Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation leading to joint destruction and deformity. The crucial role of osteoclasts in the bone erosion in RA has been ...demonstrated. Deregulated osteoclastogenesis which is affected by environmental factors including the inflammatory state, as well as genetic and epigenetic factors, is one of hallmarks of RA pathogenesis. An enhanced-monocyte-to-osteoclast transition plays an important role in osteoclast upregulation in RA because under specific stimuli, circulating monocytes might migrate to a specific location in the bones and fuse with each other to become mature multinucleated osteoclasts. To understand the mechanism of bone damage in RA and to develop novel treatments targeting osteoclast upregulation, it is important to clarify our understanding of the monocyte-to-osteoclast transition in RA. Several potential targets which inhibit both inflammation and osteoclastogenesis, as well as regulators that affect the monocyte-to-osteoclast transition have been revealed by recent studies. Here, we review the factors affecting osteoclastogenesis in RA, summarize the anti-osteoclastogenic effects of current RA treatments, and identify promising therapeutic targets relating to both inflammation and osteoclastogenesis.
A large G
C
-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this ...expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing transcripts in multiple cellular models and C9BAC transgenic mice. We optimize stereopure oligonucleotides that act through this site, and we demonstrate that their preferential activity depends on both backbone stereochemistry and asymmetric wing design. In mice, stereopure oligonucleotides produce durable depletion of pathogenic signatures without disrupting protein expression. These oligonucleotides selectively protect motor neurons harboring C9orf72-expansion mutation from glutamate-induced toxicity. We hypothesize that targeting C9orf72 with stereopure oligonucleotides may be a viable therapeutic approach for the treatment of C9orf72-associated neurodegenerative disorders.
Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeric mixtures containing as many as a half million components persist in antisense oligonucleotide (ASO) ...therapeutics because it has been feasible neither to separate the individual stereoisomers, nor to synthesize stereochemically pure ASOs. Here we report the development of a scalable synthetic process that yields therapeutic ASOs having high stereochemical and chemical purity. Using this method, we synthesized rationally designed stereopure components of mipomersen, a drug comprising 524,288 stereoisomers. We demonstrate that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. We report that Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug. Further, we elucidated a triplet stereochemical code in the stereopure ASOs, 3'-SpSpRp, that promotes target RNA cleavage by RNase H1 in vitro and provides a more durable response in mice than stereorandom ASOs.
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IJS, NUK, SBMB, UL, UM, UPUK
We investigated the relationships among M1 monocytes, M2 monocytes, osteoclast (OC) differentiation ability, and clinical characteristics in patients with rheumatoid arthritis (RA).
Peripheral blood ...mononuclear cells (PBMCs) were isolated from RA patients and healthy donors, and we then investigated the number of M1 monocytes or M2 monocytes by fluorescence-activated cell sorting. We also obtained and cultured CD14-positive cells from PBMCs from RA patients and healthy donors to investigate OC differentiation
.
Forty RA patients and 20 healthy donors were included. Twenty-two patients (55%) were anticitrullinated protein antibody (ACPA) positive. The median M1/M2 ratio was 0.59 (0.31-1.11, interquartile range). There were no significant differences between the RA patients and healthy donors. There was a positive correlation between the M1/M2 ratio and the differentiated OC number
in RA patients (ρ = 0.81,
< 0.001). The ACPA-positive patients had significantly higher M1/M2 ratios
(
= 0.028) and significantly greater numbers of OCs
(
= 0.005) than the ACPA-negative patients. Multivariable regression analysis revealed that the M1/M2 ratio was the sole significant contribution factor to
osteoclastogenesis. RA patients with M1/M2 ratios >1 (having relatively more M1 monocytes) had higher C-reactive protein and erythrocyte sedimentation rates than RA patients with M1/M2 ratios ≤1. M1-dominant monocytes
produced higher concentrations of interleukin-6 upon stimulation with lipopolysaccharide than M2 monocytes.
M1/M2 monocytes imbalance strongly contributes to osteoclastogenesis of RA patients. Our findings cast M1 and M2 monocyte subsets in a new light as a new target of treatments for RA to prevent progression of osteoclastic bone destruction.
In this paper, we describe the first stereocontrolled synthesis and properties of boranophosphate DNA (PB-DNA), which contains all of the four nucleobases longer than 10mer. Synthesis was ...accomplished via an oxazaphospholidine approach combined with acid-labile protecting groups on nucleobases. It was demonstrated that there were significant differences between all-(Rp)- and all-(Sp)-PB-DNA in terms of the duplex-formation ability, nuclease resistance, and ribonuclease H (RNase H) activity. In particular, all-(Sp)-PB-DNA was demonstrated to show a duplex-formation ability with RNA and RNase H activity, both of which are necessary for antisense-type nucleic acid therapeutics.
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IJS, KILJ, NUK, PNG, UL, UM
This exploratory study compared the inhibition of bone erosion progression in rheumatoid arthritis (RA) patients treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) ...plus denosumab versus csDMARD therapy alone and investigated the effects of denosumab on bone micro-architecture and other bone-related parameters using high-resolution peripheral quantitative computed tomography (HR-pQCT).
