activity in adulthood. The benefits of exercise are widely recognized, thus physical activity is considered the best non-pharmacologic treatment for pathologies such as osteoporosis, obesity, diabetes and cardiovascular disease. We reviewed the physiological mechanisms which control bone remodeling, the effects of physical activity on bone health, and studies on the impact of exercise in reducing bone ageing.
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Brunetti G, D'Amelio P, Mori G, Faienza MF. Editorial: Updates on Osteoimmunology: What's New on the Crosstalk Between Bone and Immune Cells. Front Endocrinol (Lausanne) 2020; 11:74. [PMID: 32153510 PMCID: PMC7045046 DOI: 10.3389/fendo.2020.00074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 02/03/2020] [Indexed: 12/18/2022] Open
Affiliation(s)
- Giacomina Brunetti
- Section of Human Anatomy and Histology, Department of Basic and Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
- *Correspondence: Giacomina Brunetti
| | - Patrizia D'Amelio
- Gerontology Section, Department of Medical Sciences, University of Torino, Turin, Italy
- Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Giorgio Mori
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Maria Felicia Faienza
- Paediatric Unit, Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy
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Irisin and Bone: From Preclinical Studies to the Evaluation of Its Circulating Levels in Different Populations of Human Subjects. Cells 2019; 8:cells8050451. [PMID: 31091695 PMCID: PMC6562988 DOI: 10.3390/cells8050451] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 12/19/2022] Open
Abstract
Almost four years after the discovery of the anabolic action of irisin on bone in mice, ample clinical evidence is emerging in support of its additional physiological relevance in human bone. Irisin inversely correlates with sclerostin levels in adults with prediabetes and with vertebral fragility fractures in post-menopausal women. Furthermore, in athletes we observed a positive correlation between irisin and bone mineral density at different anatomical sites. Our group also described a positive association between serum irisin and bone status in healthy children and multivariate regression analysis showed that irisin is a stronger determinant of bone mineral status than bone alkaline phosphatase. In children with type 1 diabetes mellitus, serum irisin concentrations are positively associated with bone quality and with glycemic control following continuous subcutaneous insulin infusion. Additionally, our in vitro studies suggest the existence of a negative interplay between PTH and irisin biology and these results were also supported by the observation that post-menopausal women with primary hyperparathyroidism have lower levels of irisin compared to matched controls. In this review, we will focus on recent findings about circulating level of irisin in different populations of human subjects and its correlation with their bone status.
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Corbo F, Brunetti G, Crupi P, Bortolotti S, Storlino G, Piacente L, Carocci A, Catalano A, Milani G, Colaianni G, Colucci S, Grano M, Franchini C, Clodoveo ML, D'Amato G, Faienza MF. Effects of Sweet Cherry Polyphenols on Enhanced Osteoclastogenesis Associated With Childhood Obesity. Front Immunol 2019; 10:1001. [PMID: 31130968 PMCID: PMC6509551 DOI: 10.3389/fimmu.2019.01001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 04/18/2019] [Indexed: 12/14/2022] Open
Abstract
Childhood obesity is associated with the development of severe comorbidities, such as diabetes, cardiovascular diseases, and increased risk of osteopenia/osteoporosis and fractures. The status of low-grade inflammation associated to obesity can be reversed through an enhanced physical activity and by consumption of food enrich of anti-inflammatory compounds, such as omega-3 fatty acids and polyphenols. The aim of this study was to deepen the mechanisms of bone impairment in obese children and adolescents through the evaluation of the osteoclastogenic potential of peripheral blood mononuclear cells (PBMCs), and the assessment of the serum levels of RANKL and osteoprotegerin (OPG). Furthermore, we aimed to evaluate the in vitro effects of polyphenol cherry extracts on osteoclastogenesis, as possible dietary treatment to improve bone health in obese subjects. High RANKL levels were measured in obese with respect to controls (115.48 ± 35.20 pg/ml vs. 87.18 ± 17.82 pg/ml; p < 0.01), while OPG levels were significantly reduced in obese than controls (378.02 ± 61.15 pg/ml vs. 436.75 ± 95.53 pg/ml, respectively, p < 0.01). Lower Ad-SoS- and BTT Z-scores were measured in obese compared to controls (p < 0.05). A significant elevated number of multinucleated TRAP+ osteoclasts (OCs) were observed in the un-stimulated cultures of obese subjects compared to the controls. Interestingly, obese subjects displayed a higher percentage of CD14+/CD16+ than controls. Furthermore, in the mRNA extracts of obese subjects we detected a 2.5- and 2-fold increase of TNFα and RANKL transcripts compared to controls, respectively. Each extract of sweet cherries determined a dose-dependent reduction in the formation of multinucleated TRAP+ OCs. Consistently, 24 h treatment of obese PBMCs with sweet cherry extracts from the three cultivars resulted in a significant reduction of the expression of TNFα. In conclusion, the bone impairment in obese children and adolescents is sustained by a spontaneous osteoclastogenesis that can be inhibited in vitro by the polyphenol content of sweet cherries. Thus, our study opens future perspectives for the use of sweet cherry extracts, appropriately formulated as nutraceutical food, as preventive in healthy children and therapeutic in obese ones.
