Transcriptomic profiling of osteoarthritis synovial macrophages reveals a tolerized phenotype compounded by a weak corticosteroid response.

Objectives: It is well-known that long-term osteoarthritis prognosis is not improved by corticosteroid treatments. Here we investigate what could underlie this phenomenon by measuring the short term corticosteroid response of OA-Mf.

Methods: We determined the genome-wide transcriptomic response to corticosteroids of end-stage osteoarthritic joint synovial macrophages (OA-Mf).

S100A8/A9 drives monocytes towards M2-like macrophage differentiation and associates with M2-like macrophages in osteoarthritic synovium.

Objectives: Macrophages are key orchestrators of the osteoarthritis (OA)-associated inflammatory response. Macrophage phenotype is dependent on environmental cues like the inflammatory factor S100A8/A9. Here, we investigated how S100A9 exposure during monocyte-to-macrophage differentiation affects macrophage phenotype and function.

Inhibition of TLR4 signalling to dampen joint inflammation in osteoarthritis.

Local and systemic low-grade inflammation, mainly involving the innate immune system, plays an important role in the development of OA. A receptor playing a key role in initiation of this inflammation is the pattern-recognition receptor Toll-like receptor 4 (TLR4). In the joint, various ligands for TLR4, many of which are damage-associated molecular patterns (DAMPs), are present that can activate TLR4 signalling.

CD64 as novel molecular imaging marker for the characterization of synovitis in rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is one of the most prevalent and debilitating joint diseases worldwide. RA is characterized by synovial inflammation (synovitis), which is linked to the development of joint destruction. Magnetic resonance imaging and ultrasonography are widely being used to detect the presence and extent of synovitis.

S100A8/A9-alarmin promotes local myeloid-derived suppressor cell activation restricting severe autoimmune arthritis.

Immune-suppressive effects of myeloid-derived suppressor cells (MDSCs) are well characterized during anti-tumor immunity. The complex mechanisms promoting MDSC development and their regulatory effects during autoimmune diseases are less understood. We demonstrate that the endogenous alarmin S100A8/A9 reprograms myeloid cells to a T cell suppressing phenotype during autoimmune arthritis.

Early pain in females is linked to late pathological features in murine experimental osteoarthritis.

Background: Osteoarthritis (OA) is a progressive joint disease and a major cause of chronic pain in adults. The prevalence of OA is higher in female patients, who tend to have worse OA outcomes, partially due to pain. The association between joint pain and OA pathology is often inconclusive.

Identification of CD64 as a marker for the destructive potential of synovitis in osteoarthritis.

Objectives: OA is characterized by cartilage degeneration and persistent pain. The majority of OA patients present with synovitis, which is associated with increased cartilage damage. Activated synovial macrophages are key contributors to joint destruction.

Activation of circulating monocytes by low-density lipoprotein-a risk factor for osteoarthritis?

Synovial macrophages are key mediators of OA pathology, and skewing of macrophage phenotype in favour of an M1-like phenotype is thought to underlie the chronicity of synovial inflammation in OA. Components of the metabolic syndrome (MetS), such as dyslipidaemia, can affect macrophage phenotype and function, which could explain the link between MetS and OA development. Recently published studies have provided novel insights into the different origins and heterogeneity of synovial macrophages.

Identification of Transcription Factors Responsible for a Transforming Growth Factor-β-Driven Hypertrophy-like Phenotype in Human Osteoarthritic Chondrocytes.

During osteoarthritis (OA), hypertrophy-like chondrocytes contribute to the disease process. TGF-β's signaling pathways can contribute to a hypertrophy(-like) phenotype in chondrocytes, especially at high doses of TGF-β. In this study, we examine which transcription factors (TFs) are activated and involved in TGF-β-dependent induction of a hypertrophy-like phenotype in human OA chondrocytes.

Local inhibition of TGF-β1 signaling improves Th17/Treg balance but not joint pathology during experimental arthritis.

