• Ankylosing spondylitis
• Northern Sweden Health and Disease Study
• biomarkers
• longitudinal observational study
• radiographic axial spondyloarthritis

• Humans
• Male
• Female
• Adult
• Biomarkers/blood
• Middle Aged
• Axial Spondyloarthritis/blood
• Axial Spondyloarthritis/diagnostic imaging
• Longitudinal Studies
• Sweden
• Cytokines/blood

• Ankylosing spondylitis
• FinnGen
• Immune cells
• Immunity
• Mendelian Randomization

• Spondylitis, Ankylosing/genetics
• Spondylitis, Ankylosing/immunology
• Humans
• Mendelian Randomization Analysis
• Genome-Wide Association Study
• Monocytes/immunology
• HLA-DR Antigens/genetics
• Lipopolysaccharide Receptors/genetics
• Receptors, IgG/genetics
• Phenotype
• Polymorphism, Single Nucleotide
• Causality

• ankylosing spondylitis
• extracellular vesicles
• interleukin‐17A
• pathological new bone formation

• Extracellular Vesicles/metabolism
• Spondylitis, Ankylosing/metabolism
• Interleukin-17/metabolism
• Interleukin-17/genetics
• Humans
• Ligaments/metabolism
• Animals
• Osteogenesis/physiology
• Male
• Bone and Bones/metabolism

• RC 2011147 Jiangsu Provincial Medical Talent
• YXZXA2016009 Jiangsu Provincial Key Medical Center
• 81372009 National Natural Science Foundation of China
• Postgraduate Research & Practice Innovation Program of Jiangsu Province
• National Natural Science Foundation of China

• Ankylosing spondylitis
• Axial spondyloarthritis
• BMP pathways
• ERAP1/2
• Endochondral ossification
• HLA-B*27
• Microbiome
• New bone formation
• Wnt signaling pathways

• Humans
• Spondylarthritis/genetics
• Genome-Wide Association Study
• Spondylitis, Ankylosing/genetics
• Spondylitis, Ankylosing/complications
• Axial Spondyloarthritis
• Inflammation/genetics
• Inflammation/complications
• HLA-B Antigens/genetics

• CD4+ T cell proliferation
• immunomodulation
• indoleamine 2,3 dioxygenase
• osteogenic differentiation
• periodontal ligament mesenchymal stem cells

• Humans
• T-Lymphocytes/metabolism
• Periodontal Ligament/metabolism
• Osteogenesis
• Cell Differentiation
• Tumor Necrosis Factor-alpha/metabolism
• Mesenchymal Stem Cells/metabolism
• Immunosuppressive Agents/pharmacology
• CD4-Positive T-Lymphocytes/metabolism
• Cells, Cultured
• Cell Proliferation

• P35037 FWF Austrian Science Fund

• ankylosing spondylitis
• dysfunction
• inflammation
• mesenchymal stem cells
• pathological ossification

• 82672126 National Natural Science Foundation of China
• 22YF1459400 Shanghai Sailing Program
• 2021JCQN06 Basic Medical Research Project of Changhai Hospital

Mesenchymal stem cells (MSCs) can differentiate into various tissue cell types including bone, adipose, cartilage, and muscle. Among those, osteogenic differentiation of MSCs has been widely explored in many bone tissue engineering studies. Moreover, the conditions and methods of inducing osteogenic differentiation of MSCs are continuously advancing. Recently, with the gradual recognition of adipokines, the research on their involvement in different pathophysiological processes of the body is also deepening including lipid metabolism, inflammation, immune regulation, energy disorders, and bone homeostasis. At the same time, the role of adipokines in the osteogenic differentiation of MSCs has been gradually described more completely. Therefore, this paper reviewed the evidence of the role of adipokines in the osteogenic differentiation of MSCs, emphasizing bone formation and bone regeneration.

