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Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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DFG Research Center and Cluster of Excellence for Regenerative Therapies, Technical University, Dresden, Germany
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Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
DFG Research Center and Cluster of Excellence for Regenerative Therapies, Technical University, Dresden, Germany
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Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
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Glucocorticoids (GC) are used for the treatment of inflammatory diseases, including various forms of arthritis. However, their use is limited, amongst others, by adverse effects on bone. The Wnt and bone formation inhibitor sclerostin was recently implicated in the pathogenesis of GC-induced osteoporosis. However, data are ambiguous. The aim of this study was to assess the regulation of sclerostin by GC using several mouse models with high GC levels and two independent cohorts of patients treated with GC. Male 24-week-old C57BL/6 and 18-week-old DBA/1 mice exposed to GC and 12-week-old mice with endogenous hypercortisolism displayed reduced bone formation as indicated by reduced levels of P1NP and increased serum sclerostin levels. The expression of sclerostin in femoral bone tissue and GC-treated bone marrow stromal cells, however, was not consistently altered. In contrast, GC dose- and time-dependently suppressed sclerostin at mRNA and protein levels in human mesenchymal stromal cells, and this effect was GC receptor dependent. In line with the human cell culture data, patients with rheumatoid arthritis (RA, n = 101) and polymyalgia rheumatica (PMR, n = 21) who were exposed to GC had lower serum levels of sclerostin than healthy age- and sex-matched controls (−40%, P < 0.01 and −26.5%, P < 0.001, respectively). In summary, sclerostin appears to be differentially regulated by GC in mice and humans as it is suppressed by GCs in humans but is not consistently altered in mice. Further studies are required to delineate the differences between GC regulation of sclerostin in mice and humans and assess whether sclerostin mediates GC-induced osteoporosis in humans.
University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
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University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
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University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
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University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
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Despite recent improvements in the composition of the diet, lower mineral bone density and overweight tendencies are incoherently described in patients with phenylketonuria (PKU). The impact of dietary factors and plasma phenylalanine levels on growth, BMI, body composition, and bone mineral density was investigated in our cohort of patients with hyperphenylalaninemia (HPA) with or without dietary treatment. The anthropometric, metabolic, BMI and other nutritional indicators and bone mineral density were compared between the group of 96 treated patients with PKU (58 classic PKU (cPKU) and 38 patients with moderate-mild PKU defined as non-classic PKU (non-cPKU)) and the untreated group of 62 patients with benign HPA. Having compared the treated and untreated groups, there were normal outcomes and no statistically significant differences in BMI, body composition, and bone mineral density. Lower body height standard deviation scores were observed in the treated as compared to the untreated group (P < 0.001), but the difference was not significant when analyzing patients older than 18 years; however, cPKU adults were shorter compared to non-cPKU treated adults (P = 0.012). Interestingly, the whole-body fat was statistically higher in non-cPKU as compared to cPKU patients. In conclusion, the dietary treatment ensured adequate nutrition without significant consequences in BMI, body composition, and bone mineral density. A low protein diet may have delayed the growth in childhood, but the treated patients gained a normal final height. Mild untreated hyperphenylalaninemia characteristic for benign HPA had no negative physiological effect on bone mineral density.
Department of Endocrinology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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We demonstrated previously that there is a correlation between glucagon-like peptide-1 (GLP-1) single-nucleotide polymorphism (SNP) and bone mineral density in postmenopausal women. Both GLP-1 and glucose-dependent insulinotropic peptide are incretins. The glucose-dependent insulinotropic peptide receptor (GIPR) SNP rs10423928 has been extensively studied. However, it is not clear whether GIPR gene mutations affect bone metabolism. The aim of this study was to investigate the association between rs10423928 and bone mineral density in postmenopausal women in Shanghai. rs10423928 was detected in 884 postmenopausal women in Shanghai, and the correlation between the GIPR SNP and bone mineral density was assessed. The dominant T/T genotype of rs10423928 was found to be related to the bone mineral density of the femoral neck (P = 0.035). Overall, our findings indicate that the dominant T/T genotype of rs10423928 in postmenopausal women is significantly associated with a higher bone mineral density and that the T/T genotype exerts a bone-protective effect.
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Department of Renal Physiology, Necker Hospital, Université de Paris, Paris, France
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Mineral and bone diseases (MBD) are predominant in patients with chronic kidney disease (CKD) and lead to several bone manifestations, from pain to skeletal fractures. Cumulative traditional clinical risk factors, such as age and gender, in addition to those related to CKD, enhance the risk of comorbidity and mortality related to fractures. Despite great advances in understanding MBD in CKD, clinical and biological targets are lacking, which leads to under-management of fractures. Optimal PTH control results in a net improvement in defining the levels of bone remodeling. In addition, circulating biomarkers such as bone-specific alkaline phosphatase and cross-linked collagen type I peptide will also provide additional information about remodeling rate, bone mineralization and the evaluation of fracture risk. Imaging techniques identify patients at risk by measurement of bone mineral density by DEXA or by high peripheral QCT, which allow the discrimination of trabecular and cortical bone. Here, we have reviewed the literature related to epidemiology and the pathophysiological role of mineral and biochemical factors involved in CKD-MBD with a special focus on fracture risk. We also provide an algorithm that could be used for the management of bone diseases and to guide treatment decisions. Finally, the combined expertise of clinicians from various disciplines is crucial for the best prevention of fractures.
Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK
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Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK
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Background
The highly plastic nature of adrenal cortex suggests the presence of adrenocortical stem cells (ACSC), but the exact in vivo identity of ACSC remains elusive. A few studies have demonstrated the differentiation of adipose or bone marrow-derived mesenchymal stem cells (MSC) into steroid-producing cells. We therefore investigated the isolation of multipotent MSC from human adrenal cortex.
Methods
Human adrenals were obtained as discarded surgical material. Single-cell suspensions from human adrenal cortex (n = 3) were cultured onto either complete growth medium (CM) or MSC growth promotion medium (MGPM) in hypoxic condition. Following ex vivo expansion, their multilineage differentiation capacity was evaluated. Phenotype markers were analysed by immunocytochemistry and flow cytometry for cell-surface antigens associated with bone marrow MSCs and adrenocortical-specific phenotype. Expression of mRNAs for pluripotency markers was assessed by q-PCR.
Results
The formation of colony-forming unit fibroblasts comprising adherent cells with fibroblast-like morphology were observed from the monolayer cell culture, in both CM and MGPM. Cells derived from MGPM revealed differentiation towards osteogenic and adipogenic cell lineages. These cells expressed cell-surface MSC markers (CD44, CD90, CD105 and CD166) but did not express the haematopoietic, lymphocytic or HLA-DR markers. Flow cytometry demonstrated significantly higher expression of GLI1 in cell population harvested from MGPM, which were highly proliferative. They also exhibited increased expression of the pluripotency markers.
Conclusion
Our study demonstrates that human adrenal cortex harbours a mesenchymal stem cell-like population. Understanding the cell biology of adrenal cortex- derived MSCs will inform regenerative medicine approaches in autoimmune Addison’s disease.
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Objective
We aimed to evaluate whether thyroid hormones, autoimmune and thyroid homeostasis status were related to bone turnover in type 2 diabetes.
Methods
The data were obtained from a cross-sectional study, the METAL study. In this study, 4209 participants (2059 men and 2150 postmenopausal women) with type 2 diabetes were enrolled. Thyroid function, thyroid antibodies and three bone turnover markers (BTMs), including a large N-mid fragment of osteocalcin (N-MID osteocalcin), β-C-terminal cross-linked telopeptides of type I collagen (β-CTX) and procollagen type I N-terminal propeptide (P1NP), were measured. Thyroid homeostasis parameters, including the sum activity of step-up deiodinases (SPINA-GD), thyroid secretory capacity (SPINA-GT), Jostel’s TSH index (TSHI) and the thyrotroph thyroid hormone resistance index (TTSI), were calculated. The associations of thyroid parameters with BTMs were analyzed using linear regression.
Results
Free and total triiodothyronine were positively associated with N-MID osteocalcin and P1NP in both sexes and positively associated with β-CTX in postmenopausal women. Thyroid-stimulating hormone was negatively associated with β-CTX in postmenopausal women, and free thyroxine was negatively associated with N-MID osteocalcin and P1NP in men. SPINA-GD was positively associated with N-MID osteocalcin and P1NP in both sexes. There was a positive relationship of SPINA-GT with β-CTX, a negative relationship of TTSI with β-CTX, and a negative relationship of TSHI with β-CTX and P1NP in postmenopausal women.
Conclusions
Among men and postmenopausal women with type 2 diabetes, significant associations were observed between N-MID osteocalcin, β-CTX and P1NP with thyroid function and thyroid homeostasis. Further prospective studies are warranted to understand the causal relationship and underlying mechanism.
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, People’s Republic of China
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Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, People’s Republic of China
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Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, People’s Republic of China
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Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, People’s Republic of China
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Diabetes-induced advanced glycation end products (AGEs) overproduction would result in compromised osseointegration of titanium implant and high rate of implantation failure. 1α,25-dihydroxyvitamin D3 (1,25VD3) plays a vital role in osteogenesis, whereas its effects on the osseointegration and the underlying mechanism are unclear. The purpose of this study was to investigate that 1,25VD3 might promote the defensive ability of osseointegration through suppressing AGEs/RAGE in type 2 diabetes mellitus. In animal study, streptozotocin-induced diabetic rats accepted implant surgery, with or without 1,25VD3 intervention for 12 weeks. After killing, the serum AGEs level, bone microarchitecture and biomechanical index of rats were measured systematically. In vitro study, osteoblasts differentiation capacity was analyzed by alizarin red staining, alkaline phosphatase assay and Western blotting, after treatment with BSA, AGEs, AGEs with RAGE inhibitor and AGEs with 1,25VD3. And the expression of RAGE protein was detected to explore the mechanism. Results showed that 1,25VD3 could reverse the impaired osseointegration and mechanical strength, which possibly resulted from the increased AGEs. Moreover, 1,25VD3 could ameliorate AGEs-induced damage of cell osteogenic differentiation, as well as downregulating the RAGE expression. These data may provide a theoretical basis that 1,25VD3 could work as an adjuvant treatment against poor osseointegration in patients with type 2 diabetes mellitus.
