Extremely late-onset chronic graft-versus-host disease presenting with bronchiolitis obliterans and pleuroparenchymal fibroelastosis.

A 35-year-old woman experienced left back pain after a 2-h flight. She reported coughing and left back pain 1 day later when she presented to our hospital. Chest computed tomography showed pneumothorax of the left lung, bronchiectasis, thickening of the bronchial wall, nodules, and cavity lesions in both lungs. A pulmonary function test revealed obstructive ventilation disorder with normal lung diffusing capacity. She had a history of haematopoietic stem cell transplantation (HSCT) at 2 years and 3 months of age during the second disease remission of acute myeloid leukaemia. She was diagnosed with chronic graft-versus-host disease (cGVHD) presenting with bronchiolitis obliterans (BO) and pleuroparenchymal fibroelastosis (PPFE). To our knowledge, this is the first reported case of BO and PPFE diagnosed more than 30 years after HSCT.

Febrile Reactions Associated with High IgG Antibody Titers after the Second and Third BNT162b2 Vaccinations in Japan.

Adverse events are potentially associated with an IgG response after BNT162b2 vaccination for severe acute respiratory syndrome coronavirus 2. In this study, we investigated the side effects of the BNT162b2 vaccine using a health questionnaire and examined its relationship with IgG antibody titers. Serum samples were collected from participants 3 months after the second vaccination, immediately before the third vaccination, and 1 and 3 months after the third vaccination. A total of 505 participants who received three doses of vaccine were eligible for inclusion in the analysis. The results showed that post-vaccination body temperature correlated with anti-spike-receptor-binding domain (anti-S-RBD) antibody titers measured 3 months after the second (r = 0.30, P < 0.001) and third (r = 0.14, P < 0.001) vaccinations. Multivariate linear regression analysis revealed that age and severe swelling were negatively associated, whereas female sex, body temperature, and heat sensation were positively associated with log-transformed anti-S-RBD antibody levels after the second vaccination. After the third vaccination, body temperature and fatigue were positively associated, and female sex was negatively associated, with the log-transformed anti-S-RBD antibody levels. These results suggest that post-vaccination fever may be a marker of a high antibody titer.

IgG4 related lung disease mimicking multiple pleural disseminated lung cancer.

IgG4-related lung disease (IgG4-RLD) can present with various types of radiological findings such as nodule, ground-glass opacity, alveolar interstitial, and bronchovascular involvement. IgG4-RLD generally manifests as mild clinical symptoms, despite evidence from the image findings. Herein we report an asymptomatic patient with IgG4-RLD mimicking multiple pleural disseminated lung cancer.

Acute eosinophilic pneumonia caused by composter vapor inhalation: A case report.

A 65-year-old woman presented to a local hospital with a 4-day history of cough, fever, and dyspnea. She had started using a composter and had been exposed to the vapor for 18 days before her first visit. She was diagnosed with acute eosinophilic pneumonia (AEP) based on her symptoms, the presence of bilateral pulmonary opacities on computed tomography, and alveolar eosinophilia confirmed by bronchoalveolar lavage. Inhalation of the composter vapor was thought to be the cause of AEP. Aspergillus fumigatus was cultured from the composter soil and the bronchoalveolar lavage fluid. She fully recovered without systemic corticosteroid administration by avoiding the composter.

A 60-Year-Old Woman With Posterior Mediastinal Tumor.

CASE PRESENTATION: A 60-year-old woman, a care worker with no known comorbidities, presented to the pulmonary clinic for assessment of a left hilar tumor detected on chest radiography. She had a history of oophorocystectomy and was a 0.5-pack/day smoker. She was asymptomatic but desired a confirmative diagnosis.

A role for neutrophils in early enthesitis in spondyloarthritis.