• Mesenchymal stem cells
• Adipokines
• Adipose tissue
• Osteogenic differentiation
• Osteogenesis
• Bone regeneration

• immunogenetics
• rheumatic diseases

• Humans
• Extracellular Vesicles/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Mesenchymal Stem Cells/metabolism
• Axial Spondyloarthritis
• Biology

• Humans
• Mice
• Animals
• Cattle
• Spondylitis, Ankylosing/pathology
• Cytokines/analysis
• Proteoglycans/adverse effects
• Spondylarthritis
• Mesenchymal Stem Cells/pathology
• Umbilical Cord/pathology

• Adult stem cells
• Chemokines
• Epigenetics
• Immunology
• Stem cells

• Axial spondyloarthritis
• Bone metabolism
• Genetic
• Immune response
• Spondyloarthritis
• Treatment target

• Humans
• Spondylarthritis
• Axial Spondyloarthritis
• Osteoporosis/drug therapy
• Osteoporosis/genetics
• Bone Diseases, Metabolic
• Molecular Biology
• Aminopeptidases
• Minor Histocompatibility Antigens

• Università degli Studi di Roma Tor Vergata

• Th17 cells
• axial spondyloarthritis
• etiology
• genetics
• hereditary autoinflammatory diseases

• Humans
• Spondylitis, Ankylosing/etiology
• Spondylarthritis/pathology
• Sacroiliac Joint/pathology
• Inflammation
• Th17 Cells/pathology

• National Natural Science Foundation of China
• Chinese Academy of Medical Sciences Initiative for Innovative Medicine
• CAMS Central Public Welfare Scientific Research Institute Basal Research Expenses

Mesenchymal stem cells (MSCs) exhibit two bidirectional immunomodulatory abilities: proinflammatory and anti-inflammatory regulatory effects. Long noncoding RNAs (lncRNAs) have important functions in the immune system. Previously, we performed high-throughput sequencing comparing lncRNA expression profiles between MSCs cocultured with or without CD14+ monocytes and screened out a new lncRNA termed lncRNA MCP1 regulatory factor (MRF). However, the mechanism of MRF in MSCs is still unknown.

MRF expression was quantified via qRT–PCR. RNA interference and lentiviruses were used to regulate MRF expression. The immunomodulatory effects of MSCs on monocytes were evaluated via monocyte migration and macrophage polarization assays. RNA pull-down and mass spectrometry were utilized to identify downstream factors of MRF. A dual-luciferase reporter assay was applied to analyze the transcription factors regulating MRF. qRT–PCR, western blotting and ELISAs were used to assess MCP1 expression. A human monocyte adoptive transfer mouse model was applied to verify the function of MRF in vivo.

MRF was upregulated in MSCs during coculture with CD14+ monocytes. MRF increased monocyte recruitment by upregulating the expression of monocyte chemotactic protein (MCP1). Knockdown of MRF enhanced the regulatory effect of MSCs on restraining M1 polarization and facilitating M2 polarization. Mechanistically, MRF bound to the downstream protein heterogeneous nuclear ribonucleoprotein D (HNRNPD) to upregulate MCP1 expression, and the transcription factor interferon regulatory factor 1 (IRF1) activated MRF transcription early during coculture. The human monocyte adoptive transfer model showed that MRF downregulation in MSCs inhibited monocyte chemotaxis and enhanced the effects of MSCs to inhibit M1 macrophage polarization and promote M2 polarization in vivo.

We identified the new lncRNA MRF, which exhibits proinflammatory characteristics. MRF regulates the ability of MSCs to accelerate monocyte recruitment and modulate macrophage polarization through the HNRNPD-MCP1 axis and initiates the proinflammatory regulatory process in MSCs, suggesting that MRF is a potential target to improve the clinical effect of MSC-based therapy or correct MSC-related immunomodulatory dysfunction under pathological conditions.

The online version contains supplementary material available at 10.1186/s12929-022-00858-3.

• Immunomodulation
• Long noncoding RNAs
• MCP1
• MRF
• Mesenchymal stem cells

Chemokines are secreted by a large variety of cells. They are involved in controlling cell trafficking, maturation, and differentiation. However, the specific responses and effects of chemokines on specific skeletal cell types under high glucose conditions have not been investigated. Chondrocytes play an important role in osteoarthritis and fracture healing. Delayed fracture healing is one of the major health complications caused by diabetes, so the goal of this study was to evaluate the response of several chemokines to high glucose conditions in chondrocyte cells and analyze their role in the catabolic effect of hyperglycemia. ATDC5 chondrocytes were cultured in normal and high glucose media, and mRNA expression levels of several chemokines and chondrocyte differentiation markers were quantified. Bindarit, a specific inhibitor of monocyte chemotactic proteins (MCPs), was used to determine the role of MCPs in mediating the effects of high glucose conditions in chondrocyte cells. High glucose treatment upregulated the expression of three Mcps, as well as the expression of matrix metalloproteinase 13 (Mmp13) and Osteocalcin (Oc). Furthermore, bindarit treatment downregulated Mmp13 and Oc but upregulated Collagen 2 (Col2) mRNA levels in chondrocytes treated with high glucose. Moreover, treatment of chondrocytes with ascorbic acid reduced the effect of high glucose conditions on the expression of chemokines and Mmps. These data together suggest that MCPs mediate the catabolic effect of high glucose in chondrocytes.