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Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Harvard Medical School, Boston, Massachusetts, USA
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Glucocorticoid use is the most common cause of secondary osteoporosis. Poor skeletal health related to glucocorticoid use is thought to involve inhibition of the Wnt/β-catenin signaling pathway, a key pathway in osteoblastogenesis. Sclerostin, a peptide produced primarily by osteocytes, is an antagonist of the Wnt/β-catenin signaling pathway, raising the possibility that sclerostin is involved in glucocorticoids’ adverse effects on bone. The aim of this study was to determine whether an acute infusion of cosyntropin (i.e. ACTH(1–24)), which increases endogenous cortisol, increases serum sclerostin levels as compared to a placebo infusion. This study was performed using blood samples obtained from a previously published, double-blind, placebo-controlled, randomized, cross-over study among healthy men and women who received infusions of placebo or cosyntropin after being supine and fasted overnight (ClinicalTrials.gov NCT02339506). A total of 17 participants were analyzed. There was a strong correlation (R2 = 0.65, P < 0.0001) between the two baseline sclerostin measurements measured at the start of each visit, and men had a significantly higher average baseline sclerostin compared to women. As anticipated, cosyntropin significantly increased serum cortisol levels, whereas cortisol levels fell during placebo infusion, consistent with the diurnal variation in cortisol. There was no significant effect of cosyntropin as compared to placebo infusions on serum sclerostin over 6–24 h (P = 0.10). In conclusion, this randomized, placebo-controlled study was unable to detect a significant effect of a cosyntropin infusion on serum sclerostin levels in healthy men and women.
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Objective
To evaluate the clinical features of Chinese women with idiopathic hypogonadotropic hypogonadism (IHH).
Methods
We retrospectively reviewed the clinical characteristics, laboratory and imaging findings, therapeutic management and fertility outcomes of 138 women with IHH. All patients had been treated and followed up at an academic medical centre during 1990–2016.
Results
Among the 138 patients, 82 patients (59.4%) were diagnosed with normosmic IHH and 56 patients (40.6%) were diagnosed with Kallmann syndrome (KS). The patients with IHH experienced occasional menses (4.3%), spontaneous thelarche (45.7%) or spontaneous pubarche (50.7%). Women with thelarche had a higher percentage of pubarche (P < 0.001) and higher gonadotropin concentrations (P < 0.01). Olfactory bulb/sulci abnormalities were found during the magnetic resonance imaging (MRI) of all patients with KS. Most patients with IHH had osteopenia and low bone age. Among the 16 women who received gonadotropin-releasing hormone treatment, ovulation induction or assisted reproductive technology, the clinical pregnancy rate was 81.3% and the live birth rate was 68.8%.
Conclusions
The present study revealed that the phenotypic spectrum of women with IHH is broader than typical primary amenorrhoea with no secondary sexual development, including occasional menses, spontaneous thelarche or pubarche. MRI of the olfactory system can facilitate the diagnosis of KS. Pregnancy can be achieved after receiving appropriate treatment.
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Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by recalcitrant hypophosphatemia. Reports from the Indian subcontinent are scarce, with most being single center experiences involving few patients. Herein, we conducted a retrospective analysis of 30 patients of TIO diagnosed at three tertiary care hospitals in India. Patients with persistent hypophosphatemia (despite correction of hypovitaminosis D), normocalcemia, elevated alkaline phosphatase, low TmP/GFR and elevated or ‘inappropriately normal’ FGF23 levels were labeled as having TIO. They were sequentially subjected to functional followed by anatomical imaging. Patients with a well-localized tumor underwent excision; others were put on phosphorous and calcitriol supplementation. The mean age at presentation was 39.6 years with female:male ratio of 3:2. Bone pain (83.3%) and proximal myopathy (70%) were the chief complaints; 40% of cases had fractures. The mean delay in diagnosis was 3.8 years. Tumors were clinically detectable in four patients (13.3%). The mean serum phosphate was 0.50 mmol/L with a median serum FGF23 level of 518 RU/mL. Somatostatin receptor-based scintigraphy was found to be superior to FDG-PET in tumor localization. Lower extremities were the most common site of the tumor (72%). Tumor size was positively correlated with serum FGF23 levels. Twenty-two patients underwent tumor resection and 16 of them had phosphaturic mesenchymal tumors. Surgical excision led to cure in 72.7% of patients whereas disease persistence and disease recurrence were seen in 18.2% and 9.1% of cases, respectively. At the last follow-up, serum phosphate in the surgically treated group was significantly higher than in the medically managed group.