In this open-label, randomized, parallel-group study, patients with RA undergoing treatment with a csDMARD were randomly assigned (1:1) to continue csDMARD therapy alone or to continue csDMARDs with denosumab (60-mg subcutaneous injection once every 6 months) for 12 months. The primary endpoint was the change from baseline in the depth of bone erosion, measured by HR-pQCT, in the second and third metacarpal heads at 6 months after starting treatment. Exploratory endpoints were also evaluated, and adverse events (AEs) were monitored for safety.
In total, 46 patients were enrolled, and 43 were included in the full analysis set (csDMARDs plus denosumab, N = 21; csDMARD therapy alone, N = 22). Most patients were female (88.4%), and the mean age was 65.3 years. The adjusted mean (95% confidence interval) change from baseline in the depth of bone erosion, measured by HR-pQCT, in the 2-3 metacarpal heads at 6 months was - 0.57 mm (- 1.52, 0.39 mm) in the csDMARDs plus denosumab group vs - 0.22 mm (- 0.97, 0.53 mm) in the csDMARD therapy alone group (between-group difference: - 0.35 mm - 1.00, 0.31; P = 0.2716). Similar results were shown for the adjusted mean between-group difference in the width and volume of bone erosion of the 2-3 metacarpal heads. Significant improvements in bone micro-architecture parameters were shown. The incidence of AEs and serious AEs was similar between the csDMARDs plus denosumab and the csDMARD therapy alone groups (AEs: 52.2% vs 56.5%; serious AEs: 4.3% vs 8.7%).
Although the addition of denosumab to csDMARDs did not find statistically significant improvements in bone erosion after 6 months of treatment, numerical improvements in these parameters suggest that the addition of denosumab to csDMARDs may be effective in inhibiting the progression of bone erosion and improving bone micro-architecture.
University Hospital Medical Information Network Clinical Trials Registry, UMIN000030575. Japan Registry for Clinical Trials, jRCTs071180018.
We herein report a case of melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis that developed in a patient with refractory gingivitis. The diagnosis of anti-MDA5 ...antibody-positive dermatomyositis was made based on a characteristic skin rash, weakness of proximal muscles, interstitial pneumonia, and positivity for anti-MDA5 antibody. The patient was started on triple therapy with high-dose prednisolone, tacrolimus, and intravenous cyclophosphamide. After treatment, the refractory gingivitis disappeared, and the other skin rash and interstitial lung disease also improved. In the diagnosis and treatment of anti-MDA5 antibody-positive dermatomyositis, it is necessary to pay attention to the intraoral findings, including the gingiva.
Rheumatoid arthritis (RA) is a systemic autoimmune disease with severe joint inflammation and destruction characterized by marked hyperplasia of the lining layer of the synovium. Fibroblast-like ...synovial cells (FLS) is a key cellular component within the synovia; it plays pivotal roles in RA pathogenesis by unfavorable behaviors such as producing inflammatory cytokines and chemokines, and hyperproliferation. MicroRNAs are evolutionarily conserved small non-coding RNAs (length is 18-25 nucleotides) that regulate gene expression at the post-transcriptional level. There is increasing interest in the involvement of microRNAs in autoimmune diseases including RA. Recent studies revealed the regulation of the function of FLS by microRNAs. Here, we review the known functional microRNAs in RA and summarize the potential uses of these small molecules in the treatment of RA.
Objective
To clarify the significance of immunometabolism in systemic lupus erythematosus (SLE), and to determine the effect of calcium/calmodulin‐dependent protein kinase 4 (CaMK4) on T cell ...metabolism.
Methods
Metabolomic profiling was performed using capillary electrophoresis mass spectrometry in naive T cells from MRL/lpr mice treated with anti‐CD3/CD28 antibodies in the absence or presence of a CaMK4 inhibitor (KN‐93). The expression of GLUT1 and CaMK4 in CD4+ T cells from healthy controls (n = 16), patients with inactive SLE (n = 13), and patients with active SLE (n = 14) was examined by flow cytometry and quantitative polymerase chain reaction. In vitro experiments were performed to determine the effect of KN‐93 on the expression of GLUT1 during Th17 cell differentiation in T cells from patients with SLE.
Results
CaMK4 inhibition significantly decreased the levels of glycolytic intermediates such as glucose‐6‐phosphate, fructose‐6‐phosphate, fructose‐1,6‐diphosphate, pyruvate, and lactate (P < 0.05), whereas it did not affect the levels of the pentose phosphate pathway intermediates such as 6‐phospho‐d‐gluconate, ribulose‐5‐phosphate, ribose‐5‐phosphate, and phosphoribosyl pyrophosphate. The expression levels of GLUT1 and CaMK4 in effector memory CD4+ T cells were significantly higher in patients with active SLE compared to healthy controls (P < 0.01 and P < 0.05, respectively) and patients with inactive SLE (P < 0.05 and P < 0.01, respectively). A functional analysis revealed that CaMK4 inhibition decreased the expression of GLUT1 during Th17 cell differentiation (P < 0.01), followed by a reduction of interleukin‐17 (IL‐17) production (P < 0.05).
Conclusion
The results of the study indicate that the activity of CaMK4 could be responsible for glycolysis, which contributes to the production of IL‐17, and CaMK4 may contribute to aberrant expression of GLUT1 in T cells from patients with active SLE.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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