Background Osteoporosis mainly occurs in postmenopausal women, which is characterized by low bone mineral density (BMD) due to unbalanced bone resorption by osteoclasts and formation by osteoblasts. Circulating monocytes play important roles in osteoclastogenesis by acting as osteoclast precursors and secreting osteoclastogenic factors, such as IL-1, IL-6 and TNF-α. MicroRNAs (miRNAs) have been implicated as important biomarkers in various diseases. The present study aimed to find significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis. Methodology/Principal Findings We used ABI TaqMan® miRNA array followed by qRT-PCR validation in circulating monocytes to identify miRNA biomarkers in 10 high and 10 low BMD postmenopausal Caucasian women. MiR-133a was upregulated ( P =0.007) in the low compared with the high BMD groups in the array analyses, which was also validated by qRT-PCR ( P =0.044). We performed bioinformatic target gene analysis and found three potential osteoclast-related target genes, CXCL11, CXCR3 and SLC39A1. In addition, we performed Pearson correlation analyses between the expression levels of miR-133a and the three potential target genes in the 20 postmenopausal women. We did find negative correlations between miR-133a and all the three genes though not significant. Conclusions/Significance This is the first in vivo miRNA expression analysis in human circulating monocytes to identify novel miRNA biomarkers underlying postmenopausal osteoporosis. Our results suggest that miR-133a in circulating monocytes is a potential biomarker for postmenopausal osteoporosis.

BackgroundMicroRNAs (miRNAs) are a class of short non-coding RNA molecules that regulate gene expression by targeting mRNAs. Recently, miRNAs have been shown to play important roles in the etiology of various diseases. However, little is known about their roles in the development of osteoporosis. Circulating monocytes are osteoclast precursors that also produce various factors important for osteoclastogenesis. Previously, we have identified a potential biomarker miR-133a in circulating monocytes for postmenopausal osteoporosis. In this study, we aimed to further identify significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis.Methodology/Principal FindingsWe used ABI TaqMan miRNA array followed by qRT-PCR validation in human circulating monocytes from 10 high BMD and 10 low BMD postmenopausal Caucasian women to identify miRNA biomarkers. MiR-422a was up-regulated with marginal significance (P = 0.065) in the low compared with the high BMD group in the array analysis. However, a significant up-regulation of miR-422a was identified in the low BMD group by qRT-PCR analysis (P = 0.029). We also performed bioinformatic target gene analysis and found several potential target genes of miR-422a which are involved in osteoclastogenesis. Further qRT-PCR analyses of the target genes in the same study subjects showed that the expression of five of these genes (CBL, CD226, IGF1, PAG1, and TOB2) correlated negatively with miR-422a expression.Conclusions/SignificanceOur study suggests that miR-422a in human circulating monocytes (osteoclast precursors) is a potential miRNA biomarker underlying postmenopausal osteoporosis.

MicroRNAs (miRNAs), which mainly inhibit protein expression by targeting the 3'UTR (untranslated region) of mRNAs, are known to play various roles in the pathogenesis of many different types of diseases. Specifically, in bone diseases, recent emphasis has been placed on the involvement of miRNAs in the differentiation and proliferation of bone and cartilage cells, particularly with regards to how these mechanisms contribute to bone homeostasis. In this review, we summarize miRNAs that are important in the differentiation and proliferation of bone cells, and specific miRNAs associated with bone diseases, such as osteoporosis, osteoarthritis and rheumatoid arthritis. This review also provides the perspective that miRNA studies will identify not only new mechanisms in basic bone research, but also potential novel diagnostic biomarkers and drug targets for bone diseases.

Asthma, chronic obstructive pulmonary disorder (COPD), and cystic fibrosis (CF), chronic diseases of the airways, are characterized by symptoms such as inflammation of the lung tissue, mucus hypersecretion, constriction of the airways, and excessive fibrosis of airway tissue. Transforming growth factor (TGF)-beta, a cytokine that affects many different cell processes, has an important role in the lungs of patients with some of these chronic airway diseases, especially with respect to airway remodeling. Eosinophils can be activated by and are a major source of TGF-beta in asthma. The action of TGF-beta also shows associations with other cell types, such as T cells and neutrophils, which are involved in the pathogenesis of asthma. TGF-beta can perpetuate the pathogenesis of COPD and CF, as well, through its induction of inflammation via release from and action on different cells. The intracellular signaling induced by TGF-beta in various cell types has been elucidated and may point to mechanisms of action by TGF-beta on different structural or immune cells in these airway diseases. Some possible treatments, especially that prevent the deleterious airway changes induced by the action of either eosinophils or TGF-beta in asthma, have been investigated. TGF-beta-induced signaling pathways, especially those in different cell types in asthma, COPD, or CF, may provide potential therapeutic targets for the treatment of some of the most devastating airway diseases.

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Nachfolgende Untersuchungen sind zuniichst unternommen worden, um die geringste Menge b~ebennierenextracts zu finden, welche noch eine deutliche BlutdruckerhShung hervorruft. Solch eine Beobachtung hat doppeltes Interesse: einmal an sich selbst, dann aber auch als Controlversuch far die sich mit der Isolation der wirksamen Substanz der Nebennieren beschifftigten Experimente. Es erscheint unzweifelhaft, class die eigentlich wirksame Substanz der Nebennieren nur einen geringen Bruchtheil des Rohauszuges ausmacht, und man muss demnach erwarten, dass ein reines Praparat dieser Substanz verhi~ltnissmassig viel wirksamer ist als tier Rohauszug. b~ehmen wit z. B. an, dass der wi~ssrige Extract, nach Entfernung der Ei-weisskSrper~ 10 % der wirksamen Substanz enthi~lt, dann muss eben die reine Substanz, Gewicht far Gewicht, zehnmal grSsseren Einfluss besitzen als der Driisenauszug, oder ein gleicher Effect mtisste mit 1/lO der Dose des reinen wirksamen KSrpers erhalten werden.Wenn nun aber Substanzen aus der Driise isolirt werden, welche die oben erwahnte Eigenschaft nicht besitzen, so kann dies nur in einer yon zwei Ursachen seinen Grund finden: entweder niimlich darin, dass durch irgend welche chemische Veranderungen die wirksame Substanz in eine weniger wirksame verwandelt worden ist, oder dass i~berhaupt nur ein geringer Procentsatz der Substanz isolift wurde, die mit einer grSsseren Menge eines unwirksamen Kiirpers vermischt ist, also kein einheitliches Product darstellt.Diese zweite Auffassung erscheint wahrscheinlicher, da die erste die Anwesenheit anderer chemischer Individuen, die aus der wirksamen ]L Pflilgsr, Archly ff~r Physiologie. Bd. 81. ~3

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