BACKGROUND: Neutrophils are present in the early phases of spondyloarthritis-related uveitis, skin and intestinal disease, but their role in enthesitis, a cardinal musculoskeletal lesion in spondyloarthritis, remains unknown. We considered the role of neutrophils in the experimental SKG mouse model of SpA and in human axial entheses. METHODS: Early inflammatory infiltrates in the axial and peripheral entheseal sites in SKG mice were evaluated using immunohistochemistry and laser capture microdissection of entheseal tissue. Whole transcriptome analysis was carried out using Affymetrix gene array MTA 1.0, and data was analyzed via IPA. We further isolated neutrophils from human peri-entheseal bone and fibroblasts from entheseal soft tissue obtained from the axial skeleton of healthy patients and determined the response of these cells to fungal adjuvant. RESULTS: Following fungal adjuvant administration, early axial and peripheral inflammation in SKG mice was characterized by prominent neutrophilic entheseal inflammation. Expression of transcripts arising from neutrophils include abundant mRNA for the alarmins S100A8 and S100A9. In normal human axial entheses, neutrophils were present in the peri-entheseal bone. Upon fungal stimulation in vitro, human neutrophils produced IL-23 protein, while isolated human entheseal fibroblasts produced chemokines, including IL-8, important in the recruitment of neutrophils. CONCLUSION: Neutrophils with inducible IL-23 production are present in uninflamed human entheseal sites, and neutrophils are prominent in early murine spondyloarthritis-related enthesitis. We propose a role for neutrophils in the early development of enthesitis.

Novel Combinatorial MicroRNA-Binding Sites in AAV Vectors Synergistically Diminish Antigen Presentation and Transgene Immunity for Efficient and Stable Transduction.

Recombinant adeno-associated virus (rAAV) platforms hold promise for in vivo gene therapy but are undermined by the undesirable transduction of antigen presenting cells (APCs), which in turn can trigger host immunity towards rAAV-expressed transgene products. In light of recent adverse events in patients receiving high systemic AAV vector doses that were speculated to be related to host immune responses, development of strategies to mute innate and adaptive immunity is imperative. The use of miRNA binding sites (miR-BSs) to confer endogenous miRNA-mediated regulation to detarget transgene expression from APCs has shown promise for reducing transgene immunity. Studies have shown that designing miR-142BSs into rAAV1 vectors were able to repress costimulatory signals in dendritic cells (DCs), blunt the cytotoxic T cell response, and attenuate clearance of transduced muscle cells in mice to allow sustained transgene expression in myofibers with negligible anti-transgene IgG production. In this study, we screened individual and combinatorial miR-BS designs against 26 miRNAs that are abundantly expressed in APCs, but not in skeletal muscle. The highly immunogenic ovalbumin (OVA) transgene was used as a proxy for foreign antigens. In vitro screening in myoblasts, mouse DCs, and macrophages revealed that the combination of miR-142BS and miR-652-5pBS strongly mutes transgene expression in APCs but maintains high myoblast and myocyte expression. Importantly, rAAV1 vectors carrying this novel miR-142/652-5pBS cassette achieve higher transgene levels following intramuscular injections in mice than previous detargeting designs. The cassette strongly inhibits cytotoxic CTL activation and suppresses the Th17 response in vivo. Our approach, thus, advances the efficiency of miRNA-mediated detargeting to achieve synergistic reduction of transgene-specific immune responses and the development of safe and efficient delivery vehicles for gene therapy.

Diagnostic Utility of Polymerase Chain Reaction for Paraffin-embedded Sinus Specimens for Rhinocerebral Mucormycosis Complicated by Internal Carotid Artery Thrombosis and Cerebral Infarction.

We herein report a 73-year-old man who experienced cerebral infarction caused by infection with a Mucromycocetes species. A delay in anti-fungal treatment might result in a lethal clinical outcome. We were unable to establish an accurate diagnosis based on histological findings and cerebrospinal fluid culture. Therefore, we performed polymerase chain reaction (PCR) using paraffin-embedded specimens, and based on the findings, successfully started administering anti-fungal treatment. We suggest that PCR using sinus specimens be applied when mucormycosis is suspected as an etiology of cerebral infarction and a confirmative diagnosis cannot be established based on the results of pathological examinations or cerebrospinal fluid culture.

