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Bariatric surgeries are integral to the management of obesity and its metabolic complications. However, these surgeries cause bone loss and increase fracture risk through poorly understood mechanisms. In a mouse model, vertical sleeve gastrectomy (VSG) caused trabecular and cortical bone loss that was independent of sex, body weight, and diet, and this loss was characterized by impaired osteoid mineralization and bone formation. VSG had a profound effect on the bone marrow niche, with rapid loss of marrow adipose tissue, and expansion of myeloid cellularity, leading to increased circulating neutrophils. Following VSG, circulating granulocyte-colony stimulating factor (G-CSF) was increased in mice, and was transiently elevated in a longitudinal study of humans. Elevation of G-CSF was found to recapitulate many effects of VSG on bone and the marrow niche. In addition to stimulatory effects of G-CSF on myelopoiesis, endogenous G-CSF suppressed development of marrow adipocytes and hindered accrual of peak cortical and trabecular bone. Effects of VSG on induction of neutrophils and depletion of marrow adiposity were reduced in mice deficient for G-CSF; however, bone mass was not influenced. Although not a primary mechanism for bone loss with VSG, G-CSF plays an intermediary role for effects of VSG on the bone marrow niche.

Obesity and obesity-related diseases like type 2 diabetes (T2D) are prominent global health issues; therefore, there is a need to better understand the mechanisms underlying these conditions. The onset of obesity is characterized by accumulation of proinflammatory cells, including Ly6chi monocytes (which differentiate into proinflammatory macrophages) and neutrophils, in metabolic tissues. This shift toward chronic, low-grade inflammation is an obese-state hallmark and highly linked to metabolic disorders and other obesity comorbidities. The mechanisms that induce and maintain increased inflammatory myelopoiesis are of great interest, with a recent focus on how obesity affects more primitive hematopoietic cells. The hematopoietic system is constantly replenished by proper regulation of hematopoietic stem and progenitor (HSPC) pools in the BM. While early research suggests that chronic obesity promotes expansion of myeloid-skewed HSPCs, the involvement of the hematopoietic stem cell (HSC) niche in regulating obesity-induced myelopoiesis remains undefined. In this review, we explore the role of the multicellular HSC niche in hematopoiesis and inflammation, and the potential contribution of this niche to the hematopoietic response to obesity. This review further aims to summarize the potential HSC niche involvement as a target of obesity-induced inflammation and a driver of obesity-induced myelopoiesis.

OBJECTIVE Systemic lupus erythematosus (SLE) has one of the highest 30-day hospital readmission rates among chronic diseases in the United States. This quality improvement initiative developed and assessed the feasibility of a multidisciplinary post-discharge intervention to reduce 30-day readmission rates among SLE patients. METHODS A retrospective study was performed using electronic health records of patients with SLE admitted to a university hospital prior to (non-intervention group) and after initiation of the study intervention (intervention group). The study population included patients with a diagnosis of SLE who were admitted to the hospital for any reason during an eight month time period. The intervention involved sending a templated message at the time of discharge to the rheumatology clinic nurses which prompted the nurses to call the patient to coordinate future visits and provide education. The primary outcome was the 30-day hospital readmission rate. Data was analyzed using a multivariate mixed binomial regression model. RESULTS There were 59 hospitalizations in the non-intervention group and 73 hospitalizations in the intervention group during the eight-month study period. The 30-day readmission rate was 29% in the non-intervention group and 19% in the intervention group. The difference in readmission rates between the two groups was not statistically significant based on the multivariate model. CONCLUSION Our study demonstrates the feasibility of implementing a multi-disciplinary post-discharge intervention to reduce readmission rates for patients with SLE in a large academic medical center. Further investigation is warranted to determine if this approach reduces the unacceptably high hospital readmission rates among SLE patients.