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Affiliation(s)
- Filomena Corbo
- Department of Pharmacy-Drug science, University of Bari Aldo Moro, Bari, Italy
| | - Giacomina Brunetti
- Section of Human Anatomy and Histology, Department of Basic and Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Pasquale Crupi
- CREA-VE, Council for Agricultural Research and Economics-Research Centre for Viticulture and Enology, Turi, Italy
| | - Sara Bortolotti
- Section of Human Anatomy and Histology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Giuseppina Storlino
- Section of Human Anatomy and Histology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Laura Piacente
- Paediatric Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - Alessia Carocci
- Department of Pharmacy-Drug science, University of Bari Aldo Moro, Bari, Italy
| | - Alessia Catalano
- Department of Pharmacy-Drug science, University of Bari Aldo Moro, Bari, Italy
| | - Gualtiero Milani
- Department of Pharmacy-Drug science, University of Bari Aldo Moro, Bari, Italy
| | - Graziana Colaianni
- Section of Human Anatomy and Histology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Silvia Colucci
- Section of Human Anatomy and Histology, Department of Basic and Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Maria Grano
- Section of Human Anatomy and Histology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Carlo Franchini
- Department of Pharmacy-Drug science, University of Bari Aldo Moro, Bari, Italy
| | - Maria Lisa Clodoveo
- Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Bari, Italy
| | | | - Maria Felicia Faienza
- Paediatric Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
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Colaianni G, Faienza MF, Sanesi L, Brunetti G, Pignataro P, Lippo L, Bortolotti S, Storlino G, Piacente L, D'Amato G, Colucci S, Grano M. Irisin serum levels are positively correlated with bone mineral status in a population of healthy children. Pediatr Res 2019; 85:484-488. [PMID: 30683930 DOI: 10.1038/s41390-019-0278-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 12/18/2018] [Accepted: 01/01/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Irisin is a myokine secreted by skeletal muscle during physical activity. Irisin treatment increased cortical bone mineral density (BMD) in young healthy mice and restored bone and muscle mass loss in a mouse model of disuse-induced osteoporosis and muscular atrophy. In humans, Irisin was positively correlated with BMD in young athletes. Considering that the bone mass reached during childhood is one of the most important determinants of lifelong skeletal health, we sought to determine if Irisin levels were correlated with bone mineral status in children. METHODS Irisin and bone metabolic markers were quantified in sera and bone mineral status was evaluated by quantitative ultrasound in a population of 34 healthy children (9.82 ± 3.2 years). RESULTS We found that Irisin levels were positively correlated with the amplitude-dependent speed of sound Z-score (r = 0.305; p < 0.001), bone transmission time Z-score (r = 0.375; p < 0.001) and osteocalcin (r = 0.370; p < 0.001), and negatively with Dickkopf WNT Signaling Pathway Inhibitor 1 (r = -0.274; p < 0.001). CONCLUSION In a regression analysis model, Irisin was one of the determinants of bone mineral status to a greater extent than bone alkaline phosphatase and parathyroid hormone, indicating that Irisin might be considered as one of the bone formation markers during childhood.