Overcoming innate immune barriers that impede AAV gene therapy vectors.

The field of gene therapy has made considerable progress over the past several years. Adeno-associated virus (AAV) vectors have emerged as promising and attractive tools for in vivo gene therapy. Despite the recent clinical successes achieved with recombinant AAVs (rAAVs) for therapeutics, host immune responses against the vector and transgene product have been observed in numerous preclinical and clinical studies. These outcomes have hampered the advancement of AAV gene therapies, preventing them from becoming fully viable and safe medicines. The human immune system is multidimensional and complex. Both the innate and adaptive arms of the immune system seem to play a concerted role in the response against rAAVs. While most efforts have been focused on the role of adaptive immunity and developing ways to overcome it, the innate immune system has also been found to have a critical function. Innate immunity not only mediates the initial response to the vector, but also primes the adaptive immune system to launch a more deleterious attack against the foreign vector. This Review highlights what is known about innate immune responses against rAAVs and discusses potential strategies to circumvent these pathways.

Effects of kallidinogenase in patients undergoing vitrectomy for diabetic macular edema.

PURPOSE: To evaluate the effectiveness of the combination of vitrectomy with kallidinogenase for diabetic macular edema (DME). METHODS: This study was designed as a prospective, randomized, multicenter study comparing 19 eyes of 19 patients who received 150 units of kallidinogenase administered a day for 52 weeks from the day after vitrectomy (study group) with 20 eyes of 20 patients who received no kallidinogenase (control group). The main outcome measurements included logMAR visual acuity and central foveal thickness (CFT) before surgery and at 3, 6, 9, and 12 months after vitrectomy. RESULTS: During follow-up, 11 patients dropped out (six in the study group and five in the control group), leaving 28 eyes in 28 patients for analysis (13 in the study group and 15 in the control group). Visual acuity improved significantly at 12 months in both groups compared with before surgery. The degree of improvement did not differ significantly between the groups. At 12 months, the mean CFT decreased significantly in both groups, with no significant difference in the rate of change between the two groups. In the study group, the visual acuity and CFT significantly improved from 3 to 12 months and from 6 to 12 months, whereas these parameters did not continue to improve in the control group after 6 months (for visual acuity) or 3 months (for CFT). CONCLUSION: After vitrectomy for DME, visual acuity and CFT improved significantly in both groups, but only patients treated with kallidinogenase continued to have significant improvement throughout the study period.

Distinct Phenotypes of Smokers with Fixed Airflow Limitation Identified by Cluster Analysis of Severe Asthma.

RATIONALE: Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. OBJECTIVES: To explore novel severe asthma phenotypes by cluster analysis when including smoking patients with asthma. METHODS: We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. RESULTS: Five clinical clusters, including two characterized by low forced expiratory volume in 1 second/forced vital capacity, were identified. When characteristics of smoking subjects in these two clusters were compared, there were marked differences between the two groups: one had high levels of circulating eosinophils, high immunoglobulin E levels, and a high sinus score, and the other was characterized by low levels of the same parameters. Sputum analysis revealed intriguing differences of cytokine/chemokine pattern in these two groups. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 3 years later. CONCLUSIONS: This study reveals two distinct phenotypes with potentially different biological pathways contributing to fixed airflow limitation in cigarette smokers with severe asthma.

Changes in choroidal thickness in patients with diabetic retinopathy.