Objective The location and mechanisms involved in the initial generation of autoantibodies to citrullinated and noncitrullinated proteins/peptides during the natural history of rheumatoid arthritis (RA) development is incompletely understood. This study sought to explore individual antibody responses to citrullinated and noncitrullinated proteins/peptides in the sputum and associations with neutrophil extracellular traps (NETs) in subjects at risk for the future development of RA. Methods Serum and sputum samples were obtained from 41 RA-free subjects who were considered at risk for the development of RA based on familial or serologic risk factors, from 20 subjects classified as having RA, and from 22 healthy control subjects. Samples were evaluated using a bead-based array for IgG reactivity to 29 citrullinated proteins/peptides and 21 noncitrullinated proteins/peptides. Cutoff levels for antibody positivity were established in a separate control group. NET levels in the sputum were measured using sandwich enzyme-linked immunosorbent assays that quantitate DNA-myeloperoxidase and DNA-neutrophil elastase complexes. Results In at-risk subjects, antibody responses to the citrullinated forms of fibrinogen, apolipoprotein E, and fibronectin were highly prevalent. The most citrulline-specific antibodies in the sputum of at-risk subjects were those to fibrinogen, vimentin, and peptides of fibrinogen A and apolipoprotein A1. Patterns of sputum autoantibody positivity differed between at-risk subjects and subjects with RA. In at-risk subjects, increasing sputum NET levels significantly correlated with several citrullinated and some noncitrullinated antibody reactivities. Conclusion These findings suggest that sputum antibody reactivity to particular citrullinated and noncitrullinated proteins/peptides is specific for RA and for subjects at risk of RA, and the association of these proteins/peptides with NETs may be a key feature of early RA-related autoimmunity in the lung. These results further support the hypothesis that the lung plays a role in early RA-related autoimmunity.

Men have a statistically higher risk of metabolic and cardiovascular disease than premenopausal women, but the mechanisms mediating these differences are elusive. Chronic inflammation during obesity contributes to disease risk and is significantly more robust in males. Prior work demonstrated that compared with obese males, obese females have reduced proinflammatory adipose tissue macrophages (ATMs). Given the paucity of data on how sex hormones contribute to macrophage responses in obesity, we sought to understand the role of sex hormones in promoting obesity-induced myeloid inflammation. We used gonadectomy, estrogen receptor–deficient alpha chimeras, and androgen-insensitive mice to model sex hormone deficiency. These models were evaluated in diet-induced obesity conditions (high-fat diet [HFD]) and in vitro myeloid assays. We found that ovariectomy increased weight gain and adiposity. Ovariectomized females had increased ATMs and bone marrow myeloid colonies compared with sham-gonadectomized females. In addition, castrated males exposed to HFD had improved glucose tolerance, insulin sensitivity, and adiposity with fewer Ly6chi monocytes and bone marrow myeloid colonies compared with sham-gonadectomized males, although local adipose inflammation was enhanced. Similar findings were observed in androgen-insensitive mice; however, these mice had fewer CD11c+ ATMs, implying a developmental role for androgens in myelopoiesis and adipose inflammation. We concluded that gonadectomy results in convergence of metabolic and inflammatory responses to HFD between the sexes, and that myeloid estrogen receptor alpha contributes minimally to diet-induced inflammatory responses, whereas loss of androgen-receptor signaling improves metabolic and inflammatory outcomes. These studies demonstrate that sex hormones play a critical role in sex differences in obesity, metabolic dysfunction, and myeloid inflammation.

Background: Type 2 diabetes (T2D) is the leading cause of nephropathy in the United States. Renal complications of T2D include proteinuria and suboptimal serum 25-hydroxycholecalciferol (25D) concentrations. 25D is the major circulating form of vitamin D and renal reabsorption of the 25D–vitamin D–binding protein (DBP) complex via megalin-mediated endocytosis is believed to determine whether 25D can be activated to 1,25-dihydroxycholecalciferol (1,25D) or returned to circulation. We previously demonstrated that excessive urinary excretion of 25D–DBP and albuminuria occurred in rats with type 1 diabetes (T1D) and T2D. Moreover, feeding rats with T1D high-amylose maize partially resistant to digestion [resistant starch (RS)] prevented excretion of 25D–DBP without significantly affecting hyperglycemia. Objective: We used Zucker diabetic fatty (ZDF) rats, a model of obesity-related T2D, to determine whether feeding RS could similarly prevent loss of vitamin D and maintain serum 25D concentrations. Methods: Lean control Zucker rats (n = 8) were fed a standard semi-purified diet (AIN-93G) and ZDF rats were fed either the AIN-93G diet (n = 8) or the AIN-93G diet in which cornstarch was replaced with RS (550 g/kg diet; 35% resistant to digestion) (n = 8) for 6 wk. Results: RS attenuated hyperglycemia by 41% (P < 0.01) and prevented urinary DBP excretion and albuminuria, which were elevated 3.0- (P < 0.01) and 3.6-fold (P < 0.01), respectively, in control diet–fed ZDF rats. Additionally, urinary excretion of 25D (P 5 0.01) and 1,25D (P5 0.03) was higher (89% and 97%, respectively), whereas serum 25D concentrations were 31% lower (P< 0.001) in ZDF rats fed the control diet compared with RS-fed ZDF rats. Histopathologic scoring of the kidney revealed that RS attenuated diabetes-mediated damage by 21% (P 5 0.12) despite an ;50% decrease in megalin protein abundance. Conclusions: Taken together, these data provide evidence that suggests vitamin D balance can be maintained by dietary RS through nephroprotective actions in T2D, which are independent of vitamin D supplementation and renal expression of megalin. J. Nutr. doi: 10.3945/jn.114.198200.