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Affiliation(s)
- Graziana Colaianni
- Department of Emergency and Organ Transplantation, School of Medicine-University of Bari, Bari, Italy
| | - Maria F Faienza
- Paediatric Unit, Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy
| | - Lorenzo Sanesi
- Department of Emergency and Organ Transplantation, School of Medicine-University of Bari, Bari, Italy
- PhD School in "Tissue and Organ Transplantation and Cellular Therapies", Department of Emergency and Organ Transplantation, School of Medicine-University of Bari, Bari, Italy
| | - Giacomina Brunetti
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, School of Medicine-University of Bari, Bari, Italy
| | - Patrizia Pignataro
- Department of Emergency and Organ Transplantation, School of Medicine-University of Bari, Bari, Italy
| | - Luciana Lippo
- Department of Emergency and Organ Transplantation, School of Medicine-University of Bari, Bari, Italy
| | - Sara Bortolotti
- Department of Emergency and Organ Transplantation, School of Medicine-University of Bari, Bari, Italy
| | - Giuseppina Storlino
- Department of Emergency and Organ Transplantation, School of Medicine-University of Bari, Bari, Italy
| | - Laura Piacente
- Paediatric Unit, Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy
| | | | - Silvia Colucci
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, Section of Human Anatomy and Histology, School of Medicine-University of Bari, Bari, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, School of Medicine-University of Bari, Bari, Italy.
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Brunetti G, D'Amato G, Chiarito M, Tullo A, Colaianni G, Colucci S, Grano M, Faienza MF. An update on the role of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways in pediatric diseases. World J Pediatr 2019; 15:4-11. [PMID: 30343446 DOI: 10.1007/s12519-018-0198-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 10/04/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs), the bone-reabsorbing cells, and osteoblasts (OBs), and the bone-forming cells. This equilibrium is regulated by numerous cytokines, but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis, respectively. The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1). RANKL, sclerostin and DKKs-1 are often up-regulated in bone diseases, and they are the target of new monoclonal antibodies. DATA SOURCES The authors performed a systematic literature search in PubMed and EMBASE to June 2018, reviewed and selected articles, based on pre-determined selection criteria. RESULTS We re-evaluated the role of RANKL, osteoprotegerin, sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases, such as type 1 diabetes mellitus (T1DM), alkaptonuria (AKU), hemophilia A, osteogenesis imperfecta (OI), 21-hydroxylase deficiency (21OH-D) and Prader-Willi syndrome (PWS). To do so, we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways have been investigated, and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed. CONCLUSIONS The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases. Furthermore, for some of them, bone damage began in childhood but only manifested with age. The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children, although further studies need to be carried out.
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Affiliation(s)
- Giacomina Brunetti
- Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy
| | | | - Mariangela Chiarito
- Pediatric Section, Department of Biomedical Sciences and Human Oncology, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Apollonia Tullo
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies-IBIOM, CNR, 70126, Bari, Italy
| | - Graziana Colaianni
- Department of Emergency and Organ Transplantation, University "A. Moro" of Bari, Bari, Italy
| | - Silvia Colucci
- Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, University "A. Moro" of Bari, Bari, Italy
| | - Maria Felicia Faienza
- Pediatric Section, Department of Biomedical Sciences and Human Oncology, University "A. Moro" of Bari, Piazza G. Cesare 11, 70124, Bari, Italy.