• AR048139 NIH HHS

Pathological osteogenesis and inflammation possess critical significance in ankylosing spondylitis (AS). The current study aimed to elucidate the mechanisms regarding extracellular vesicle (EV)-packaged microRNA-22-3p (miR-22-3p) from M2 macrophages in the osteogenic differentiation of mesenchymal stem cells (MSCs) in AS. EVs were initially isolated from M2 macrophages, which had been treated with either restored or depleted miR-22-3p. AS-BMSCs were subsequently treated with M2 macrophage-derived EVs to detect osteogenic differentiation in BMSCs using gain- or loss-of-function experiments. The binding affinity among miR-22-3p, period circadian protein 2 (PER2), and Wnt7b was identified. Finally, AS mouse models were established for testing the effects of M2-EV-miR-22-3p on the bone metastatic microenvironment in vivo. miR-22-3p from M2 macrophages could be transferred into BMSCs via EVs, which promoted the osteogenic differentiation of AS-BMSCs. miR-22-3p inhibited PER2, while PER2 blocked the Wnt/β-catenin signaling pathway via Wnt7b inhibition. M2-EV-shuttled miR-22-3p facilitated alkaline phosphatase activity and extracellular matrix mineralization via PER2-regulated Wnt/β-catenin axis, stimulating the BMSC osteogenic differentiation. Taken together, these findings demonstrate that miR-22-3p in M2 macrophage-released EVs downregulates PER2 to facilitate the osteogenesis of MSCs via Wnt/β-catenin axis.

To evaluate the efficacy and safety of mesenchymal stem cell (MSC) transplantation in the treatment of autoimmune diseases.

The Chinese and English databases were searched for clinical research on the treatment of autoimmune diseases with mesenchymal stem cells. The search time range is from a self-built database to October 1, 2021. Two reviewers independently screened the literature according to the inclusion and exclusion criteria, extracted data, and evaluated the bias of the included studies. RevMan 5.3 analysis software was used for meta-analysis.

A total of 18 RCTs involving 5 autoimmune diseases were included. The 5 autoimmune disease were rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease, ankylosing spondylitis, and multiple sclerosis. For RA, the current randomized controlled trials (RCTs) still believe that stem cell transplantation may reduce disease activity, improve the clinical symptoms (such as DAS28), and the percentage of CD4+CD 25+Foxp3+Tregs in the response group increased and the percentage of CD4+IL-17A+Th17 cells decreased. The total clinical effective rate of RA is 54%. For SLE, the results showed that mesenchymal stem cell transplantation may improve SLEDAI [-2.18 (-3.62, -0.75), P = 0.003], urine protein [-0.93 (-1.04, -0.81), P < 0.00001], and complement C3 [0.31 (0.19, 0.42), P < 0.00001]. For inflammatory bowel disease, the results showed that mesenchymal stem cell transplantation may improve clinical efficacy [2.50 (1.07, 5.84), P = 0.03]. For ankylosing spondylitis, MSC treatment for 6 months may increase the total effective rate; reduce erythrocyte sedimentation rate, intercellular adhesion molecules, and serum TNF-α; and improve pain and activity. For multiple sclerosis, the current research results are still controversial, so more RCTs are needed to amend or confirm the conclusions. No obvious adverse events of mesenchymal stem cell transplantation were found in all RCTs.

MSCs have a certain effect on different autoimmune diseases, but more RCTs are needed to further modify or confirm the conclusion.

The immune system and the skeletal system have complex interactions in the bone marrow and even in the joints, which has promoted the development of the concept of osteoimmunology. Some evidence has indicated that T cells and B cells contribute to the balance between the resorption and formation of bone. However, there has been little discussion on the regulation of CD4⁺ T lymphocytes by cells involved in bone metabolism. Mesenchymal stem cells (MSCs), which exert core functions related to immunoregulation and osteogenic differentiation, are crucial cells linked to both bone metabolism and the immune system. Previous studies have shown that the immunoregulatory capacity of MSCs changes following differentiation. However, it is still unclear whether the osteogenic differentiation of MSCs affects the migration and differentiation of CD4⁺ T cells.

