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Splenic differentiation and emergence of CCR5+CXCL9+CXCL10+ monocyte-derived dendritic cells in the brain during cerebral malaria

Wed, 05/03/2017 - 12:07pm

Dendritic cells have an important role in immune surveillance. After being exposed to microbial components, they migrate to secondary lymphoid organs and activate T lymphocytes. Here we show that during mouse malaria, splenic inflammatory monocytes differentiate into monocyte-derived dendritic cells (MO-DCs), which are CD11b+F4/80+CD11c+MHCIIhighDC-SIGNhighLy6c+ and express high levels of CCR5, CXCL9 and CXCL10 (CCR5+CXCL9/10+ MO-DCs). We propose that malaria-induced splenic MO-DCs take a reverse migratory route. After differentiation in the spleen, CCR5+CXCL9/10+ MO-DCs traffic to the brain in a CCR2-independent, CCR5-dependent manner, where they amplify the influx of CD8+ T lymphocytes, leading to a lethal neuropathological syndrome.

IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection

Wed, 05/03/2017 - 12:07pm

IL-21 is produced predominantly by activated CD4+ T cells and has pleiotropic effects on immunity via the IL-21 receptor (IL-21R), a member of the common gamma chain (gammac) cytokine receptor family. We show that IL-21 signaling plays a crucial role in T cell responses during Mycobacterium tuberculosis infection by augmenting CD8+ T cell priming, promoting T cell accumulation in the lungs, and enhancing T cell cytokine production. In the absence of IL-21 signaling, more CD4+ and CD8+ T cells in chronically infected mice express the T cell inhibitory molecules PD-1 and TIM-3. We correlate these immune alterations with increased susceptibility of IL-21R-/- mice, which have increased lung bacterial burden and earlier mortality compared to WT mice. Finally, to causally link the immune defects with host susceptibility, we use an adoptive transfer model to show that IL-21R-/- T cells transfer less protection than WT T cells. These results prove that IL-21 signaling has an intrinsic role in promoting the protective capacity of T cells. Thus, the net effect of IL-21 signaling is to enhance host resistance to M. tuberculosis. These data position IL-21 as a candidate biomarker of resistance to tuberculosis.

Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations

Wed, 05/03/2017 - 12:07pm

The conformation of HIV-1 envelope (Env) glycoprotein trimers is key in ensuring protection against waves of neutralizing antibodies generated during infection, while maintaining sufficient exposure of the CD4 binding site (CD4bs) for viral entry. The CD4 binding loop on Env is an early contact site for CD4 while penetration of a proximal cavity by CD4 triggers Env conformational changes for entry. The role of residues in the CD4 binding loop in regulating the conformation of the trimer and trimer association domain (TAD) was investigated using a novel saturation mutagenesis approach. Single mutations identified, resulted in distinct trimer conformations affecting CD4bs exposure, the glycan shield and the TAD across diverse HIV-1 clades. Importantly, mutations that improve access to the CD4bs without exposing the immunodominant V3 loop were identified. The different trimer conformations identified will affect the specificity and breadth of nabs elicited in vivo and are important to consider in design of Env immunogens for vaccines.

Design and methods for a community-based intervention to reduce sugar-sweetened beverage consumption among youth: H2GO! study

Wed, 05/03/2017 - 12:07pm

BACKGROUND: Reducing sugar-sweetened beverage (SSB) intake is an important dietary target among underserved children at high risk for obesity and associated morbidities. Community-based approaches to reduce SSB intake are needed. The use of narrative-based approaches (presenting messages within the context of a story) can facilitate connection with target health messages and empower children as behavior change agents within their families. The H2GO! program is a community-based behavioral intervention that integrates narrative-based strategies to reduce SSB consumption and promote water intake among school-age youth and parents.