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Zhang W, Robertson WB, Zhao J, Chen W, Xu J. Emerging Trend in the Pharmacotherapy of Osteoarthritis. Front Endocrinol (Lausanne) 2019; 10:431. [PMID: 31312184 PMCID: PMC6614338 DOI: 10.3389/fendo.2019.00431] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 06/14/2019] [Indexed: 12/25/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative joint disorder and one of the most prevalent diseases among the elderly population. Due to the limited spontaneous healing capacity of articular cartilage, it still remains challenging to find satisfactory treatment for OA. This review covers the emerging trends of pharmacologic therapies for OA such as traditional OA drugs (acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, serotonin-norepinephrine reuptake inhibitors (SNRIs), intra-articular injections of corticosteroids, and dietary supplements), which are effective in pain relief but not in reversing damage, and are frequently associated with adverse events. Alternatively, disease-modifying drugs provide promising alternatives for the management of OA. The development of these emerging OA therapeutic agents requires a comprehensive understanding of the pathophysiology of OA progression. The process of cartilage anabolism/catabolism, subchondral bone remodeling and synovial inflammation are identified as potential targets. These emerging OA drugs such as bone morphogenetic protein-7 (BMP-7), fibroblast growth factor-18 (FGF-18), human serum albumin (HSA), interleukin-1 (IL-1) inhibitor, β-Nerve growth factor (β-NGF) antibody, matrix extracellular phosphoglycoprotein (MEPE) and inverse agonist of retinoic acid-related orphan receptor alpha (RORα) etc. have shown potential to modify progression of OA with minimal adverse effects. However, large-scale randomized controlled trials (RCTs) are needed to investigate the safety and efficacy before translation from bench to bedside.
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Affiliation(s)
- Wei Zhang
- School of Medicine, Southeast University, Nanjing, China
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
| | - William Brett Robertson
- Australian Institute of Robotic Orthopaedics, Perth, WA, Australia
- School of Surgery, The University of Western Australia, Perth, WA, Australia
- School of Science, Faculty of Science and Engineering, Curtin University, Perth, WA, Australia
- Department of Materials Science and Engineering, College of Engineering, University of North Texas, Denton, TX, United States
| | - Jinmin Zhao
- Research Centre for Regenerative Medicine, Guangxi Medical University, Nanning, China
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Weiwei Chen
- Research Centre for Regenerative Medicine, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, China
- *Correspondence: Weiwei Chen
| | - Jiake Xu
- School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
- Jiake Xu
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Faienza MF, D'Amato G, Chiarito M, Colaianni G, Colucci S, Grano M, Corbo F, Brunetti G. Mechanisms Involved in Childhood Obesity-Related Bone Fragility. Front Endocrinol (Lausanne) 2019; 10:269. [PMID: 31130918 PMCID: PMC6509993 DOI: 10.3389/fendo.2019.00269] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 04/11/2019] [Indexed: 01/11/2023] Open
Abstract
Childhood obesity is one of the major health problems in western countries. The excessive accumulation of adipose tissue causes inflammation, oxidative stress, apoptosis, and mitochondrial dysfunctions. Thus, obesity leads to the development of severe co-morbidities including type 2 diabetes mellitus, liver steatosis, cardiovascular, and neurodegenerative diseases which can develop early in life. Furthermore, obese children have low bone mineral density and a greater risk of osteoporosis and fractures. The knowledge about the interplay bone tissue and between adipose is still growing, although recent findings suggest that adipose tissue activity on bone can be fat-depot specific. Obesity is associated to a low-grade inflammation that alters the expression of adiponectin, leptin, IL-6, Monocyte Chemotactic Protein 1 (MCP1), TRAIL, LIGHT/TNFSF14, OPG, and TNFα. These molecules can affect bone metabolism, thus resulting in osteoporosis. The purpose of this review was to deepen the cellular mechanisms by which obesity may facilitate osteoporosis and bone fractures.
