Systemic Mastocytosis With Decreased Bone Density and Fractures.
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ABSTRACT:
SUBMITTER: Zechner C
PROVIDER: S-EPMC5526622 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
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Systemic Mastocytosis With Decreased Bone Density and Fractures.
Zechner Christoph C Gruntmanis Ugis U
Mayo Clinic proceedings 20150601 6
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Project description:Patients with systemic mastocytosis (SM) have a wide variety of problems, including skeletal abnormalities. The disease results from a mutation of the stem cell receptor (c-kit) in mast cells and we wondered if the function of bone marrow stromal cells (BMSCs; also known as MSCs or mesenchymal stem cells) might be affected by the invasion of bone marrow by mutant mast cells. As expected, BMSCs from SM patients do not have a mutation in c-kit, but they proliferate poorly. In addition, while osteogenic differentiation of the BMSCs seems to be deficient, their adipogenic potential appears to be increased. Since the hematopoietic supportive abilities of BMSCs are also important, we also studied the engraftment in NSG mice of human CD34(+) hematopoietic progenitors, after being co-cultured with BMSCs of healthy volunteers vs. BMSCs derived from patients with SM. BMSCs derived from the bone marrow of patients with SM could not support hematopoiesis to the extent that healthy BMSCs do. Finally, we performed an expression analysis and found significant differences between healthy and SM derived BMSCs in the expression of genes with a variety of functions, including the WNT signaling, ossification, and bone remodeling. We suggest that some of the symptoms associated with SM might be driven by epigenetic changes in BMSCs caused by dysfunctional mast cells in the bone marrow of the patients.
| S-EPMC4557871 | biostudies-literature
Project description:IntroductionBone mineral density (BMD) measured with dual-energy X-ray absorptiometry (DXA) can be used to predict fractures, but its clinical utility has not been fully established in chronic kidney disease (CKD) patients. Magnesium is an essential trace element. Although magnesium is associated with the risk of fractures in non-CKD populations, the relationship is unknown in CKD patients.MethodsBMD and serum magnesium levels were measured in 358 stable outpatients undergoing maintenance hemodialysis therapy. The primary outcome was fragility fracture. Patients were divided into groups according to the median level of magnesium and the normal threshold value of lumbar spine BMD.ResultsDuring the median follow-up period of 36 months, 36 (10.0%) fractures occurred. The cumulative incidence rates of fractures were 17.6% and 5.2% [adjusted hazard ratio (aHR) 2.31, 95% confidence interval (CI) 1.03-5.17, P = 0.030] in the lower (<2.6 mg/dL) and higher (≥2.6 mg/dL) magnesium (Mg) groups, respectively, and 21.2% and 7.3% (aHR 2.59, 95% CI 1.09-6.16, P = 0.027) in the low- and high-BMD groups, respectively. The lower-Mg and low-BMD group had a 9.21-fold higher risk of fractures (95% CI; 2.35-47.00; P = 0.0010) than the higher-Mg and high-BMD group. Furthermore, adding both magnesium levels and lumbar spine BMD levels to the established risk factors significantly improved the prediction of fractures (C-index: 0.784 to 0.830, p = 0.041).Discussion/conclusionsThe combination of serum magnesium and lumbar spine BMD can be used for fracture risk stratification and synergistically improves the prediction of fractures in CKD patients.
