title: Mechanisms of enhanced osteoclastogenesis in girls and young women with Turner's Syndrome.
abstract: Subjects with hypergonadotropic hypogonadism due to Turner's syndrome show low cortical mineral density, osteoporosis and risk of fractures. It is not clear if this bone fragility derives from chromosomal abnormalities or is the result of inadequate bone formation due to estrogen deficiency. The aim of this study was to investigate the cellular mechanisms underlying bone fragility in subjects with Turner's syndrome before induction of puberty and after hormonal replacement therapy (HRT). For this purpose, we have evaluated the osteoclastogenic potential of non-fractioned and T-cell depleted cultures of peripheral blood mononuclear cells (PBMCs) belonging to girls with Turner's syndrome who had not been treated with HRT yet, girls and young women who were on HRT and age-matched controls. Untreated subjects showed high FSH serum levels, whereas the other subjects displayed normal FSH serum levels. T-cell immunophenotype was analyzed through flow cytometry. Biochemical and DXA analyses were performed. Spontaneous osteoclastogenesis in non-fractioned and T-cell depleted cultures of PBMC belonging to girls with high FSH levels was more evident than in cultures of subjects with normal FSH levels. In the former, osteoclastogenesis was sustained by monocytes expressing high levels of c-fms, TNF-α and RANK, and T-cells producing high RANKL and TNF-α; in the latter it was supported by T-cells expressing high RANKL levels. CD4(+)CD25(high) T-cells were reduced in all subjects, whereas CD3(+)/CD16(+)/CD56(+) NKT-cells were increased in those with high FSH levels. High RANKL and CTX levels were detected in the sera. Bone impairment was already detectable by DXA in subjects aged under 10, although it became more evident with aging. In conclusion, our results demonstrated that bone fragility in subjects with Turner's syndrome is associated to enhanced osteoclastogenesis. This process seems to be due to high FSH serum levels before HRT, whereas it is caused by high RANKL during HRT.
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Bari, Italy. Electronic address: mariafelicia.faienza@uniba.it.
authors.forename: Maria Felicia
authors.initials: MF
authors.lastname: Faienza
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Bari, Italy. Electronic address: giacomina.brunetti@uniba.it.
authors.forename: Giacomina
authors.initials: G
authors.lastname: Brunetti
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ventura
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Piacente
authors.affiliation: Department of Pediatric, Gynecologic, Microbiologic and Biomedical Sciences, University of Messina, Messina, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Messina
authors.affiliation: Department of Pediatric, Gynecologic, Microbiologic and Biomedical Sciences, University of Messina, Messina, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: De Luca
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Ciccarelli
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Oranger
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Mori
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Natale
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Gigante
authors.affiliation: Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ranieri
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Colucci
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Cavallo
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University "A. Moro" of Bari, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Grano
mesh_terms: D000293:Adolescent; D000328:Adult; D015519:Bone Density / Q000187:drug effects / Q000502:physiology*; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D020249:Hormone Replacement Therapy / Q000379:methods; D006801:Humans; D007223:Infant; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D012741:Sexual Maturation / Q000187:drug effects / Q000502:physiology; D014424:Turner Syndrome / Q000097:blood* / Q000188:drug therapy; D055815:Young Adult
chemical_list: D005640:Follicle Stimulating Hormone
keywords: FSH; Osteoclastogenesis; RANKL; T cells; Turner's syndrome