TGF-β1 is an important growth factor to promote the differentiation of T helper 17 (Th17) and regulatory T cells (Treg). The potential of TGF-β1 as therapeutic target in T cell-mediated diseases like rheumatoid arthritis (RA) is unclear. We investigated the effect of TGF-β1 inhibition on murine Th17 differentiation in vitro, on human RA synovial explants ex vivo, and on the development of experimental arthritis in vivo.

2 Deficiency Reduces Cartilage Damage and Ectopic Bone Formation in an Experimental Model for Osteoarthritis.

Osteoarthritis (OA) is a destructive disease of the joint with age and obesity being its most important risk factors. Around 50% of OA patients suffer from inflammation of the synovial joint capsule, which is characterized by increased abundance and activation of synovial macrophages that produce reactive oxygen species (ROS) via NADPH-oxidase 2 (NOX2). Both ROS and high blood levels of low-density lipoprotein (LDL) are implicated in OA pathophysiology, which may interact to form oxidized LDL (oxLDL) and thereby promote disease.

S100A8/A9 is not essential for the development of inflammation and joint pathology in interleukin-1 receptor antagonist knockout mice.

Background: Excessive osteoclast activity, which is strongly stimulated by pro-inflammatory mediators, results in bone and cartilage degeneration as central features of many arthritides. Levels of the alarmin S100A8/A9 and interleukin (IL)-1β are both increased in arthritis patients and correlate with disease activity and progression of tissue erosion. We previously presented S100A8/A9 as a good biomarker for joint inflammation and arthritis pathology under circumstances of high IL-1 signaling in mice that lack the gene encoding IL-1 receptor antagonist (Il1rn mice).

Osteoarthritis-Related Inflammation Blocks TGF-β's Protective Effect on Chondrocyte Hypertrophy via (de)Phosphorylation of the SMAD2/3 Linker Region.

Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases.

The role of inflammation in mesenchymal stromal cell therapy in osteoarthritis, perspectives for post-traumatic osteoarthritis: a review.

OA is a complex and highly prevalent degenerative disease affecting the whole joint, in which factors like genetic predisposition, gender, age, obesity and traumas contribute to joint destruction. ∼50-80% of OA patients develop synovitis. OA-associated risk factors contribute to joint instability and the release of cartilage matrix fragments, activating the synovium to release pro-inflammatory factors and catabolic enzymes in turn damaging the cartilage and creating a vicious circle.

Systemic overexpression of interleukin-22 induces the negative immune-regulator SOCS3 and potently reduces experimental arthritis in mice.

Objective: High levels of IL-22 are present in serum and synovial fluid of patients with RA. As both pro- and anti-inflammatory roles for IL-22 have been described in studies using animal models of RA, its exact function in arthritis remains poorly defined. With this study we aimed to further unravel the mechanism by which IL-22 exerts its effects and to decipher its therapeutic potential by overexpression of IL-22 either locally or systemically during experimental arthritis.

Selective Increment of Synovial Soluble TYRO3 Correlates with Disease Severity and Joint Inflammation in Patients with Rheumatoid Arthritis.

Objective: To investigate the role of TAM receptors in rheumatoid arthritis (RA) by determining synovial tissue TAM receptor expression, synovial fluid levels of soluble TAM receptors, and the relationship between soluble TAM receptors, joint inflammation and disease activity.

Methods: TAM receptor expression was determined by immunohistochemistry on the synovium from RA and osteoarthritis (OA) patients. Soluble (s) Tyro3, sAxl, sMer, and their ligand Gas6 were measured by ELISA in the synovial fluid of RA ( = 28) and OA ( = 12) patients and cytokine levels by multiplex immunoassay in RA samples.

The alarmins S100A8 and S100A9 mediate acute pain in experimental synovitis.

Background: Synovitis-associated pain is mediated by inflammatory factors that may include S100A8/9, which is able to stimulate nociceptive neurons via Toll-like receptor 4. In this study, we investigated the role of S100A9 in pain response during acute synovitis.

Methods: Acute synovitis was induced by streptococcal cell wall (SCW) injection in the knee joint of C57Bl/6 (WT) and S100A9 mice.