| S-EPMC8136656 | biostudies-literature
Project description:BackgroundObservational studies have indicated a high but heterogeneous prevalence of low bone mineral density (BMD) and vertebral fractures (VF) in patients with systemic lupus erythematosus (SLE). Therefore, the objectives of this systematic review and meta-regression were: 1) to compare BMD between SLE patients and healthy controls and 2) to evaluate the relationship between BMD and glucocorticoid therapy and VF in SLE patients.Methods and findingsArticles were identified from electronic databases (PubMed, Embase, VHL, SciELO and the Cochrane Library). Prospective longitudinal and cross-sectional studies were considered for review. We evaluated the quality of the evidence included using the Oxford Centre for evidence-based medicine (EBM) Levels of Evidence. In total, 38 articles were identified and analyzed (3442 SLE cases and 6198 controls) in the analysis of BMD (9232 women and 408 men). There were significant differences in mean BMD between SLE patients and controls. BMD mean difference in cases/controls: -0.0566 95% CI (-0.071, -0.0439; p = < 0.0001). When only SLE patients were analyzed, the BMD did not significantly differ between patients who had or had not received glucocorticoid (GCT) therapy. 694 SLE patients were included in the analysis of VF (189 with VF vs. 505 without VF). Patients with VF had lower BMD than patients without VF (BMD mean difference without VF/with VF: 0.033 (95%CI: 0.006-0.060); p-value: 0.0156).ConclusionsPatients with SLE had lower BMD than healthy controls. Moreover, SLE patients with VF had lower BMD than patients without VF. However, our data did not show that GCT therapy had an impact on BMD.
| S-EPMC5999233 | biostudies-literature
Project description:BackgroundPoor fracture healing in geriatric populations is a significant source of morbidity, mortality, and cost to individuals and society; however, a fundamental biologic understanding of age-dependent healing remains elusive. The development of an aged-based fracture model system would allow for a mechanistic understanding that could guide future biologic treatments.Questions/purposesUsing a small animal model of long-bone fracture healing based on chronologic age, we asked how aging affected (1) the amount, density, and proportion of bone formed during healing; (2) the amount of cartilage produced and the progression to bone during healing; (3) the callus structure and timing of the fracture healing; and (4) the behavior of progenitor cells relative to the observed deficiencies of geriatric fracture healing.MethodsTransverse, traumatic tibial diaphyseal fractures were created in 5-month-old (n=104; young adult) and 25-month-old (n=107; which we defined as geriatric, and are approximately equivalent to 70-85 year-old humans) C57BL/6 mice. Fracture calluses were harvested at seven times from 0 to 40 days postfracture for micro-CT analysis (total volume, bone volume, bone volume fraction, connectivity density, structure model index, trabecular number, trabecular thickness, trabecular spacing, total mineral content, bone mineral content, tissue mineral density, bone mineral density, degree of anisotropy, and polar moment of inertia), histomorphometry (total callus area, cartilage area, percent of cartilage, hypertrophic cartilage area, percent of hypertrophic cartilage area, bone and osteoid area, percent of bone and osteoid area), and gene expression quantification (fold change).ResultsThe geriatric mice produced a less robust healing response characterized by a pronounced decrease in callus amount (mean total volume at 20 days postfracture, 30.08±11.53 mm3 versus 43.19±18.39 mm3; p=0.009), density (mean bone mineral density at 20 days postfracture, 171.14±64.20 mg hydroxyapatite [HA]/cm3 versus 210.79±37.60 mg HA/cm3; p=0.016), and less total cartilage (mean cartilage area at 10 days postfracture, 101,279±46,755 square pixels versus 302,167±137,806 square pixels; p=0.013) and bone content (mean bone volume at 20 days postfracture, 11.68±3.18 mm3 versus 22.34±10.59 mm3; p<0.001) compared with the young adult mice. However, the amount of cartilage and bone relative to the total callus size was similar between the adult and geriatric mice (mean bone volume fraction at 25 days postfracture, 0.48±0.10 versus 0.50±0.13; p=0.793), and the relative expression of chondrogenic (mean fold change in SOX9 at 10 days postfracture, 135+25 versus 90±52; p=0.221) and osteogenic genes (mean fold change in osterix at 20 days postfracture, 22.2±5.3 versus 18.7±5.2; p=0.324) was similar. Analysis of mesenchymal cell proliferation in the geriatric mice relative to adult mice showed a decrease in proliferation (mean percent of undifferentiated mesenchymal cells staining proliferating cell nuclear antigen [PCNA] positive at 10 days postfracture, 25%±6.8% versus 42%±14.5%; p=0.047).ConclusionsOur findings suggest that the molecular program of fracture healing is intact in geriatric mice, as it is in geriatric humans, but callus expansion is reduced in magnitude.Clinical relevanceOur study showed altered healing capacity in a relevant animal model of geriatric fracture healing. The understanding that callus expansion and bone volume are decreased with aging can help guide the development of targeted therapeutics for these difficult to heal fractures.