PURPOSE: To investigate the changes in choroidal thickness (ChT) following panretinal photocoagulation (PRP) for diabetic retinopathy (DR) and compare ChT in relation to DR severity. METHODS: Thirty-two eyes [19 eyes with proliferative DR (PDR) and 13 eyes with severe nonproliferative DR (NPDR)] for which PRP was necessary were analyzed. ChT was measured before PRP and at 1, 3, and 6 months after PRP using the swept-source optical coherence tomography. ChT of the 61 eyes matched with the PDR patients for the mean age and axial length was also measured and statistically compared in relation to severity. RESULTS: The central field ChT before PRP treatment was 268.6 ± 104.5 µm (mean ± standard deviation) and was significantly decreased at 1, 3, and 6 months after PRP (254.5 ± 105.3, 254.2 ± 108.2, and 248.1 ± 101.8 µm, respectively, P < 0.0001). The central field ChT of severe NPDR (323.2 ± 61.3 µm) was significantly thicker than that of normal (248.3 ± 70.7 µm) and mild to moderate NPDR (230.0 ± 70.3 µm, P = 0.0455 and 0.0099, respectively). Moreover, the central field ChT of PDR (307.3 ± 84.1 µm) was significantly thicker than of mild to moderate NPDR (P = 0.0169). CONCLUSION: ChT significantly decreased after PRP, which continued for at least 6 months after treatment. ChT of severe NPDR and PDR was significantly thicker than that of mild to moderate NPDR. ChT of patients with DR was changed according to the treatment and severity of DR.

Synovium-Derived MicroRNAs Regulate Bone Pathways in Rheumatoid Arthritis.

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. © 2016 American Society for Bone and Mineral Research.

RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis.

OBJECTIVE: Proinflammatory molecules promote osteoclast-mediated bone erosion by up-regulating local RANKL production. However, recent evidence suggests that combinations of cytokines, such as tumor necrosis factor (TNF) plus interleukin-6 (IL-6), induce RANKL-independent osteoclastogenesis. The purpose of this study was to better understand TNF/IL-6-induced osteoclast formation and to determine whether RANK is absolutely required for osteoclastogenesis and bone erosion in murine inflammatory arthritis. METHODS: Myeloid precursors from wild-type (WT) mice or mice with either germline or conditional deletion of Rank, Nfatc1, Dap12, or Fcrg were treated with either RANKL or TNF plus IL-6. Osteoprotegerin, anti-IL-6 receptor (anti-IL-6R), and hydroxyurea were used to block RANKL, the IL-6R, and cell proliferation, respectively. Clinical scoring, histologic assessment, micro-computed tomography, and quantitative polymerase chain reaction (qPCR) were used to evaluate K/BxN serum-transfer arthritis in WT and RANK-deleted mice. Loss of Rank was verified by qPCR and by osteoclast cultures. RESULTS: TNF/IL-6 generated osteoclasts in vitro that resorbed mineralized tissue through a pathway dependent on IL-6R, NFATc1, DNAX-activation protein 12, and cell proliferation, but independent of RANKL or RANK. Bone erosion and osteoclast formation were reduced, but not absent, in arthritic mice with inducible deficiency of RANK. TNF/IL-6, but not RANKL, induced osteoclast formation in bone marrow and synovial cultures from animals deficient in Rank. Multiple IL-6 family members (IL-6, leukemia inhibitory factor, oncostatin M) were up-regulated in the synovium of arthritic mice. CONCLUSION: The persistence of bone erosion and synovial osteoclasts in Rank-deficient mice, and the ability of TNF/IL-6 to induce osteoclastogenesis, suggest that more than one cytokine pathway exists to generate these bone-resorbing cells in inflamed joints.

IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis.