MSCs were cultured in growth medium or osteogenic medium for 10 days and then cocultured with CD4+ T cells. CD4+ T cell migration and differentiation were detected by flow cytometry. Further, gene expression levels of specific cytokines were analyzed by quantitative real-time PCR and enzyme-linked immunosorbent assays. A Proteome Profiler Human XL Cytokine Array Kit was used to analyze supernatants collected from MSCs. Alizarin red S staining and Alkaline phosphatase assay were used to detect the osteogenic differentiation of MSCs.

Here, we found that the migration of CD4⁺ T cells was elevated, and the capacity to induce the differentiation of regulatory T (Treg) cells was weakened during MSC osteogenic differentiation, while the differentiation of T helper 1 (Th1), T helper 2 (Th2) and T helper 17 (Th17) cells was not affected. Further studies revealed that interleukin (IL)-8 was significantly upregulated during MSC osteogenic differentiation. Both a neutralizing antibody and IL-8-specific siRNA significantly inhibited the migration of CD4⁺ T cells and promoted the differentiation of Treg cells. Finally, we found that the transcription factor c-Jun was involved in regulating the expression of IL-8 and affected the osteogenic differentiation of MSCs, thereby mediating the migration and differentiation of CD4⁺ T cells.

This study demonstrated that MSC osteogenic differentiation promoted c-Jun-dependent secretion of IL-8 and mediated the migration and differentiation of CD4⁺ T cells. These results provide a further understanding of the crosstalk between bone and the immune system and reveal information about the relationship between osteogenesis and inflammation in the field of osteoimmunology.

The online version contains supplementary material available at 10.1186/s13287-022-02735-0.

Ankylosing spondylitis (AS) is a type of rheumatic disease characterized by chronic inflammation and pathological osteogenesis in the entheses. Previously, we demonstrated that enhanced osteogenic differentiation of MSC from AS patients (AS-MSC) resulted in pathological osteogenesis, and that during the enhanced osteogenic differentiation course, AS-MSC induced TNF-α-mediated local inflammation. However, whether TNF-α in turn affects AS-MSC remains unknown. Herein, we further demonstrate that a high-concentration TNF-α treatment triggers enhanced directional migration of AS-MSC in vitro and in vivo, which enforces AS pathogenesis. Mechanistically, TNF-α leads to increased expression of ELMO1 in AS-MSC, which is mediated by a METTL14 dependent m⁶A modification in ELMO1 3′UTR. Higher ELMO1 expression of AS-MSC is found in vivo in AS patients, and inhibiting ELMO1 in SKG mice produces therapeutic effects in this spondyloarthritis model. This study may provide insight into not only the pathogenesis but also clinical therapy for AS.

Abnormal functions of mesenchymal stem cells (MSC) contribute into the pathogenensis of ankylosing spondylitis (AS). Here, the authors show that TNF-α at high concentration induces enhances migration of AS-MSC through METTL14 mediated m6A modification of the ELMO1 3′ UTR.

• ERK1/2
• chemokines
• diabetes mellitus
• fracture
• migration
• mononuclear cells
• osteoprogenitor cells

• Animals
• Biomarkers
• Cell Movement
• Cells, Cultured
• Chemokine CCL2/genetics
• Chemokine CCL2/metabolism
• Chemokine CCL8/metabolism
• Chemokines/metabolism
• Chemotaxis, Leukocyte/immunology
• Culture Media, Conditioned/metabolism
• Diabetes Mellitus/metabolism
• Fracture Healing
• Humans
• Hyperglycemia/metabolism
• Leukocytes, Mononuclear/immunology
• Leukocytes, Mononuclear/metabolism
• MAP Kinase Signaling System
• Monocytes/immunology
• Monocytes/metabolism
• Osteoblasts/metabolism
• Osteogenesis
• THP-1 Cells

• EH 471/2 Deutsche Forschungsgemeinschaft
• Stipendium CL Studienstiftung des Deutschen Volkes

T-cell-mediated adaptive immunity contributes to the development and persistence of ankylosing spondylitis (AS). Mesenchymal stromal/stem cells (MSCs) have immunomodulatory potential and are able to inhibit T-cell proliferation, but their functionality in AS patients is relatively unknown. The aim of the study was to assess the direct anti-proliferative effects of MSCs isolated from subcutaneous abdominal adipose tissue of AS patients (AS/ASCs) on allogeneic T lymphocytes, using commercially available ASC lines from healthy donors (HD/ASCs) as a control.