| S-EPMC4182401 | biostudies-literature
Project description:A 53 year old woman presented with abnormal liver function tests and subsequently developed intermittent abdominal pain, vomiting and diarrhoea. There were no rash or anaphylactoid reactions. Endoscopic biopsies showed excessive density of eosinophils and immunohistochemical staining for tryptase revealed a florid mast cell infiltrate. A diagnosis of systemic mastocytosis was made by bone marrow biopsy. Systemic mastocytosis is a rare myeloid neoplasm often associated with gastrointestinal symptoms due usually to mediator release but may rarely represent organ infiltration. While endoscopic and routine biopsy appearances are non-specific, suggestive features should lead to staining for mast cell tryptase or CD 117. However, diagnose generally requires bone marrow biopsy. The prognosis in the majority of patients is good and supportive management only is required. For patients with aggressive disease, cytoreductive therapy may be needed.
| S-EPMC5517246 | biostudies-other
Project description:Despite recent therapeutic advances, systemic mastocytosis (SM) remains an incurable disease due to limited complete remission (CR) rates even after novel therapies. To date, no study has evaluated the expression on SM bone marrow mast cells (BMMC) of large panel of cell surface suitable for antibody-targeted therapy. In this study, we analyzed the expression profile of six cell-surface proteins for which antibody-based therapies are available, on BMMC from 166 SM patients vs. 40 controls. Overall, variable patterns of expression for the markers evaluated were observed among SM BMMC. Thus, CD22, CD30, and CD123, while expressed on BMMC from patients within every subtype of SM, showed highly variable patterns with a significant fraction of negative cases among advanced SM (aggressive SM (ASM), ASM with an associated clonal non-MC lineage disease (ASM-AHN) and MC leukemia (MCL)), 36%, 46%, and 39%, respectively. In turn, CD25 and Fc?RI were found to be expressed in most cases (89% and 92%) in virtually all BMMC (median: 92% and 95%) from both indolent and advanced SM, but with lower/absent levels in a significant fraction of MC leukemia (MCL) and both in MCL and well-differentiated SM (WDSM) patients, respectively. In contrast, CD33 was the only marker expressed on all BMMC from every SM patient. Thus, CD33 emerges as the best potentially targetable cell-surface membrane marker in SM, particularly in advanced SM.
| S-EPMC6387409 | biostudies-literature
Project description:Mastocytosis is a rare hematological neoplasm characterized by the proliferation of abnormal clonal mast cells (MCs) in different cutaneous and extracutaneous organs. Its diagnosis is based on well-defined major and minor criteria, including the pathognomonic dense infiltrate of MCs detected in bone marrow (BM), elevated serum tryptase level, abnormal MCs CD25 expression, and the identification of KIT D816V mutation. The World Health Organization (WHO) classification subdivides mastocytosis into a cutaneous form (CM) and five systemic variants (SM), namely indolent/smoldering (ISM/SSM) and advanced SM (AdvSM) including aggressive SM (ASM), SM associated to hematological neoplasms (SM-AHN), and mast cell leukemia (MCL). More than 80% of patients with SM carry a somatic point mutation of KIT at codon 816, which may be targeted by kinase inhibitors. The presence of additional somatic mutations detected by next generation sequencing analysis may impact prognosis and drive treatment strategy, which ranges from symptomatic drugs in indolent forms to kinase-inhibitors active on KIT. Allogeneic stem cell transplant (SCT) may be considered in selected SM cases. Here, we review the clinical, diagnostic, and therapeutic issues of SM, with special emphasis on the translational implications of SM genetics for a precision medicine approach in clinical practice.
