br Conclusions Osteoclcastogenesis is regulated by multiple

Conclusions Osteoclcastogenesis is regulated by multiple signal transduction pathways. To maintain bone homeostasis, osteoclast cells must achieve a balance regulation of formation, function, and trafficking of its precursors. Here, we proposed a model in which crosstalk between Fas and S1P/S1P1 signaling occurs in osteoclast precursor cells and it is dependent on activation of NF-κΒ. Moreover, this signaling affects the migratory behavior of osteoclast precursor cells which is crucial for the pathogenesis of RA.
Author contributions
Acknowledgments This work was supported by the grants provided by JSPS KAKENHI (Grant Numbers. 25713063, 15K15757, 17K19758, 18H03011 to T.I.), The Ichiro Kanehara Foundation, Suzuken Memorial Foundation, The Nakatomi Foundation, Smoking Research Foundation, Takeda Science Foundation, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, Sumitomo Denko Foundation, Mitsui Sumitomo Insurance Welfare Foundation to T.I., and Otsuka Toshimi Scholarship Foundation, Fujii-Otsuka Scholarship to I.H.
Introduction Human genome-wide analyses reveal the majority of transcriptional events result in a vast collection of noncoding RNAs. One emerging class, long noncoding RNAs (lncRNAs), are >200 nucleotide transcripts that are involved in developmental processes via diverse mechanisms, including chromatin modification, transcriptional regulation and alternative splicing of pre-mRNA [1], [2], [3]. LncRNAs are generally transcribed at lower levels compared to protein coding genes, may be polyadenylated or not, and found in the nucleus or cytoplasm. They can interact with other RNAs, DNA, and/or proteins through ISX 9 pairing or stem-loop structures created by RNA folding [4]. These characteristics allow lncRNAs to regulate gene expression through transcriptional and post-transcriptional mechanisms [5]. As a result, lncRNAs function in various cellular processes during normal development and disease. LncRNAs modulate genes involved in cell survival, division, and differentiation to facilitate accurate tissue development. Hematopoiesis is one developmental process wherein hematopoietic stem/progenitor cells (HSPC, CD34+ cells) respond to physiologic cues to ensure homeostasis of all blood cells. LncRNAs involved in hematopoiesis have been identified [1], [6], but only a few have described functions. In normal physiology, the lncRNA antisense to PU.1 ensures precise levels of this important hematopoietic transcription factor by negatively regulating PU.1 mRNA translation [7]. Profiling studies of lncRNA expression during lineage-specific hematopoietic differentiation have identified Eosinophil Granule Ontogeny (EGO) [8], HOTAIRM1 [9], and lnc-DC [10], which control genes required for maturation of eosinophils, myeloid cells, and dendritic cells, respectively. Additional expression studies demonstrate an important contribution of lncRNAs in development and function of T cells [11]. Alternatively, deregulated expression of lncRNAs has been linked to hematopoietic disease. Comparison of CD34+ cells from healthy volunteers and patients with myelodysplastic syndrome (MDS) identified sixty-five noncoding transcripts that were differentially expressed in MDS [12]. Distinct lncRNA expression profiles have also been detected for patients with human T cell acute lymphoblastic leukemia (T-ALL) [13], acute (AML) [14], [15] and chronic myeloid leukemia (CML) [16], [17], and B-acute lymphoblastic leukemia (B-ALL) [18]. These collective findings confirm a role for lncRNAs in normal development and function of blood cells, and imply that altered expression patterns may be linked to pathology. However, relatively little is known regarding how lncRNAs are differentially regulated, expressed, and function in different cell populations or during proliferation and differentiation. Erythropoiesis, responsible for red blood cell (RBC) production, requires tight control of transcription factors and microRNAs (miRNAs) to function properly [19], [20]. This process has been the subject of intensive study because of its value to the biology of developmental gene regulation, proliferation, differentiation, and apoptosis. A few studies have explored the role of lncRNAs during murine erythropoiesis [21], [22]; however, conserved human transcripts have not been identified. Deep sequencing of RNA from mouse and human erythroblasts of similar developmental stages revealed the majority of mouse lncRNAs lacked human homologs [23], highlighting a lack of lncRNA conservation. Mouse models may be further limited in the ability to detect candidate lncRNAs that facilitate human RBC development due to the rapid developmental program of mouse erythroid cells, heterologous transcription factor environment relative to humans, and absence of fetal globin genes or fetal stage of globin gene expression.