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Affiliation(s)
- Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | | | - Mariangela Chiarito
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
| | - Graziana Colaianni
- Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Silvia Colucci
- Department of Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari Aldo Moro, Bari, Italy
| | - Maria Grano
- Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology, University of Bari, Bari, Italy
| | - Filomena Corbo
- Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, Italy
| | - Giacomina Brunetti
- Department of Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari Aldo Moro, Bari, Italy
- *Correspondence: Giacomina Brunetti
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Faienza MF, D'Amato E, Natale MP, Grano M, Chiarito M, Brunetti G, D'Amato G. Metabolic Bone Disease of Prematurity: Diagnosis and Management. Front Pediatr 2019; 7:143. [PMID: 31032241 PMCID: PMC6474071 DOI: 10.3389/fped.2019.00143] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 03/26/2019] [Indexed: 12/17/2022] Open
Abstract
Metabolic Bone Disease (MBD) of prematurity is a multifactorial disorder commonly observed in very low birth weight (VLBW, <1,500 g) newborns, with a greater incidence in those extremely low birth weight (ELBW, <1,000 g). MBD is characterized by biochemical and radiological findings related to bone demineralization. Several antenatal and postnatal risk factors have been associated to MBD of prematurity, although the main pathogenetic mechanism is represented by the reduced placental transfer of calcium and phosphate related to preterm birth. The diagnosis of MBD of prematurity requires the assessment of several biochemical markers, radiological, and ultrasonographic findings. However, the best approach is the prevention of the symptomatic disease, based on the screening of subjects exposed to the risks of developing MBD. Regarding the subjects who need to be screened, there is a substantial agreement on the potential risk factors for MBD. On the contrary, different recommendations exist on the diagnosis, management and treatment of this disorder of bone metabolism. This review was aimed at: (1) identifying the subjects at risk for MBD of prematurity; (2) indicating the biochemical findings to take in consideration for the prevention of MBD of prematurity; (3) suggesting practical recommendations on nutritional intake and supplementation in these subjects. We searched for papers which report the current recommendations for biochemical assessment of MBD of prematurity and for its prevention and treatment. The majority of the authors suggest that MBD of prematurity is a disease which tends to normalize overtime, thus it is not mandatory to mimic the rate of mineral fetal accretion through parenteral or enteral supplementation. The optimization of total parenteral nutrition (TPN) and the early achievement of a full enteral feeding are important goals for the prevention and management of MBD of prematurity.
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Affiliation(s)
- Maria Felicia Faienza
- Pediatric Section, Department of Biomedicine and Human Oncology, University of Bari A. Moro, Bari, Italy
| | - Elena D'Amato
- Department of Electric and Electronic Engineering, City University of London, London, United Kingdom
| | | | - Maria Grano
- Section of Human Anatomy and Histology, Department of Emergency and Organ Transplantation, University of Bari A. Moro, Bari, Italy
| | - Mariangela Chiarito
- Pediatric Section, Department of Biomedicine and Human Oncology, University of Bari A. Moro, Bari, Italy
| | - Giacomina Brunetti
- Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari A. Moro, Bari, Italy
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Tajima T. Health problems of adolescent and adult patients with 21-hydroxylase deficiency. Clin Pediatr Endocrinol 2018; 27:203-213. [PMID: 30393437 PMCID: PMC6207803 DOI: 10.1297/cpe.27.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 07/02/2018] [Indexed: 12/30/2022] Open
Abstract
Twenty-one-hydroxylase deficiency (21-OHD) is one of the most common forms of congenital adrenal hyperplasias. Since the disease requires life-long steroid hormone replacement, transition from pediatric clinical care to adolescent and adult care is necessary. Recently, several studies have shown that morbidity and quality of life in adolescent and adult patients with 21-OHD are impaired by obesity, hypertension, diabetes mellitus, impaired glucose tolerance, dyslipidemia, and osteoporosis. In addition, excess adrenal androgen impairs fertility in both females and males. This mini review discusses the current health problems in adolescent and adult patients with 21-OHD and ways to prevent them.