CD3+CD4+ T-cells were isolated from peripheral blood of healthy blood donors, activated with anti-CD3/CD28 beads, and co-cultured for 5 days with untreated and TNF+IFN-γ pre-stimulated HD/ASCs (5 cell lines) and AS/ASCs, obtained from 11 patients (6F/5M). The proliferative response of T-cells was analysed by flow cytometry, while the concentrations of kynurenines, prostaglandin E2 (PGE-2), interleukin 10 (IL-10), and interleukin 1 receptor antagonist (IL-1Ra) were measured spectrophotometrically or using a specific enzyme-linked immunosorbent assay (ELISA).

HD/ASCs and AS/ASCs similarly reduced the T-cell proliferation response, i.e. the percentage of proliferating cells, the proliferation, and replication indices, and these effects were dependent mostly on soluble factors. In the co-cultures of activated CD4+ T-cells with HD/ASCs and AS/ASCs significant increases of kynurenines, PGE-2, and IL-1Ra, but not IL-10, production were observed. The release of these factors was dependent either on cell-to-cell contact (IL-10, IL-1Ra) or soluble factors (kynurenines, PGE-2). There was a moderate to strong negative correlation between T-cell proliferative response, and the concentrations of kynurenines, PGE-2, and IL-10, but not IL-1Ra. This association was more evident in the case of TI-treated AS/ASCs than HD/ASCs.

AS/ASCs, similar to HD/ASCs, exert a direct effective anti-proliferative impact on CD4+ T cells, acting via soluble factors that are released in cell contact-dependent (IL-10) and independent (kynurenines, PGE-2) pathways. Thus, our results suggest that AS/ASCs are potentially useful for therapeutic application.

• T-cell proliferation
• adipose-derived mesenchymal stem cells
• ankylosing spondylitis
• kynurenines

In ankylosing spondylitis (AS), accompanied by chronic inflammation, T cell expansion plays a pathogenic role; the immunoregulatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) are impaired, while functional characteristics of their adipose tissue-derived counterparts are (ASCs) unknown.

We evaluated the antiproliferative activity of AS/ASCs, obtained from 20 patients, towards allogeneic and autologous T lymphocytes, using ASCs from healthy donors (HD/ASCs) as the reference cell lines. The PHA-activated peripheral blood mononuclear cells (PBMCs) were cocultured in cell-cell contact and transwell conditions with untreated or TNF + IFNγ- (TI-) licensed ASCs, then analyzed by flow cytometry to identify proliferating and nonproliferating CD4⁺ and CD8⁺ T cells. The concentrations of kynurenines, prostaglandin E₂ (PGE₂), and IL-10 were measured in culture supernatants.

In an allogeneic system, HD/ASCs and AS/ASCs similarly decreased the proliferation of CD4⁺ and CD8⁺ T cells and acted mainly via soluble factors. The concentrations of kynurenines and PGE₂ inversely correlated with T cell proliferation, and selective inhibitors of these factors synthesis significantly restored T cell response. AS/ASCs exerted a similar antiproliferative impact also on autologous T cells.

We report for the first time that despite chronic in vivo exposure to inflammatory conditions, AS/ASCs retain the normal capability to restrain expansion of allogeneic and autologous CD4⁺ and CD8⁺ T cells, act primarily via kynurenines and PGE₂, and thus may have potential therapeutic value. Some distinctions between the antiproliferative effects of AS/ASCs and HD/ASCs suggest in vivo licensing of AS/ASCs.

• angiogenesis
• arthritis
• autoimmune disease
• mesenchymal stem cells (MSCs)
• tube formation

• T helper cell subsets
• adipose-derived mesenchymal stem cells
• ankylosing spondylitis
• cytokines
• transcription factors

• Adipose Tissue/metabolism
• Cell Differentiation
• Female
• Humans
• Male
• Mesenchymal Stem Cells/metabolism
• Spondylitis, Ankylosing/genetics
• Spondylitis, Ankylosing/pathology
• Th1 Cells/metabolism