BACKGROUND: Interleukin-17A (IL-17A) plays a pathogenic role in several rheumatic diseases including spondyloarthritis and, paradoxically, has been described to both promote and protect from bone formation. We therefore examined the effects of IL-17A on osteoblast differentiation in vitro and on periosteal bone formation in an in vivo model of inflammatory arthritis. METHODS: K/BxN serum transfer arthritis was induced in IL-17A-deficient and wild-type mice. Clinical and histologic inflammation was assessed and periosteal bone formation was quantitated. Murine calvarial osteoblasts were differentiated in the continuous presence of IL-17A with or without blockade of secreted frizzled related protein (sFRP)1 and effects on differentiation were determined by qRT-PCR and mineralization assays. The impact of IL-17A on expression of Wnt signaling pathway antagonists was also assessed by qRT-PCR. Finally, regulation of Dickkopf (DKK)1 expression in murine synovial fibroblasts was evaluated after treatment with IL-17A, TNF, or IL-17A plus TNF. RESULTS: IL-17A-deficient mice develop significantly more periosteal bone than wild-type mice at peak inflammation, despite comparable severity of inflammation and bone erosion. IL-17A inhibits calvarial osteoblast differentiation in vitro, inducing mRNA expression of the Wnt antagonist sFRP1 in osteoblasts, and suppressing sFRP3 expression, both potentially contributing to inhibition of osteoblast differentiation. Furthermore, a blocking antibody to sFRP1 reduced the inhibitory effect of IL-17A on differentiation. Although treatment with IL-17A suppresses DKK1 mRNA expression in osteoblasts, IL-17A plus TNF synergistically upregulate DKK1 mRNA expression in synovial fibroblasts. CONCLUSIONS: IL-17A may limit the extent of bone formation at inflamed periosteal sites in spondyloarthritis. IL-17A inhibits calvarial osteoblast differentiation, in part by regulating expression of Wnt signaling pathway components. These results demonstrate that additional studies focusing on the role of IL-17A in bone formation in spondyloarthritis are indicated.

Calorimetric studies of the growth of anaerobic microbes.

This article aims to validate the use of calorimetry to measure the growth of anaerobic microbes. It has been difficult to monitor the growth of strict anaerobes while maintaining optimal growth conditions. Traditionally, optical density and ATP concentration are usually used as measures of the growth of anaerobic microbes. However, to take these measurements it is necessary to extract an aliquot of the culture, which can be difficult while maintaining anaerobic conditions. In this study, calorimetry was used to continuously and nondestructively measure the heat generated by the growth of anaerobic microbes as a function of time. Clostridium acetobutylicum, Clostridium beijerinckii, and Clostridium cellulovorans were used as representative anaerobic microbes. Using a multiplex isothermal calorimeter, we observed that peak time (tp) of C. acetobutylicum heat evolution increased as the inoculation rate decreased. This strong correlation between the inoculation rate and tp showed that it was possible to measure the growth rate of anaerobic microbes by calorimetry. Overall, our results showed that there is a very good correlation between heat evolution and optical density/ATP concentration, validating the use of the method.

Distinct Phenotypes of Cigarette Smokers Identified by Cluster Analysis of Patients with Severe Asthma.

RATIONALE: Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. OBJECTIVES: To explore novel severe asthma phenotypes by cluster analysis when including cigarette smokers. METHODS: We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Twelve clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. MEASUREMENTS AND MAIN RESULTS: Five clinical clusters were identified, including two characterized by high pack-year exposure to cigarette smoking and low FEV1/FVC. There were marked differences between the two clusters of cigarette smokers. One had high levels of circulating eosinophils, high IgE levels, and a high sinus disease score. The other was characterized by low levels of the same parameters. Sputum analysis revealed increased levels of IL-5 in the former cluster and increased levels of IL-6 and osteopontin in the latter. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 1 year later. CONCLUSIONS: This study reveals two distinct phenotypes of severe asthma in current and former cigarette smokers with potentially different biological pathways contributing to fixed airflow limitation. Clinical trial registered with www.umin.ac.jp (000003254).

Contrasting associations of body mass index and measles with asthma and rhinitis in young adults.