METHODS: Guided by the Social Cognitive Theory and the Social Ecological Model, the H2GO! intervention consists of 6 weekly sessions that target beverage knowledge, attitudes, and behaviors through youth-produced messages and narratives to reduce SSB intake and encourage water intake and parent-child activities. To reach underserved youth and families, we identified Boys and Girls Clubs (BandGC) (youth-based community centers that serve an ethnically diverse and predominantly low socioeconomic status population) as a community partner and study setting. Participants (children ages 9-12 years and their parents) will be recruited from BandGC sites in Massachusetts, USA. Intervention efficacy will be assessed through a site-randomized trial (N = 2 youth-based community sites, pair-matched for size and racial/ethnic composition) with 54 parent-child pairs (N = 108) enrolled per site (N = 216 total). The comparison site will carry on with usual practice. Child and parental SSB and water consumption (primary outcomes) and parent and child beverage knowledge and attitudes (secondary outcomes) will be measured via self-report surveys. Additional outcomes include children's anthropometric data, additional dietary behaviors, and physical activity. Measures will be collected at baseline, 2 and 6 months follow-up. With an estimated 20 % dropout rate, the study will have 80 % power to detect a group difference of 3.9 servings of SSBs per week.

DISCUSSION: Community-based approaches hold potential for decreasing SSB consumption among youth and families, particularly among underserved populations who are at greater obesity risk. This article describes the design and methods of a community-based behavioral intervention designed to reduce SSB consumption among youth and parents/caregivers.

TRIAL REGISTRATION: NCT02890056 . Date of Registration: August 31, 2016.

Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS

Wed, 05/03/2017 - 12:07pm

Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway orchestrates an antiviral program that includes type I IFNs and immune-priming of other cell types.

Recombinant Adeno-Associated Virus Serotype 6 (rAAV6) Potently and Preferentially Transduces Rat Astrocytes In vitro and In vivo

Wed, 05/03/2017 - 12:07pm

Recombinant adeno-associated virus vectors are an increasingly popular tool for gene delivery to the CNS because of their non-pathological nature, low immunogenicity, and ability to stably transduce dividing and non-dividing cells. One of the limitations of rAAVs is their preferential tropism for neuronal cells. Glial cells, specifically astrocytes, appear to be infected at low rates. To overcome this limitation, previous studies utilized rAAVs with astrocyte-specific promoters or assorted rAAV serotypes and pseudotypes with purported selectivity for astrocytes. Yet, the reported glial infection rates are not consistent from study to study. In the present work, we tested seven commercially available recombinant serotypes- rAAV1, 2, and 5 through 9, for their ability to transduce primary rat astrocytes [visualized via viral expression of green fluorescent protein (GFP)]. In cell cultures, rAAV6 consistently demonstrated the highest infection rates, while rAAV2 showed astrocytic transduction in some, but not all, of the tested viral batches. To verify that all rAAV constructs utilized by us were viable and effective, we confirmed high infectivity rates in retinal pigmented epithelial cells (ARPE-19), which are known to be transduced by numerous rAAV serotypes. Based on the in vitro results, we next tested the cell type tropism of rAAV6 and rAAV2 in vivo, which were both injected in the barrel cortex at approximately equal doses. Three weeks later, the brains were sectioned and immunostained for viral GFP and the neuronal marker NeuN or the astrocytic marker GFAP. We found that rAAV6 strongly and preferentially transduced astrocytes (>90% of cells in the virus-infected areas), but not neurons ( approximately 10% infection rate). On the contrary, rAAV2 preferentially infected neurons ( approximately 65%), but not astrocytes ( approximately 20%). Overall, our results suggest that rAAV6 can be used as a tool for manipulating gene expression (either delivery or knockdown) in rat astrocytes in vivo.

Examination of Huntington's disease with atypical clinical features in a Bangladeshi family tree

Wed, 05/03/2017 - 12:07pm

Atypical manifestation of Huntington's disease (HD) could inform ongoing research into HD genetic modifiers not present in the primarily European populations studied to date. This work demonstrates that expanding HD genetic testing into under-resourced healthcare settings can benefit both local communities and ongoing research into HD etiology and new therapies.

One-step immortalization of primary human airway epithelial cells capable of oncogenic transformation

Wed, 05/03/2017 - 12:07pm

BACKGROUND: The ability to transform normal human cells into cancer cells with the introduction of defined genetic alterations is a valuable method for understanding the mechanisms of oncogenesis. Easy establishment of immortalized but non-transformed human cells from various tissues would facilitate these genetic analyses.