Ankylosing spondylitis (AS) is a chronic inflammatory disease possessing a morbid serum microenvironment with enhanced oxidative stress. Long-term exposure to an oxidative environment usually results in cellular senescence alone with cellular dysfunction. Mesenchymal stem cells (MSCs) are a kind of stem cell possessing strong capabilities for immunoregulation, and senescent MSCs may increase inflammation and participate in AS pathogenesis. The objective of this study was to explore whether and how the oxidative serum environment of AS induces MSC senescence. Here, we found that AS serum facilitated senescence of MSCs in vitro, and articular tissues from AS patients exhibited higher expression levels of the cell cycle arrest-related proteins p53, p21 and p16. Importantly, the levels of advanced oxidative protein products (AOPPs), markers of oxidative stress, were increased in AS serum and positively correlated with the extent of MSC senescence induced by AS serum. Furthermore, MSCs cultured with AS serum showed decreased mitochondrial membrane potential and ATP production together with a reduced oxygen consumption rate. Finally, we discovered that AS serum-induced mitochondrial dysfunction resulted in elevated reactive oxygen species (ROS) in MSCs, and ROS inhibition successfully rescued MSCs from senescence. In conclusion, our data demonstrated that the oxidative serum environment of AS facilitated MSC senescence through inducing mitochondrial dysfunction and excessive ROS production. These results may help elucidate the pathogenesis of AS and provide potential targets for AS treatment.

Intervertebral disc degeneration (IDD) is a condition involving disruption of the bone tissue distribution. Nucleus pulposus mesenchymal stem cells (NPMSCs) and Sirtuin 1 (SIRT1) play important roles in bone diseases, therefore the aim of the present study was to evaluate the roles of SIRT1 and NPMSCs in IDD. First, NPMSCs were harvested from patients with IDD. Then, the NPMSCs were treated with a SIRT activator, and monocyte chemoattractant protein 1 (MCP1) and chemokine receptor 2 (CCR2) inhibitors. Indices related to NPMSC growth, proliferation, differentiation and apoptosis were measured. Subsequently, IDD rat models were established and were transfected with NPMSCs overexpressing SIRT1. NPMSC apoptosis and cartilage differentiation were detected in the rat IDD model. SIRT1 expression was found to be decreased, and the expression of MCP1 and CCR2 increased in NPMSCs of patients with IDD. The upregulation of SIRT1 and the downregulation of the MCP1/CCR2 axis promoted cartilage differentiation and reduced the number of apoptotic NPMSCs. Furthermore, MCP1 reversed the progression of the cartilage differentiation of NPMSCs and the inhibition of NPMSC apoptosis induced by SIRT1 overexpression. Moreover, the transplantation of rat NPMSCs overexpressing SIRT1 relieved IDD in rats. Therefore, SIRT1 overexpression improved cartilage differentiation and reduced the apoptosis of NPMSCs by inactivating the MCP1/CCR2 axis, thus attenuating IDD in rats.

• Autoimmunity
• Bone Biology
• Bone disease
• Rheumatology

• Alkaline Phosphatase/antagonists & inhibitors
• Alkaline Phosphatase/physiology
• Animals
• Core Binding Factor Alpha 1 Subunit/physiology
• Female
• HLA-B27 Antigen/physiology
• Humans
• Male
• Mesenchymal Stem Cells/physiology
• Mice
• Mice, SCID
• Ossification, Heterotopic/etiology
• Receptors, Retinoic Acid/physiology
• Spondylitis, Ankylosing/complications
• Spondylitis, Ankylosing/diagnostic imaging
• X-Box Binding Protein 1/physiology

• Academia Sinica
• Ministry of Science and Technology, Taiwan

• Ang2
• MCP1
• PTX3
• pro-inflammatory cytokine
• sepsis

• Adult
• Aged
• Aged, 80 and over
• Angiopoietin-2/blood
• Biomarkers
• C-Reactive Protein
• Case-Control Studies
• Chemokine CCL2/blood
• Humans
• Middle Aged
• Prognosis
• ROC Curve
• Sepsis/blood
• Sepsis/diagnosis
• Sepsis/therapy
• Serum Amyloid P-Component
• Severity of Illness Index
• Shock, Septic/blood
• Shock, Septic/diagnosis
• Shock, Septic/therapy

• 184119500900 Shanghai Science and Technology Innovation Fund
• 2016ZB0206 Key Discipline Construction of Shanghai Municipal Commission of Health and Family Planning
• 81772040 National Natural Science Foundation of China
• ZY(2018-2020)-FWTX-1108 Project of Shanghai Municipal Commission of Health and Family Planning
• National Natural Science Foundation of China

Bone marrow mesenchymal stem cells (BM-MSCs) can dampen inflammation in animal models of inflammatory rheumatisms and human osteoarthritis. They are expected to be a solution for numerous human conditions. However, in rheumatoid arthritis (RA) and spondyloarthritis (SpA), subsets of subchondral BM-MSCs might conversely fuel synovitis and enthesitis.