An optimized method for plasma extracellular vesicles isolation to exclude the copresence of biological drugs and plasma proteins which impairs their biological characterization.

Extracellular vesicles (EVs) are cell membrane-derived phospholipid bilayer nanostructures that contain bioactive proteins, enzymes, lipids and polymers of nucleotides. They play a role in intercellular communication and are present in body fluids. EVs can be isolated by methods like ultracentrifugation (UC), polyethylene-glycol-precipitation (PEG) or size exclusion chromatography (SEC).

Increase in the Number of Bone Marrow Osteoclast Precursors at Different Skeletal Sites, Particularly in Long Bone and Jaw Marrow in Mice Lacking IL-1RA.

Recently, it was shown that interleukin-1β (IL-1β) has diverse stimulatory effects on different murine long bone marrow osteoclast precursors (OCPs) in vitro. In this study, interleukin-1 receptor antagonist deficient () and wild-type (WT) mice were compared to investigate the effects of enhanced IL-1 signaling on the composition of OCPs in long bone, calvaria, vertebra, and jaw. Bone marrow cells were isolated from these sites and the percentage of early blast (CD31 Ly-6C), myeloid blast (CD31 Ly-6C), and monocyte (CD31 Ly-6C) OCPs was assessed by flow cytometry.

Elevation of inflammatory S100A8/S100A9 complexes in intracranial aneurysms.

Background: Inflammation-related factors might give further insight into the pathophysiology of vessel wall inflammation and intracranial aneurysm (IA) rupture. One of these factors is the protein complex S100A8/A9, which is released by neutrophils, monocytes, and activated macrophages and is known for its role in cardiovascular disease.

Objective: To determine if venous S100A8/A9 levels in patients with a ruptured IA (rIA) or unruptured IA (uIA) are elevated compared with a control group.

Galectin 3 Deficiency Alters Chondrocyte Primary Cilium Formation and Exacerbates Cartilage Destruction via Mitochondrial Apoptosis.

Mechanical overload and aging are the main risk factors of osteoarthritis (OA). Galectin 3 (GAL3) is important in the formation of primary cilia, organelles that are able to sense mechanical stress. The objectives were to evaluate the role of GAL3 in chondrocyte primary cilium formation and in OA in mice.

Correction: Supplementation of diet with non-digestible oligosaccharides alters the intestinal microbiota, but not arthritis development, in IL-1 receptor antagonist deficient mice.

[This corrects the article DOI: 10.1371/journal.pone.

Macrophage-Derived Extracellular Vesicles as Carriers of Alarmins and Their Potential Involvement in Bone Homeostasis.

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures, which facilitate intercellular communication. Recent studies have highlighted the importance of extracellular vesicles in bone homeostasis, as mediators of crosstalk between different bone-resident cells. Osteoblasts and osteoclasts are capable of releasing various types of extracellular vesicles that promote both osteogenesis, as well as, osteoclastogenesis, maintaining bone homeostasis.

Supplementation of diet with non-digestible oligosaccharides alters the intestinal microbiota, but not arthritis development, in IL-1 receptor antagonist deficient mice.

The intestinal microbiome is perturbed in patients with new-onset and chronic autoimmune inflammatory arthritis. Recent studies in mouse models suggest that development and progression of autoimmune arthritis is highly affected by the intestinal microbiome. This makes modulation of the intestinal microbiota an interesting novel approach to suppress inflammatory arthritis.

The alarmin S100A9 hampers osteoclast differentiation from human circulating precursors by reducing the expression of RANK.

The alarmin S100A8/A9 is implicated in sterile inflammation-induced bone resorption and has been shown to increase the bone-resorptive capacity of mature osteoclasts. Here, we investigated the effects of S100A9 on osteoclast differentiation from human CD14 circulating precursors. Hereto, human CD14 monocytes were isolated and differentiated toward osteoclasts with M-CSF and receptor activator of NF-κB (RANK) ligand (RANKL) in the presence or absence of S100A9.