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Introduction: The dysregulation of cell fate toward osteoprecursor cells associated with most GNAS-based disorders may lead to episodic de novo extraskeletal or ectopic bone formation in subcutaneous tissues. The bony lesion distribution suggests the involvement of abnormal differentiation of mesenchymal stem cells (MSCs) and/or more committed precursor cells. Data from transgenic mice support the concept that GNAS is a crucial factor in regulating lineage switching between osteoblasts (OBs) and adipocyte fates. The mosaic nature of heterotopic bone lesions suggests that GNAS genetic defects provide a sensitized background for ectopic osteodifferentiation, but the underlying molecular mechanism remains largely unknown. Methods: The effect of GNAS silencing in the presence and/or absence of osteoblastic stimuli was evaluated in the human L88/5 MSC line during osteodifferentiation. A comparison of the data obtained with data coming from a bony lesion from a GNAS-mutated patient was also provided. Results: Our study adds some dowels to the current fragmented notions about the role of GNAS during osteoblastic differentiation, such as the premature transition of immature OBs into osteocytes and the characterization of the differences in the deposed bone matrix. Conclusion: We demonstrated that our cell model partially replicates the in vivo behavior results, resulting in an applicable human model to elucidate the pathophysiology of ectopic bone formation in GNAS-based disorders.
Assuntos
Diferenciação Celular , Cromograninas , Subunidades alfa Gs de Proteínas de Ligação ao GTP , Células-Tronco Mesenquimais , Osteoblastos , Osteogênese , Humanos , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Cromograninas/genética , Diferenciação Celular/genética , Osteogênese/genética , Osteoblastos/metabolismo , Osteoblastos/citologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Inativação Gênica , Linhagem CelularRESUMO
BACKGROUND: Pseudohypoparathyroidism (PHP) refers to a group of rare hereditary disorders associated with resistance to parathormone (PTH) and other hormones now termed inactivating PTH/PTHrP disorders (iPPSD). Hypercalcitoninemia has been seldom reported in small series. Our aim was to investigate the characteristics of hypercalcitoninemia in paediatric and adult patients with PHP/iPPSD. METHODS: We retrospectively collected data from two cohorts from two European Endocrinology tertiary centers: the paediatric cohort comprised 88 children with available calcitonin (CT) measurements; the adult cohort included 43 individuals with simultaneous CT and PTH measurements. RESULTS: In the paediatric cohort 65.9% had hypercalcitoninemia (median CT 15 ng/L); in the adult cohort 53.5% (mean CT 21.6 ng/L). There was no difference between CT in paediatric and adult population; we observed stable CT levels over a median follow-up of 134.5 months in adults. Notably, no correlations were detected between CT and PTH levels. Other etiologies of hypercalcitoninemia were excluded, adult patients underwent regular thyroid ultrasound (US) to screen for medullary thyroid cancer (MTC). We performed 20 calcium stimulation tests in adult patients. While there was a significant difference in basal and peak CT between our patients, healthy subjects and subjects with MTC, there was no difference with patients with C-cell hyperplasia. CONCLUSIONS: This study underscores the common occurrence of hypercalcitoninemia in both paediatric and adult PHP/iPPSD patients, in particular with subtypes iPPSD2-iPPSD3. Furthermore, these patients show an hyperresponsiveness to calcium stimulation test falling between healthy subjects and patients with MTC. These findings contribute into the understanding of CT dynamics in the context of PHP/iPPSD.
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CONTEXT: Testosterone therapy has been variably associated with increased thrombotic risk but investigations of global coagulation in this setting are lacking. OBJECTIVE: To compare global coagulation of hypogonadal men before (T0) and 6 months after (T1) starting testosterone replacement therapy (TRT), and healthy controls. DESIGN: Observational prospective cohort study. SETTING: Two tertiary endocrinological ambulatory care centers. PATIENTS: Thirty-eight men with hypogonadism (mean age 55, SD 13) and 38 age-matched healthy controls. INTERVENTIONS: Thrombin generation assay (TGA) was performed at T0 and T1 in hypogonadal men and in controls. TGA is an in vitro procedure based on the continuous registration of thrombin generation and decay under conditions mimicking the process that occurs in vivo. MAIN OUTCOME MEASURES: The following TGA parameters were recorded: lag-time; thrombin-peak concentration; time-to-reach the peak, velocity index and endogenous thrombin potential (ETP), the latter representing the total amount of thrombin generated under the driving forces of procoagulants opposed by the anticoagulants. PC, antithrombin, factor (F)VIII, and fibrinogen were assessed. RESULTS: No changes of TGA parameters were observed between T0 and T1. Hypogonadal men displayed significantly higher ETP, fibrinogen, and significantly lower antithrombin levels both at T0 and T1 compared to controls. Thrombin-peak of hypogonadal men was significantly higher than controls at T0 but not at T1. ETP and antithrombin were correlated with testosterone levels. CONCLUSIONS: Hypogonadal men display a procoagulant imbalance detected by increased thrombin generation. Short-term TRT does not worsen global coagulation, suggesting that the treatment can be safely prescribed to men diagnosed with hypogonadism.
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BACKGROUND: After Denosumab (Dmab) discontinuation C-terminal telopeptide (CTX) levels increase, bone mineral density (BMD) decreases and multiple vertebral fractures (FX) may occur with relevant impact on women's health. A sequential therapy with bisphosphonates is recommended and the European Calcified Tissue Society (ECTS) proposed repeated zoledronate (ZOL) administrations in patients with persistently high CTX levels, although the efficacy of this schedule is unknown. In this retrospective study we describe BMD changes and FX rate in 52 patients managed according to the ECTS recommendations. METHODS: We measured CTX levels and administered ZOL after one month from Dmab withdrawal (t0). After 6 months (t1), we administered a second ZOL infusion, if CTX levels were ≥280 ng/L. BMD changes and FX rate were assessed on average after 17 months from Dmab withdrawal. RESULTS: 75% of patients repeated ZOL infusion. In this group spine BMD declined significantly (-5.5 ± 5.6%), while it remained stable in the group with CTX levels <280 ng/L (-0.1 ± 5.5%, p = 0.008). All fractured patients (9.6%) had received >5 Dmab injections and two ZOL infusions. The BMD worsening after Dmab withdrawal was associated with CTX t1 (OR 2.9, IQR 1.3-6.6, p = 0.009) and spine BMD gain during Dmab therapy corrected for the number of Dmab injections (OR 3.0, IQR 1.2-7.2, p = 0.014). A CTX level at t1 > 212 ng/L had 100% sensitivity in predicting the BMD loss. CONCLUSIONS: In patients with uncontrolled CTX levels after Dmab withdrawal, two ZOL infusions at 6 months apart do not prevent BMD loss and FX.