Abnormal behaviour of BM-MSCs and/or their progeny has been found in RA and SpA. BM-MSCs also contribute to the ossifying processes observed in ankylosing spondylitis. Some synovial fibroblastic stem cells probably derive from BM-MSCs, but some stem cells can also migrate through the bare zone area of joints, not covered by cartilage, into the synovium. BM-MSCs can also migrate in the synovium over tendons. Sub-populations of bone marrow stem cells also invade the soft tissue side of enthesis via small holes in the bone cortex. The present review aims (1) to make a focus on these two aspects and (2) to put forward the hypothesis that lasting epigenetic changes of some BM-MSCs, induced by transient infections of the bone marrow close to the synovium and/or entheses (i.e. trained immunity of BM-MSCs and/or their progeny), contribute to the pathogenesis of inflammatory rheumatisms. Such hypothesis would fit with (1) the uneven distribution and/or flares of arthritis and enthesitis observed at the individual level in RA and SpA (reminiscent of what is observed following reactive arthritis and/or in Whipple’s disease); (2) the subchondral bone marrow oedema and erosions occurring in many RA patients, in the bare zone area; and (3) the frequent relapses of RA and SpA despite bone marrow transplantation, whereas most BM-MSCs resist graft preconditioning.

Some BM-MSCs might be more the problem than the solution in inflammatory rheumatisms. Subchondral bone marrow BM-MSCs and their progeny trafficking through the bare zone area of joints or holes in the bone cortex of entheses should be thoroughly studied in RA and SpA respectively. This may be done first in animal models. Mini-arthroscopy of joints could also be used in humans to specifically sample tissues close to the bare zone and/or enthesis areas.

• Ankylosing spondylitis
• Bone marrow
• Enthesis
• Epigenetic
• Mesenchymal
• Rheumatoid arthritis
• Spondyloarthritis
• Stem cells
• Stromal
• Synovium

The goals of this study were to explore the expression profiles and functional networks of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in mesenchymal stromal cells (MSCs) involved in regulating the function of monocytes and to clarify the mechanisms by which MSCs exert immunoregulatory effects on monocytes.

MSCs and CD14+ monocytes were separately isolated. The immunoregulatory effects of MSCs on monocytes were determined by flow cytometry. lncRNAs and mRNAs that were differentially expressed (DE) between the control group (MSCs only) and co-culture group (MSCs co-cultured with monocytes) were identified through high-throughput sequencing and bioinformatic analyses and were confirmed by qRT-PCR. Bioinformatic analyses were performed to identify the critical biological functions and signalling pathways involved in MSC-mediated monocyte regulation and to identify the functional networks formed between DE mRNAs and lncRNAs.

MSCs showed a strong ability to induce monocyte migration but inhibited monocyte differentiation into M1 macrophages. A total of 145 DE lncRNAs and 768 DE mRNAs were identified between the control and co-culture groups. Significant fold changes in lncRNAs and mRNAs were confirmed by qRT-PCR. GO analysis demonstrated that DE mRNAs and lncRNAs were highly associated with terms related to binding and biological regulation. KEGG analysis revealed 122 significantly regulated pathways, including the cytokine-cytokine receptor pathway and chemokine signalling pathway. Interaction and co-expression networks were constructed for DE mRNAs and lncRNAs, and several key microRNAs were identified in the competitive endogenous RNA (ceRNA) network. Target genes of the DE lncRNAs were analysed to predict critical mRNA-lncRNA axes involved in the immunoregulatory function of MSCs.

Our research describes the lncRNA and mRNA expression profiles and functional networks involved in MSC-mediated regulation of monocytes. These results provide possible molecular mechanisms for the immunoregulatory function of MSCs and may help to elucidate possible molecular therapeutic targets in MSCs for the treatment of autoimmune diseases.

The online version of this article (10.1186/s13287-019-1306-x) contains supplementary material, which is available to authorized users.

• Immunoregulation
• Long non-coding RNA
• Mesenchymal stromal cells
• Monocytes

The aim of our study was to assess potential correlations between serum galectin‐3 concentrations and Ankylosing Spondylitis Disease Activity (ASDAS) index in patients with ankylosing spondylitis (AS).

A total of 112 patients with AS were included, and 130 healthy subjects were considered as controls. We collected the detailed medical history, and ASDAS index was used to assess the disease severity in patients with AS.