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Affiliation(s)
- Toshihiro Tajima
- Jichi Medical University Children's Medical Center Tochigi, Tochigi, Japan
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Faienza MF, Chiarito M, D'amato G, Colaianni G, Colucci S, Grano M, Brunetti G. Monoclonal antibodies for treating osteoporosis. Expert Opin Biol Ther 2017; 18:149-157. [PMID: 29113523 DOI: 10.1080/14712598.2018.1401607] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Osteoporosis is the most widespread skeletal disease requiring innovative therapeutic strategies for its management. The understanding of receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin's role in bone cell biology is completely changing the therapeutic landscape. RANKL supports osteoclast formation and activity and is mainly produced by cells of osteoblastic lineage. Sclerostin, an antagonist of the Wnt pathway, has a key role in bone formation and is mainly secreted by osteocytes. High levels of RANKL and sclerostin have been detected in osteoporosis, leading to the production of antibodies able to neutralize their activity. AREAS COVERED In this review, the authors give an overview and discuss the literature and data on denosumab and romosozumab to treat osteoporosis. Clinical studies indicate that long-term treatment with denosumab causes a continuous increase in bone mineral density with low incidence of adverse effects. Romosozumab treatment gives increases bone formation and improves bone mineral density (BMD) though further studies are needed to better evaluate the adverse effects. EXPERT OPINION Denosumab and romosozumab show promise in the treatment of osteoporosis. Furthermore, their different mechanisms of action compared to existing anti-osteoporotic drugs may permit alternative strategies for osteoporosis treatment down the line
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Affiliation(s)
- Maria Felicia Faienza
- a Department of Biomedical Sciences and Human Oncology, Pediatric Section , University 'A. Moro' of Bari , Bari , Italy
| | - Mariangela Chiarito
- a Department of Biomedical Sciences and Human Oncology, Pediatric Section , University 'A. Moro' of Bari , Bari , Italy
| | - Gabriele D'amato
- b Neonatal Intensive Care Unit , Di Venere Hospital , Bari , Italy
| | - Graziana Colaianni
- c Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology , University 'A. Moro' of Bari , Bari , Italy
| | - Silvia Colucci
- d Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology , University 'A. Moro' of Bari , Bari , Italy
| | - Maria Grano
- c Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology , University 'A. Moro' of Bari , Bari , Italy
| | - Giacomina Brunetti
- d Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology , University 'A. Moro' of Bari , Bari , Italy
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Abstract
The congenital adrenal hyperplasias comprise a family of autosomal recessive disorders that disrupt adrenal steroidogenesis. The most common form is due to 21-hydroxylase deficiency associated with mutations in the 21-hydroxylase gene, which is located at chromosome 6p21. The clinical features associated with each disorder of adrenal steroidogenesis represent a clinical spectrum that reflect the consequences of the specific mutations. Treatment goals include normal linear growth velocity and "on-time" puberty in affected children. For adolescent and adult women, treatment goals include regularization of menses, prevention of progression of hirsutism, and preservation of fertility. For adolescent and adult men, prevention and early treatment of testicular adrenal rest tumors is beneficial. In this article key aspects regarding pathophysiology, diagnosis, and treatment of congenital adrenal hyperplasia are reviewed.
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Affiliation(s)
- Selma Feldman Witchel
- Division of Pediatric Endocrinology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania.
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27
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Colaianni G, Sun L, Zaidi M, Zallone A. The "love hormone" oxytocin regulates the loss and gain of the fat-bone relationship. Front Endocrinol (Lausanne) 2015; 6:79. [PMID: 26042088 PMCID: PMC4435037 DOI: 10.3389/fendo.2015.00079] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Accepted: 04/30/2015] [Indexed: 12/01/2022] Open
Abstract
The involvement of oxytocin (OT) in bone metabolism is an interesting area of research that recently achieved remarkable results. Moreover, several lines of evidence have largely demonstrated that OT also participates in the regulation of energy metabolism. Hence, it has recently been determined that the posterior pituitary hormone OT directly regulates bone mass: mice lacking OT or OT receptor display severe osteopenia, caused by impaired bone formation. OT administration normalizes ovariectomy-induced osteopenia, bone marrow adiposity, body weight, and intra-abdominal fat depots in mice. This effect is mediated through inhibition of adipocyte precursor differentiation and reduction of adipocyte size. The exquisite role of OT in regulating the bone-fat connection adds another milestone to the biological evidence supporting the existence of a tight relationship between the adipose tissue and the skeleton.
