Recent advances in the bioengineering of monoclonal antibodies (mAbs) have revolutionized the treatment of several immunological and rheumatic diseases. mAbs exhibit high specificity and affinity, ...and are very effective targeting agents, associated with minimal off‐target adverse effects. Of several relevant immunological diseases, rheumatoid arthritis was the condition initially treated with mAbs, with great success. Currently, many immunological disorders are targeted and successfully treated using such novel approaches; these include inflammatory bowel diseases, multiple sclerosis, lupus and psoriasis. Today, the efforts of researchers in basic immunology (with a long history) have borne fruit; bioengineered mAbs are employed in clinical practice. In this brief review, I will describe the current and emerging therapeutic mAbs and molecular targeted agents, and discuss the future of the field, especially from the viewpoint of pharmacology.
Immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase. In vitro studies have shown that 1,25-dihydroxyvitamin D, the active form ...of vitamin D, has an anti-inflammatory effect. Recent epidemiological evidence has indicated a significant association between vitamin D deficiency and an increased incidence, or aggravation, of infectious diseases and inflammatory autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, the impact of vitamin D on treatment and prevention, particularly in infectious diseases such as the 2019 coronavirus disease (COVID-19), remains controversial. Here, we review recent evidence associated with the relationship between vitamin D and inflammatory diseases and describe the underlying immunomodulatory effect of vitamin D.
Bone metabolism is regulated by the cooperative activity between bone-forming osteoblasts and bone-resorbing osteoclasts. However, the mechanisms mediating the switch between the osteoblastic and ...osteoclastic phases have not been fully elucidated. Here, we identify a specific subset of mature osteoblast-derived extracellular vesicles that inhibit bone formation and enhance osteoclastogenesis. Intravital imaging reveals that mature osteoblasts secrete and capture extracellular vesicles, referred to as small osteoblast vesicles (SOVs). Co-culture experiments demonstrate that SOVs suppress osteoblast differentiation and enhance the expression of receptor activator of NF-κB ligand, thereby inducing osteoclast differentiation. We also elucidate that the SOV-enriched microRNA miR-143 inhibits Runt-related transcription factor 2, a master regulator of osteoblastogenesis, by targeting the mRNA expression of its dimerization partner, core-binding factor β. In summary, we identify SOVs as a mode of cell-to-cell communication, controlling the dynamic transition from bone-forming to bone-resorbing phases in vivo.
Training skillful and competent surgeons is critical to ensure high quality of care and to minimize disparities in access to effective care. Traditional models to train surgeons are being challenged ...by rapid advances in technology, an intensified patient-safety culture, and a need for value-driven health systems. Simultaneously, technological developments are enabling capture and analysis of large amounts of complex surgical data. These developments are motivating a "surgical data science" approach to objective computer-aided technical skill evaluation (OCASE-T) for scalable, accurate assessment; individualized feedback; and automated coaching. We define the problem space for OCASE-T and summarize 45 publications representing recent research in this domain. We find that most studies on OCASE-T are simulation based; very few are in the operating room. The algorithms and validation methodologies used for OCASE-T are highly varied; there is no uniform consensus. Future research should emphasize competency assessment in the operating room, validation against patient outcomes, and effectiveness for surgical training.
Introduction
Overexpression studies have been commonly used to yield significant advances in cell biology. In vitro osteoclast culturing involves the differentiation of bone marrow-derived monocyte ...macrophage precursors (BMMs) in medium supplemented with macrophage colony-stimulating factor and receptor activator of nuclear factor-kB ligand (RANKL) into mature osteoclasts. Retroviral vectors are the gold standards for efficient gene delivery into BMMs. While this strategy is effective in BMMs that are in the early stages of differentiation, it is ineffective in RANKL-treated BMMs such as mono- and multinucleated osteoclasts. This study attempted to enhance gene delivery into differentiated BMMs using liposome-mediated RNA transfection.
Material and methods
BMMs were transfected with an EYFP overexpression plasmid or EYFP RNA by lipofection, or transduced with a retroviral vector expressing EYFP. EYFP expression was assessed by flow cytometry.
Results
We performed overexpression analyses using enhanced yellow fluorescent protein (EYFP). Although EYFP expression was observed 24 h after infection of BMMs with a recombinant retrovirus containing EYFP, expression of EYFP was observed within 3 h of transfection with EYFP RNA. Moreover, the efficiency of EYFP RNA for gene delivery into BMMs was comparable to that of retroviral transduction of EYFP. In contrast, while very few BMMs stimulated by RANKL for two days expressed EYFP after retroviral infection, more than half of the cells expressed EYFP after transfection with EYFP RNA.