RESULTS: We report here a simple, one-step immortalization method that involves retroviral vector mediated co-expression of the human telomerase protein and a shRNA targeting the CDKN2A gene locus. We demonstrate that this method could successfully immortalize human small airway epithelial cells while maintaining their chromosomal stability. We further showed that these cells retain p53 activity and can be transformed by the KRAS oncogene.

CONCLUSIONS: Our method simplifies the immortalization process and is broadly applicable for establishing immortalized epithelial cell lines from primary human tissues for cancer research.

The Case for Adopting the "Species Complex" Nomenclature for the Etiologic Agents of Cryptococcosis

Wed, 05/03/2017 - 9:52am

Cryptococcosis is a potentially lethal disease of humans/animals caused by Cryptococcus neoformans and Cryptococcus gattii. Distinction between the two species is based on phenotypic and genotypic characteristics. Recently, it was proposed that C. neoformans be divided into two species and C. gattii into five species based on a phylogenetic analysis of 115 isolates. While this proposal adds to the knowledge about the genetic diversity and population structure of cryptococcosis agents, the published genotypes of 2,606 strains have already revealed more genetic diversity than is encompassed by seven species. Naming every clade as a separate species at this juncture will lead to continuing nomenclatural instability. In the absence of biological differences between clades and no consensus about how DNA sequence alone can delineate a species, we recommend using "Cryptococcus neoformans species complex" and "C. gattii species complex" as a practical intermediate step, rather than creating more species. This strategy recognizes genetic diversity without creating confusion.

Important patient characteristics differ prior to total knee arthroplasty and total hip arthroplasty between Switzerland and the United States

Wed, 05/03/2017 - 9:52am

BACKGROUND: Outcomes after total knee (TKA) and hip (THA) arthroplasty are often generalized internationally. Patient-dependent factors and preoperative symptom levels may differ across countries. We compared preoperative patient and clinical characteristics from two large cohorts, one in Switzerland, the other in the US.

METHODS: Patient characteristics were collected prospectively on all elective primary TKAs and THAs performed at a large Swiss hospital and in a US national sample. Data included age, sex, education level, BMI, diagnosis, medical co-morbidities, PROMs (WOMAC pain/function), global health (SF-12).

RESULTS: Six thousand six hundred eighty primary TKAs (US) and 823 TKAs (Swiss) were evaluated. US vs. Switzerland TKA patients were younger (mean age 67 vs. 72 years.), more obese (BMI >/=30 55% vs. 43%), had higher levels of education, more cardiac disease. Swiss patients had lower preoperative WOMAC pain scores (41 vs. 52) but pre-operative physical disability were comparable. 4,647 primary THAs (US) and 1,023 THAs (Swiss) were evaluated. US vs. Switzerland patients were younger (65 vs. 68 years.), more obese (BMI >/=30: 38% vs. 24%), had higher levels of education, more diabetes. Swiss patients had lower preoperative WOMAC pain scores (40 vs. 48 points). Physical disability was reported comparable, but Swiss patients indicated lower mental health scores.

CONCLUSION: We found substantial differences between US and Swiss cohorts in pre-operative patient characteristics and pain levels, which has potentially important implications for cross-cultural comparison of TKA/THA outcomes. Reports from national registries lack detailed patient information while these data suggest the need for adequate risk adjustment of patient factors.

Immunobiology of Long Noncoding RNAs

Wed, 05/03/2017 - 9:52am

The discovery of long noncoding RNAs (lncRNA) has provided a new perspective on gene regulation in diverse biological contexts. lncRNAs are remarkably versatile molecules that interact with RNA, DNA, or proteins to promote or restrain the expression of protein-coding genes. Activation of immune cells is associated with dynamic changes in expression of genes, the products of which combat infectious microorganisms, initiate repair, and resolve inflammatory responses in cells and tissues. Recent evidence indicates that lncRNAs play important roles in directing the development of diverse immune cells and controlling the dynamic transcriptional programs that are a hallmark of immune cell activation. The importance of these molecules is underscored by their newly recognized roles in inflammatory diseases. In this review, we discuss the contribution of lncRNAs in the development and activation of immune cells and their roles in immune-related diseases. We also discuss challenges faced in identifying biological functions for this large and complex class of genes.