| S-EPMC8623914 | biostudies-literature
Project description:The Systemic Lupus International Clinics (SLICC)-Frailty Index (FI) is associated with adverse outcomes in systemic lupus erythematosus (SLE). However, to our knowledge, its association with bone mineral density (BMD) and vertebral fractures (VF), has not been investigated using a standardized methods. Our aim was to evaluate the relationship between frailty assessed by SLICC-FI, and BMD and VF in Mestizo women with SLE. Adult women were included in this cross-sectional study. Information concerning the risk factors for VF and BMD in the lumbar spine and total hip was acquired. SLICC-FI was assessed at baseline. A semi-quantitative method was utilized to evaluate the prevalence of VF on lateral thoracolumbar radiographs. Univariate and multivariate regression analyses were performed adjusting for age, body mass index (BMI), SLE duration, cumulative glucocorticoid dose, bisphosphonate use, and BMD measurements. We included 202 women with SLE (mean age [SD] = 43.3 [13.6] years). The mean (SD) SLICC-FI value was 0.14 (0.09). Eleven (5.4%) patients were categorized as robust, 62 (30.7%) as relatively less fit, 84 (41.6%) as least fit, and 45 (22.3%) as frail. Both univariate and multivariate models showed associations between frailty (defined as SLICC-FI > 0.21) and prevalent VF in the entire population (OR 5.76, 95% CI 2.53-13.12; P < 0.001) and in the premenopausal group (OR 4.29, 95% CI; P = 0.047). We also found an association between the SLICC-FI and low BMD. In conclusion, frailty assessed by SLICC-FI might be associated with VF and low BMD in mestizo females with SLE.
| S-EPMC10618373 | biostudies-literature
Project description:Systemic mastocytosis (SM) is characterized by abnormal accumulation of neoplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal organs. As found in other myeloproliferative neoplasms, increased production of profibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the proangiogenic cytokine CCL2 in neoplastic mast cells. Correspondingly, the KIT-targeting drug midostaurin and RNA interference-mediated knockdown of KIT reduced expression of CCL2. We also found that nuclear factor κB contributes to KIT-dependent upregulation of CCL2 in mast cells. In addition, CCL2 secreted by KIT D816V+ mast cells was found to promote the migration of human endothelial cells in vitro. Furthermore, knockdown of CCL2 in neoplastic mast cells resulted in reduced microvessel density and reduced tumor growth in vivo compared with CCL2-expressing cells. Finally, we measured CCL2 serum concentrations in patients with SM and found that CCL2 levels were significantly increased in mastocytosis patients compared with controls. CCL2 serum levels were higher in patients with advanced SM and were found to correlate with poor survival. In summary, we have identified CCL2 as a novel KIT D816V-dependent key regulator of vascular cell migration and angiogenesis in SM. CCL2 expression correlates with disease severity and prognosis. Whether CCL2 may serve as a therapeutic target in advanced SM remains to be determined in forthcoming studies.
| S-EPMC7115851 | biostudies-literature
Project description:IntroductionOur objective was to systematically review and analyze published data on bone mineral density (BMD) and fracture rates in patients with phenylketonuria (PKU), and relationships between BMD and phenylalanine levels.MethodologyWe searched PubMed, CINAHL, and Cochrane databases from January 1966 to November 2013 for studies of spine BMD or fracture in PKU and control subjects. We excluded studies assessing skeletal health by ultrasound or peripheral quantitative computer tomography. Both authors reviewed abstracts for inclusion, and read full text papers to extract data.ResultsSixteen studies met eligibility criteria. Meta-analysis of three studies found that spine BMD was 0.100 g/cm(2) lower (95% CI, -0.110, -0.090 g/cm(2)) in 67 subjects with PKU, compared to 161 controls. Among six studies, 20% (53 of 263) of PKU subjects experienced clinical fractures. In the single study with controls, the fracture rate was 2.6 fold higher (95% CI, 1.1-6.1) after age 8 in PKU subjects, compared to healthy sibling controls. When considering a total of 12 studies in 412 subjects, nine or 75% of studies representing 71% of studied subjects reported no association between phenylalanine levels and BMD. Spine BMD is lower in PKU than control subjects, but only one study controlled for smaller body size. Existing studies suggest a clinical fracture rate of 20% among PKU subjects, but fracture rates in controls are lacking. Finally, existing data shows no consistent relationship between phenylalanine levels and BMD. Future studies are needed to clarify the etiology and health consequences of low BMD in PKU.
| S-EPMC4208974 | biostudies-literature