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Affiliation(s)
- Graziana Colaianni
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, Bari, Italy
- *Correspondence: Graziana Colaianni, Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Piazza Giulio Cesare 11, Bari 70124, Italy,
| | - Li Sun
- Mount Sinai Bone Program, Mount Sinai School of Medicine, New York, NY, USA
| | - Mone Zaidi
- Mount Sinai Bone Program, Mount Sinai School of Medicine, New York, NY, USA
| | - Alberta Zallone
- Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, Bari, Italy
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Upadhyay J, Farr OM, Mantzoros CS. The role of leptin in regulating bone metabolism. Metabolism 2015; 64:105-13. [PMID: 25497343 PMCID: PMC4532332 DOI: 10.1016/j.metabol.2014.10.021] [Citation(s) in RCA: 178] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 10/22/2014] [Accepted: 10/22/2014] [Indexed: 01/17/2023]
Abstract
Leptin was initially best known for its role in energy homeostasis and regulation of energy expenditure. In the past few years we have realized that leptin also plays a major role in neuroendocrine regulation and bone metabolism. Here, we review the literature the indirect and direct pathways through which leptin acts to influence bone metabolism and discuss bone abnormalities related to leptin deficiency in both animal and human studies. The clinical utility of leptin in leptin deficient individuals and its potential to improve metabolic bone disease are also discussed. We are beginning to understand the critical role leptin plays in bone metabolism; future randomized studies are needed to fully assess the potential and risk-benefit of leptin's use in metabolic bone disease particularly in leptin deficient individuals.
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Affiliation(s)
- Jagriti Upadhyay
- Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA 02215.
| | - Olivia M Farr
- Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA 02215
| | - Christos S Mantzoros
- Division of Endocrinology, Boston VA Healthcare System/Harvard Medical School, Boston, MA 02215
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Aceto G, D'Addato O, Messina G, Carbone V, Cavallo L, Brunetti G, Faienza MF. Bone health in children and adolescents with steroid-sensitive nephrotic syndrome assessed by DXA and QUS. Pediatr Nephrol 2014; 29:2147-55. [PMID: 24902941 DOI: 10.1007/s00467-014-2834-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 04/14/2014] [Accepted: 04/17/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND The management of steroid-sensitive nephrotic syndrome (SSNS) requires treatment with high-dose glucocorticoids (GCs), but GC usage causes the most frequent form of drug-induced osteoporosis. The aim of our study was to evaluate the impact of GCs on bone mineralization in patients with SSNS using two diagnostic tools, dual-energy X-ray densitometry (DXA) and quantitative ultrasound (QUS), and to compare the diagnostic efficacy of these two imaging tools. METHODS A total of 30 children with SSNS (age 5.20 ± 2.20 years) were evaluated at the start (T0) and after 1 (T1), 2.44 ± 0.75 (T2, 18 patients) and 5.96 ± 2.33 years (T4, 12 patients) of GC treatment. Patients who stopped at T2 were also evaluated at the 1-year timepoint after ceasing GC treatment (T3). RESULTS Of the patients assessed at T2, 11 had bone mineralization at the lower limit of normal versus those at T0 and T1, with bone mineralization rescue at the 1-year timepoint after GC discontinuation. At T4, 6/12 patients had densitometric parameters at the lower limit of normal values, and 3/12 patients showed reduced bone mineralization. The parameters derived from measurements of DXA and QUS were significantly related to each timepoint. CONCLUSIONS Patients with SSNS receiving GC therapy undergo bone status alteration related to the dosage and duration of the therapy. In terms of diagnostic efficacy, DXA and QUS were comparable, indicating that QUS is a reliable tool to evaluate bone health in children with SSNS.
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Affiliation(s)
- Gabriella Aceto
- Division of Pediatric Nephrology, Children's Hospital Giovanni XXIII, Bari, Italy
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30
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Faienza MF, Luce V, Lonero A, Ventura A, Colaianni G, Colucci S, Cavallo L, Grano M, Brunetti G. Treatment of osteoporosis in children with glucocorticoid-treated diseases. Expert Rev Endocrinol Metab 2014; 9:525-534. [PMID: 30736214 DOI: 10.1586/17446651.2014.936384] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Glucocorticoid induced osteoporosis (GIO) is the most frequent form of drug induced osteoporosis. Glucocorticoids affect osteoblastogenesis, osteoclastogenesis and promote the apoptosis of osteoblasts and osteocytes. A decrease of bone mineral density has been described in several pediatric diseases that require glucocorticoids, both as long-term replacement therapy, such as Congenital Adrenal Hyperplasia, and as treatment of acute phase or relapses, such as asthma, juvenile rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, organ transplantation and Steroid Sensitive Nephrotic Syndrome. The increasing number of children with GIO and at risk of fractures reflects the complex nature of this condition, and the need of development of anti-osteoporotic drugs. In this review, we focus on the mechanisms of GIO in some pediatric diseases and on treatment of osteoporosis. We also report data on new signaling pathways as potential targets for future anti-osteoporotic drugs.