Race and place differences in patients hospitalized with an acute coronary syndrome: Is there double jeopardy? Findings from TRACE-CORE

Wed, 05/03/2017 - 9:52am

The objectives of this longitudinal study were to examine differences between whites and blacks, and across two geographical regions, in the socio-demographic, clinical, and psychosocial characteristics, hospital treatment practices, and post-discharge mortality for hospital survivors of an acute coronary syndrome (ACS). In this prospective cohort study, we performed in-person interviews and medical record abstractions for patients discharged from the hospital after an ACS at participating sites in Central Massachusetts and Central Georgia during 2011-2013. Among the 1143 whites in Central Massachusetts, 514 whites in Central Georgia, and 277 blacks in Central Georgia, we observed a gradient of socioeconomic position with whites in Central Massachusetts being the most privileged, followed by whites and then blacks from Central Georgia; similar gradients pertained to psychosocial vulnerability (e.g., 10.7%, 25.1%, and 49.1% had cognitive impairment, respectively) and to the hospital receipt of all 4 evidence-based cardiac medications (35.5%, 18.1%, and 14.4%, respectively) used in the acute management of patients hospitalized with an ACS. Multivariable adjusted odds ratios (95% confidence intervals) for the receipt of a percutaneous coronary intervention for whites and blacks in Georgia vs. whites in Massachusetts were 0.57 (0.46-0.71) and 0.40(0.30-0.52), respectively. Thirty-day and one-year mortality risks exhibited a similar gradient. The results of this contemporary clinical/epidemiologic study in a diverse patient cohort suggest that racial and geographic disparities continue to exist for patients hospitalized with an ACS.

Receipt of Pain Management Information Preoperatively Is Associated With Improved Functional Gain After Elective Total Joint Arthroplasty

Wed, 05/03/2017 - 9:52am

BACKGROUND: Poorly controlled postoperative pain may adversely affect total joint arthroplasty (TJA) patients' outcomes and associated healthcare cost. Understanding effective pain management after surgery is important to patients, surgeons, and hospitals. We evaluated patient-reported receipt of preoperative pain management information in a national prospective cohort evaluating postoperative pain and function following elective TJA.

METHODS: Preoperative and 2-week and 6-month postoperative survey data of 1609 TJA patients collected between June 2013 and December 2014 were analyzed. Data included demographics, medical and musculoskeletal comorbidity, operative joint pain, physical function, and mental health. At 2 weeks postoperative, patients were asked if they had received pain management information prior to surgery, the content of that education, and pain management strategies. Descriptive statistics were performed.

RESULTS: At 2 weeks post-TJA, one-third of patients reported not receiving information about pain management; an additional 11% did not find the information helpful. There were no differences preoperatively in demographics or clinical profiles between those who received pain information and those who did not. Patients who received pain information reported less pain 2 weeks postoperatively, greater use of non-narcotic pain care strategies, and better physical function scores at 6 months postoperatively. No differences in operative joint pain were identified at 6 months between education and noneducation groups.

CONCLUSION: Forty-four percent of the patients reported that they did not receive/received unhelpful information regarding postoperative pain management, highlighting a need for improved patient education. In this sample, the lack of pain management information was associated with poorer 6-month postoperative function.

Duration of the menopausal transition is longer in women with young age at onset: the multiethnic Study of Women's Health Across the Nation

Wed, 05/03/2017 - 9:52am

OBJECTIVE: The menopausal transition (MT) is a critical period associated with physiologic changes that influence women's long-term health and longevity. Information is, however, limited regarding factors that influence age at the onset of the MT and its duration (ie, time from MT onset to the final menstrual period).

METHODS: We analyzed data for 1,145 women from four sites of the Study of Women's Health Across the Nation who participated in the menstrual calendar substudy, had the start of the MT identified, and had no missing covariate information. Participants included from four racial/ethnic groups: African American, white, Chinese, and Japanese. Women completed daily menstrual calendars from 1996 to 2006 and questions on hormone therapy use monthly. Baseline measures included education, economic strain, and menstrual cycle characteristics. Annual measures included height, weight, and smoking status. Cox proportional hazards models were used to analyze the data.