Conclusion
RNA-mediated gene delivery is quick and easy method for performing gain-of-function analyses in primary osteoclast precursors and mature osteoclasts.
Osteoclasts have a unique bone-destroying capacity, playing key roles in steady-state bone remodeling and arthritic bone erosion. Whether the osteoclasts in these different tissue settings arise from ...the same precursor states of monocytoid cells is presently unknown. Here, we show that osteoclasts in pannus originate exclusively from circulating bone marrow-derived cells and not from locally resident macrophages. We identify murine CX
CR1
Ly6C
F4/80
I-A
/I-E
macrophages (termed here arthritis-associated osteoclastogenic macrophages (AtoMs)) as the osteoclast precursor-containing population in the inflamed synovium, comprising a subset distinct from conventional osteoclast precursors in homeostatic bone remodeling. Tamoxifen-inducible Foxm1 deletion suppressed the capacity of AtoMs to differentiate into osteoclasts in vitro and in vivo. Furthermore, synovial samples from human patients with rheumatoid arthritis contained CX
CR1
HLA-DR
CD11c
CD80
CD86
cells that corresponded to mouse AtoMs, and human osteoclastogenesis was inhibited by the FoxM1 inhibitor thiostrepton, constituting a potential target for rheumatoid arthritis treatment.
Bone is a dynamic organ that is continuously turned over during growth, even in adults. During bone remodeling, homeostasis is regulated by the balance between bone formation by osteoblasts and bone ...resorption by osteoclasts. However, in pathological conditions such as osteoporosis, osteopetrosis, arthritic joint destruction, and bone metastasis, this equilibrium is disrupted. Since osteoclasts are excessively activated in osteolytic diseases, the inhibition of osteoclast function has been a major therapeutic strategy. It has recently been demonstrated that sphingosine-1-phosphate (S1P), a biologically active lysophospholipid that is enriched in blood, controls the trafficking of osteoclast precursors between the circulation and bone marrow cavities via G protein-coupled receptors, S1PRs. While S1PR1 mediates chemoattraction toward S1P in bone marrow, where S1P concentration is low, S1PR2 mediates chemorepulsion in blood, where the S1P concentration is high. The regulation of precursor recruitment may represent a novel therapeutic strategy for controlling osteoclast-dependent bone remodeling. By means of intravital multiphoton imaging of bone tissues, we have recently revealed that the reciprocal action of S1P controls the migration of osteoclast precursors between bone tissues and blood stream. Imaging technologies have enabled us to visualize the in situ behaviors of different cell types in intact tissues. In this review we also discuss future perspectives on this new method in the field of bone biology and medical sciences in general. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
► Osteoclast precursors are circulating in blood and migrating into bone surface. ► Sphingosine-1-phosphate (S1P) controls osteoclast precursor migration in vivo. ► Osteoclast precursors express bidirectional S1P receptors, S1PR1 and S1PR2. ► Osteoclast precursor migration is regulated reciprocally by these two receptors. ► Intravital multiphoton imaging is useful for revealing S1P action in vivo.
The International Symposium onWinter Lightning (ISWL) is a unique international symposium dedicated to information exchange and discussion on winter lightning, held only in Japan since the first ...symposium in 1996. It is held irregularly and the 4th symposium was held in Joetsu, Niigata
Macrophages comprise a variety of subsets with diverse biological functions, including inflammation, tissue repair, regeneration, and fibrosis. In the bone marrow, macrophages differentiate into ...multinucleated osteoclasts, which have a unique bone-destroying capacity and play key roles in physiological bone remodelling. In contrast, osteoclasts are also involved in inflammatory bone erosion in arthritis and it has been unclear whether the osteoclasts in different tissue settings arise from similar monocytoid precursors and share similar phenotypes. Rapid progresses in the sequencing technologies have provided many important insights regarding the heterogeneity of different types of osteoclasts. The application of single-cell RNA sequencing (scRNA-seq) to the osteoclast precursor-containing macrophages enabled to identify the specific subpopulation differentiating into pathological mature osteoclasts in joints. Furthermore, an intravital imaging technology using two-photon microscopy has succeeded in visualizing the real-time dynamics of immune cells in the synovial microenvironment. These technologies together contributed to characterize the unique macrophages in the inflamed synovium, termed "arthritis-associated osteoclastogenic macrophages (AtoMs)", causing the pathological bone destruction in inflammatory arthritis. Here, we review and discuss how novel technologies help to better understand the role of macrophages in inflammatory arthritis, especially focusing of osteoclastogenesis at the pannus-bone interface.
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