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Affiliation(s)
- Maria Felicia Faienza
- a Section of Pediatrics, Department of Biomedical Sciences and Human Oncology, University "A. Moro", Bari, Italy
| | - Vincenza Luce
- a Section of Pediatrics, Department of Biomedical Sciences and Human Oncology, University "A. Moro", Bari, Italy
| | - Antonella Lonero
- a Section of Pediatrics, Department of Biomedical Sciences and Human Oncology, University "A. Moro", Bari, Italy
| | - Annamaria Ventura
- a Section of Pediatrics, Department of Biomedical Sciences and Human Oncology, University "A. Moro", Bari, Italy
| | - Graziana Colaianni
- b Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
| | - Silvia Colucci
- b Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
| | - Luciano Cavallo
- a Section of Pediatrics, Department of Biomedical Sciences and Human Oncology, University "A. Moro", Bari, Italy
| | - Maria Grano
- b Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
| | - Giacomina Brunetti
- b Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy
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Colaianni G, Brunetti G, Faienza MF, Colucci S, Grano M. Osteoporosis and obesity: Role of Wnt pathway in human and murine models. World J Orthop 2014; 5:242-246. [PMID: 25035826 PMCID: PMC4095016 DOI: 10.5312/wjo.v5.i3.242] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 03/04/2014] [Accepted: 04/19/2014] [Indexed: 02/06/2023] Open
Abstract
Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research. Although the onset of these two diseases can occur in a different way, recent studies have shown that obesity and osteoporosis share common genetic and environmental factors. Despite being a risk factor for health, obesity has traditionally been considered positive to bone because of beneficial effect of mechanical loading, exerted by high body mass, on bone formation. However, contrasting studies have not achieved a clear consensus, suggesting instead that excessive fat mass derived from obesity condition may not protect against osteoporosis or, even worse, could be rather detrimental to bone. On the other hand, it is hitherto better established that, since adipocytes and osteoblasts are derived from a common mesenchymal stem cell precursor, molecules that lead to osteoblastogenesis inhibit adipogenesis and vice versa. Here we will discuss the role of the key molecules regulating adipocytes and osteoblasts differentiation, which are peroxisome proliferators activated receptor-γ and Wnts, respectively. In particular, we will focus on the role of both canonical and non-canonical Wnt signalling, involved in mesenchymal cell fate regulation. Moreover, at present there are no experimental data that relate any influence of the Wnt inhibitor Sclerostin to adipogenesis, although it is well known its role on bone metabolism. In addition, the most common pathological condition in which there is a simultaneous increase of adiposity and decrease of bone mass is menopause. Given that postmenopausal women have high Sclerostin level inversely associated with circulating estradiol level and since the sex hormone replacement therapy has proved to be effective in attenuating bone loss and reversing menopause-related obesity, we hypothesize that Sclerostin contribution in adipogenesis could be an active focus of research in the coming years.
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Faienza MF, Ventura A, Marzano F, Cavallo L. Postmenopausal osteoporosis: the role of immune system cells. Clin Dev Immunol 2013; 2013:575936. [PMID: 23762093 PMCID: PMC3677008 DOI: 10.1155/2013/575936] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 05/10/2013] [Indexed: 01/09/2023]
Abstract
In the last years, new evidences of the relationship between immune system and bone have been accumulated both in animal models and in humans affected by bone disease, such as rheumatoid arthritis, bone metastasis, periodontitis, and osteoporosis. Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue with a subsequent increase in bone fragility and susceptibility to fractures. The combined effects of estrogen deprivation and raising of FSH production occurring in menopause cause a marked stimulation of bone resorption and a rapid bone loss which is central for the onset of postmenopausal osteoporosis. This review focuses on the role of immune system in postmenopausal osteoporosis and on therapeutic strategies targeting osteoimmunology pathways.
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Affiliation(s)
- Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70124 Bari, Italy.
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