RESULTS: The adjusted median duration of the MT ranged from 4.37 years among the oldest age-at-onset quartile to 8.57 years among the youngest age-at-onset quartile (P < 0.001). Cigarette smoking was associated with an earlier onset (P < 0.001) and a shorter duration (P < 0.001). African American women had a longer duration (P = 0.012) than white women. Body mass index was associated with a later onset of the MT (P = 0.001) but not its duration.

CONCLUSIONS: The duration of the MT was largely influenced by the age at which it began: earlier onset was associated with a longer transition. This finding provides a strong rationale for developing improved markers of the onset of the early MT.

Warfarin in Complex Older Patients: Have we Reached a Tipping Point

Wed, 05/03/2017 - 9:52am

Two papers in this issue of JAGS explore the use of warfarin among older persons with atrial fibrillation.

Research Priorities for Optimal Use of Patient-reported Outcomes in Quality and Outcome Improvement for Total Knee Arthroplasty

Wed, 05/03/2017 - 9:52am

The national Functional and Outcomes Research for Comparative Effectiveness in Total Joint Replacement program routinely collects pre- and postoperative patient-reported outcomes for clinicians to use when making individual patient treatment decisions and monitoring aggregate quality of care and outcomes. When the pre-post gains in pain or function at one site vary from the national norms, the next question is, "how do we improve?" This paper will use the traditional quality management's framework of inputs (patients), processes (clinical care), and outcomes to outline priority research questions to learn how clinicians, hospital managers, and patients can interpret patient-reported outcomes to improve total knee arthroplasty care and outcomes. In summary, research should identify best practices to minimize variation in a patient's health status before surgery, tailor peri-total knee arthroplasty care pathways to match individual patient risks to optimize safe care, and implement patient-reported measures to document optimal outcomes.

STING Contributes to Abnormal Bone Formation Induced by Deficiency of DNase II in Mice

Wed, 05/03/2017 - 9:51am

OBJECTIVE: Cytosolic DNA sensors detect microbial DNA and promote type I interferon (IFN) and proinflammatory cytokine production through the adaptor stimulator of IFN genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. This study sought to identify the role of STING in regulating bone formation and to define the bone phenotype and its pathophysiologic mechanisms in arthritic mice double deficient in DNase II and IFN-alpha/beta/omega receptor (IFNAR) (DNase II-/- /IFNAR-/- double-knockout [DKO] mice) compared with controls.

METHODS: Bone parameters were evaluated by micro-computed tomography and histomorphometry in DKO mice in comparison with mice triple deficient in STING, DNase II, and IFNAR and control mice. Cell culture techniques were employed to determine the parameters of osteoclast and osteoblast differentiation and function. NanoString and Affymetrix array analyses were performed to identify factors promoting ectopic bone formation.

RESULTS: Despite the expression of proinflammatory cytokines that would be expected to induce bone loss in the skeleton of DKO mice, the results, paradoxically, demonstrated an accumulation of bone in the long bones and spleens, sites of erythropoiesis and robust DNA accrual. In addition, factors promoting osteoblast recruitment and function were induced. Deficiency of STING significantly inhibited bone accrual.

CONCLUSION: These data reveal a novel role for cytosolic DNA sensor pathways in bone in the setting of autoimmune disease. The results demonstrate the requirement of an intact STING pathway for bone formation in this model, a finding that may have relevance to autoimmune diseases in which DNA plays a pathogenic role. Identification of pathways linking innate immunity and bone could reveal novel targets for the treatment of bone abnormalities in human autoimmune diseases.

Supported Education for Individuals With Psychiatric Disabilities: State of the Practice and Policy Implications

Wed, 05/03/2017 - 9:51am

OBJECTIVE: Supported education (SEd) is a promising practice that supports and encourages educational goals and attainment among individuals with psychiatric disabilities. This paper provides insights into how SEd objectives are pursued in different settings, assesses the evidence base, and discusses policy implications.

METHOD: Insights from 3 data sources were synthesized: published literature, an environmental scan, and 3 site visits to programs that support the education goals of individuals with psychiatric disabilities.

RESULTS: While setting, target populations, level of coordination with supported employment, and financing strategies varied, common SEd components emerged: specialized and dedicated staffing, one-on-one and group skill-building activities, assistance with navigating the academic setting and coordinating different services, and linkages with mental health counseling. The evidence base is growing; however, many published studies to date do not employ rigorous methodology.