The serum galectin concentrations were higher in AS patients compared to the health groups (14.1 ± 9.6 vs 9.2 ± 3.7, P < 0.001). The correlation analysis showed that serum galectin concentrations were significantly positively correlated with C‐reactive protein and erythrocyte sedimentation rate (r = 0.369, P < 0.001; r = 0.240, P = 0.011). In addition, the positively correlation of serum galectin‐3 with global pain index (r = 0.238, P = 0.011) was observed in AS patients. A significant positively correlation between serum galectin and ASDAS index in AS patients was found (r = 0.367; P < 0.001). In multiple linear regression analysis, the results indicated that increased serum galectin still was correlated with ASDAS index (r = 0.322, P < 0.001) in patients with AS.

Serum galectin concentrations were found to be correlated with ASDAS index in patients with AS.

• ASDAS index
• ankylosing spondylitis
• serum galectin-3

The mechanism of pathological osteogenesis in Ankylosing spondylitis (AS) is largely unknown. Our previous studies demonstrated that the imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of marrow-derived mesenchymal stem cells (MSCs) from AS patients in a two-dimensional culture environment. In this study, HA/β-TCP scaffolds were further used as a three-dimensional (3D) biomimetic culture system to mimic the bone microenvironment in vivo to determine the abnormal osteogenic differentiation of AS-MSCs. We demonstrated that when cultured in HA/β-TCP scaffolds, AS-MSCs had a stronger osteogenic differentiation capacity than that of MSCs from healthy donors (HD-MSCs) in vitro and in vivo. This dysfunction resulted from BMP2 overexpression in AS-MSCs, which excessively activated the Smad1/5/8 and ERK signalling pathways and finally led to enhanced osteogenic differentiation. Both the signalling pathway inhibitors and siRNAs inhibiting BMP2 expression could rectify the enhanced osteogenic differentiation of AS-MSCs. Furthermore, BMP2 expression in ossifying entheses was significantly higher in AS patients. In summary, our study demonstrated that AS-MSCs possess enhanced osteogenic differentiation in HA/β-TCP scaffolds as a 3D biomimetic microenvironment because of BMP2 overexpression, but not Noggin. These results provide insights into the mechanism of pathological osteogenesis, which can aid in the development of niche-targeting medications for AS.

Ankylosing spondylitis (AS) is a common inflammatory autoimmune disease, characterized by pathological osteogenesis. Mesenchymal stem cells (MSCs), as the main source of osteoblasts, participate in bone remodeling not only through differentiation into osteoblasts but also through indirect regulation of osteoclastogenesis. Our previous study indicated that the stronger osteogenic differentiation of MSCs from AS patients (ASMSCs) involved in pathological osteogenesis. However, whether there is any abnormality in the regulation of osteoclastogenesis by ASMSCs remains unclear. In this study, ASMSCs or MSCs from healthy donors (HDMSCs) were co-cultured with CD14 + monocytes in osteoclast induction medium. Our results demonstrated that ASMSCs exhibited a stronger capacity to inhibit osteoclastogenesis than HDMSCs. To explore underlying mechanisms, cytokine array assays were performed, showing that ASMSCs secreted more CXCL5 than HDMSCs, which was confirmed by enzyme-linked immunosorbent assays. Moreover, inhibition of osteoclastogenesis by ASMSCs was recovered by decreasing CXCL5. Besides, the inhibitory effect of CXCL5 on osteoclastogenesis was confirmed by exogenous addition. Bioinformatics analysis was applied to find the interaction between miR-4284 and CXCL5, which was verified by luciferase reporter assays. Furthermore, we used miR-4284 inhibitors or mimics to prove that the expression of CXCL5 was regulated by miR-4284. Further analysis showed that downregulation of miR-4284 in MSCs resulted in increase of CXCL5, markedly inhibiting osteoclastogenesis, whereas upregulation of miR-4284 in MSCs had the opposite effect. Our findings indicate that ASMSCs exhibit a stronger capacity to inhibit osteoclastogenesis than HDMSCs through the miR-4284/CXCL5 axis, which provide a new perspective on the mechanism of pathologic osteogenesis in AS.

• Heterogeneous nuclear ribonucleoprotein K
• Long noncoding RNA
• Mesenchymal stem cells
• Osteogenic differentiation

• Cell Differentiation
• Heterogeneous-Nuclear Ribonucleoprotein K/genetics
• Humans
• Mesenchymal Stem Cells/metabolism
• Osteogenesis
• RNA, Long Noncoding/genetics

• National Natural Science Foundation of China

• Ankylosing spondylitis
• DEPTOR
• NLRP3
• TNFAIP3
• autophagy
• inflammasome
• monocytes