Asthma and allergic rhinitis often coexist and are increasing worldwide, particularly among the younger generation. Although the prevalences of adult asthma and allergic rhinitis and their risk factors have been reported, there have been few studies focusing on young adults. The aim of this study was to evaluate the prevalences of asthma and allergic rhinitis and their associated factors in Japanese young adults. A questionnaire survey of new students at Hokkaido University about the presence of current wheeze and rhinitis and a history of several viral infections during childhood was conducted in 2008 and 2010. The prevalences of wheeze and rhinitis and their associated factors were evaluated. Of 4076 nonsmoking subjects aged 18-25 years, 261 (6.4%) had current wheeze and 1373 (33.7%) had allergic rhinitis. On multivariate analyses, current wheeze was associated with high body mass index (BMI), atopic dermatitis, allergic rhinitis, food allergy, and a history of measles infection. In contrast, allergic rhinitis was associated with low BMI, current wheeze, atopic dermatitis, food allergy, and no history of measles. When subjects were classified into four groups by the presence or absence of wheeze and rhinitis, both high BMI and a history of measles were positively associated with wheeze without rhinitis but negatively associated with rhinitis without wheeze. High BMI and past measles infection showed contrasting associations with asthma and allergic rhinitis in nonsmoking young adults. It is important to not only recognize the common pathophysiological characteristics of asthma and allergic rhinitis but also to understand their differences.

Association of the CAT-262C>T polymorphism with asthma in smokers and the nonemphysematous phenotype of chronic obstructive pulmonary disease.

BACKGROUND: Catalase (CAT) is a part of the active antioxidant defense system and has been studied with regard to its association with asthma and chronic obstructive pulmonary disease (COPD), which are heterogeneous obstructive pulmonary diseases characterized by chronic airway inflammation. We hypothesized that the CAT gene might be involved in the common pathogenesis underlying asthma and COPD. OBJECTIVE: To evaluate the association of CAT polymorphisms with specific phenotypes of asthma and COPD to identify the common underlying pathophysiologic mechanisms of these 2 diseases. METHODS: The -262C>T and -21A>T polymorphisms in the CAT gene were genotyped in 493 individuals with asthma, 265 with COPD, and 1,076 healthy controls. Asthmatic patients were categorized according to smoking status (smokers and nonsmokers) and age at onset (early onset and adult onset) as part of a case-control study. In patients with COPD, visual scoring (computed tomographic score) was assessed to determine emphysema severity, which was used to evaluate associations with CAT gene polymorphisms. RESULTS: Overall, the -262C>T and -21A>T polymorphisms were not associated with asthma. However, the -262CT+TT genotype was significantly associated with adult-onset asthma in smokers (P = .005), and a significant interaction between smoking status and the effect of -262C>T genotype on asthma were observed (P = .01). In patients with COPD, this genotype was significantly associated with a low computed tomographic score (P = .03), which indicates a nonemphysematous type of COPD. CONCLUSION: The present study indicates that the CAT gene is involved in the common pathogenesis underlying adult-onset asthma in smokers and the nonemphysematous type of COPD.

miR-218 directs a Wnt signaling circuit to promote differentiation of osteoblasts and osteomimicry of metastatic cancer cells.

MicroRNAs (miRNAs) negatively and post-transcriptionally regulate expression of multiple target genes to support anabolic pathways for bone formation. Here, we show that miR-218 is induced during osteoblast differentiation and has potent osteogenic properties. miR-218 promotes commitment and differentiation of bone marrow stromal cells by activating a positive Wnt signaling loop. In a feed forward mechanism, miR-218 stimulates the Wnt pathway by down-regulating three Wnt signaling inhibitors during the process of osteogenesis: Sclerostin (SOST), Dickkopf2 (DKK2), and secreted frizzled-related protein2 (SFRP2). In turn, miR-218 expression is up-regulated in response to stimulated Wnt signaling and functionally drives Wnt-related transcription and osteoblast differentiation, thereby creating a positive feedback loop. Furthermore, in metastatic breast cancer cells but not in normal mammary epithelial cells, miR-218 enhances Wnt activity and abnormal expression of osteoblastic genes (osteomimicry) that contribute to homing and growth of cells metastatic to bone. Thus, miR-218/Wnt signaling circuit amplifies both the osteoblast phenotype and osteomimicry-related tumor activity.