Type 2 diabetes (T2D) is an epidemic that leads to renal disease if left untreated. Compromised renal function has been implicated in vitamin D deficiency as the renal proximal tubule maintains cir...

In addition to eliminating host hematopoietic cells myeloablation also disrupts the blood vessels that sustain hematopoiesis. Regeneration of the bone marrow (BM) vasculature is necessary for hematopoietic recovery and survival after transplantation (Cell Stem Cell. 2009 Mar 6;4(3):263-74) but the mechanisms that drive vascular regeneration are not clear. We found that, fourteen days after lethal irradiation and transplantation, mice transplanted with 20x106 bone marrow nucleated cells (BMNC) had ~6-fold more CD45-Ter119-CD31+CD105+ endothelial cells (6.9x103 vs 0.96x103 EC/femur, p Because hematopoietic progenitors inhibit vascular regeneration via angiopoietin 1 (Elife2015 Mar 30;4:e05521) we hypothesized that mature hematopoietic cells mediated vascular recovery. To test this we adoptively transferred, B and T cells, monocytes and macrophages (MO), granulocytes and erythroid cells into lethally irradiated recipients previously transplanted with 105 donor BMNC. Only CD115-Gr1+ granulocytes promoted endothelial cell regeneration (2.5x103 for granulocyte treated mice vs 0.9x103 for PBS, 0.3x103 for B- and T-cell, 0.7 1x103 for MO and 0.3x103 EC/femur for erythroid cell-treated mice; p We found that granulocytes produced high levels of the angiogenic cytokine TNFα. This cytokine signals via Tnfrsf1aand Tnfrsf1b. Tnfrsf1a was upregulated specifically in BM endothelial cells. After myeloablation with 5-fluorouracil Tnfa-/-mice have reduced survival (Tnfa-/-= 13% vs WT= 93%; p We have identified a new type of cellular crosstalk in the microenvironment that drives regeneration. Our research also provides proof of principle for studies targeting BM granulocytes to enhance vascular recovery and survival after transplantation in patients. Disclosures No relevant conflicts of interest to declare.

1.1 Myelogenous leukemia and the need for novel drug targets The successful treatment of myelogenous leukemia depends upon the continuing coordinate efforts of the medical and research communities and patients to understand the complex nature of leukemia development and progression, and to battle drug resistant cells. Novel drug therapies, like Imatinib, have been developed which target the mutant BCR-ABL (Breakpoint Cluster Region-Abelson Kinase) protein, and have significantly changed the treatment regimens for chronic myelogenous leukemia (CML). However, while Imatinib is frequently effective against the majority of the leukemic cells, and patients often undergo remission after treatment, these patients also relapse due to a leukemic drug-resistant population (Schemionek et al., 2010). In comparison to CML, the treatment for acute myelogenous leukemia (AML) is predominantly induction therapy using strong anti-mitotic agents, followed by consolidation therapy to kill residual diseased cells (Venditti et al., 2000). These therapies are not specifically targeted to mutated proteins in the cells, and therefore can be more toxic to the patient's normal cells. Researchers have attempted to target mutated proteins in AML. However, unlike BCR-ABL, targeting FLT3-ITD (FMS-like tyrosine kinase 3-Internal Tandem Duplication) and FLT3-TKD (FMS-like tyrosine kinase 3Tyrosine Kinase Domain) mutations have not been as successful as CML-Imatinib therapy (Kindler et al., 2010). Therefore, challenges facing patients with AML remain significant, and drug-resistant relapses remain a threat.