Conclusions and Implications for Policy and Practice: Continued specification, operationalization, and testing of SEd core components are needed. The components of the evolving SEd model would benefit from rigorous testing to evaluate impact on degree completion and other key impacts such as employment; health, mental health, or recovery; and community participation. In addition to funding streams from special education and Medicaid, new opportunities for increasing the availability of SEd include the Workforce Innovation and Opportunities Act (WIOA) reauthorization, which requires state vocational rehabilitation agencies to fund preemployment services for transition-age individuals. New "set-aside" requirements for the Mental Health Services Block Grant will increase funding for early intervention services for individuals with serious mental illness, potentially including SEd.

Antiemetic use among pregnant women in the United States: the escalating use of ondansetron

Wed, 05/03/2017 - 9:51am

PURPOSE: To examine ondansetron use in pregnancy in the context of other antiemetic use among a large insured United States population of women delivering live births. METHODS: We assessed ondansetron and other antiemetic use among pregnant women delivering live births between 2001 and 2015 in 15 data partners contributing data to the Mini-Sentinel Distributed Database. We identified live birth pregnancies using a validated algorithm, and all forms of ondansetron and other available antiemetics were identified using National Drug Codes or procedure codes. We assessed the prevalence of antiemetic use by trimester, calendar year, and formulation. RESULTS: In over 2.3 million pregnancies, the prevalence of ondansetron, promethazine, metoclopramide, or doxylamine/pyridoxine use anytime in pregnancy was 15.2, 10.3, 4.0, and 0.4%, respectively. Ondansetron use increased from <1% of pregnancies in 2001 to 22.2% in 2014, with much of the increase attributable to oral ondansetron beginning in 2006. Promethazine and metoclopramide use increased modestly between 2001 (13.8%, 3.2%) and 2006 (16.0%, 6.0%) but decreased annually through 2014 (8.0%, 3.2%). Doxylamine/pyridoxine, approved for management of nausea and vomiting in pregnancy in 2013, was used in 1.8% of pregnancies in 2014. For all antiemetics, use was highest in the first trimester. CONCLUSIONS: We observed a marked increase in ondansetron use by study year, prescribed to nearly one-quarter of insured pregnant women in 2014, occurring in conjunction with decreased use of promethazine and metoclopramide. Given the widespread use of ondansetron in pregnancy, data establishing product efficacy and methodologically rigorous evaluation of post-marketing safety are needed.

Synovium-Derived MicroRNAs Regulate Bone Pathways in Rheumatoid Arthritis

Wed, 05/03/2017 - 9:51am

Articular bone erosion in rheumatoid arthritis (RA) is mediated by the interaction between inflammation and pathways regulating bone metabolism. Inflammation promotes osteoclastogenesis and also inhibits osteoblast function, further contributing to the persistence of erosions. MicroRNAs (miRNAs) are important regulators of skeletal remodeling and play a role in RA pathogenesis. We therefore determined the expression of miRNAs in inflamed synovial tissue and the role they play in pathways regulating osteoblast and osteoclast function. Using the serum transfer mouse model of RA in C57BL/6 mice, we performed Fluidigm high-throughput qPCR-based screening of miRNAs from nonarthritic and arthritic mice. Global gene expression profiling was also performed on Affymetrix microarrays from these same synovial samples. miRNA and mRNA expression profiles were subjected to comparative bioinformatics. A total of 536 upregulated genes and 417 downregulated genes were identified that are predicted targets of miRNAs with reciprocal expression changes. Gene ontology analysis of these genes revealed significant enrichment in skeletal pathways. Of the 22 miRNAs whose expression was most significantly changed (p < 0.01) between nonarthritic and arthritic mice, we identified their targets that both inhibit and promote bone formation. These miRNAs are predicted to target Wnt and BMP signaling pathway components. We validated miRNA array findings and demonstrated that secretion of miR-221-3p in exosomes was upregulated by synovial fibroblasts treated with the proinflammatory cytokine TNF. Overexpression of miR-221-3p suppressed calvarial osteoblast differentiation and mineralization in vitro. These results suggest that miRNAs derived from inflamed synovial tissues may regulate signaling pathways at erosion sites that affect bone loss and potentially also compensatory bone formation.