Bona fide dendritic cells are pivotal precursors for osteoclasts.

Objectives: Osteoclasts (OCs) are myeloid-derived multinucleated cells uniquely able to degrade bone. However, the exact nature of their myeloid precursors is not yet defined.

Methods: CD11c-diphtheria toxin receptor (CD11cDTR) transgenic mice were treated with diphtheria toxin (DT) or phosphate buffered saline (PBS) during serum transfer arthritis (STA) and human tumour necrosis factor transgenic (hTNFtg) arthritis and scored clinically and histologically.

Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss.

Aims: Insufficient treatment response in rheumatoid arthritis (RA) patients requires novel treatment strategies to halt disease progression. The potential benefit of combination of cytokine-inhibitors in RA is still unclear and needs further investigation. To explore the impact of combined deficiency of two major cytokines, namely interleukin (IL)-1 and IL-6, in this study double deficient mice for IL-1αβ and IL-6 were investigated in different tumour necrosis factor (TNF)-driven inflammatory bone disorders, namely peripheral arthritis and sacroiliitis, as well as systemic bone loss.

Additional heterologous versus homologous booster vaccination in immunosuppressed patients without SARS-CoV-2 antibody seroconversion after primary mRNA vaccination: a randomised controlled trial.

Objectives: SARS-CoV-2-induced COVID-19 has led to exponentially rising mortality, particularly in immunosuppressed patients, who inadequately respond to conventional COVID-19 vaccination.

Methods: In this blinded randomised clinical trial, we compare the efficacy and safety of an additional booster vaccination with a vector versus mRNA vaccine in non-seroconverted patients. We assigned 60 patients under rituximab treatment, who did not seroconvert after their primary mRNA vaccination with either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), to receive a third dose, either using the same mRNA or the vector vaccine ChAdOx1 nCoV-19 (Oxford-AstraZeneca).

Hyposmia Is Associated with Reduced Cognitive Function in COVID-19: First Preliminary Results.

Background: Hyposmia is frequently reported as an initial symptom in coronavirus disease 2019 (COVID-19).

Objective: As hyposmia accompanies cognitive impairment in several neurological disorders, we aimed to study whether hyposmia represents a clinical biomarker for both neurological involvement and cognitive impairment in mild CO-VID-19. We aimed to study whether olfactory dysfunction (OD) represents a clinical biomarker for both neurological involvement and cognitive impairment in mild COVID-19.

MicroRNA-155 Controls T Helper Cell Activation During Viral Infection.

MicroRNA (miR) 155 has been implicated in the regulation of innate and adaptive immunity as well as autoimmune processes. Importantly, it has been shown to regulate several antiviral responses, but its contribution to the immune response against cytopathic viruses such as vesicular stomatitis virus (VSV) infections is not known. Using transgenic/recombinant VSV expressing ovalbumin, we show that miR-155 is crucially involved in regulating the T helper cell response against this virus.

Multimodal [ F]FDG PET/CT Is a Direct Readout for Inflammatory Bone Repair: A Longitudinal Study in TNFα Transgenic Mice.

In rheumatoid arthritis (RA), chronic joint inflammation leading to bone and cartilage damage is the major cause of functional impairment. Whereas reduction of synovitis and blockade of joint damage can be successfully achieved by disease modifying antirheumatic therapies, bone repair upon therapeutic interventions has only been rarely reported. The aim of this study was to use fluorodeoxyglucose ([ F]FDG) and [ F]fluoride µPET/CT imaging to monitor systemic inflammatory and destructive bone remodeling processes as well as potential bone repair in an established mouse model of chronic inflammatory, erosive polyarthritis.

Functional consultation and exercises improve grip strength in osteoarthritis of the hand - a randomised controlled trial.

Background: Evidence for non-pharmacological interventions in hand osteoarthritis is promising but still scarce. Combined interventions are most likely to best cover the clinical needs of patients with hand osteoarthritis (OA). The aim of this study was to evaluate the effect of a combined, interdisciplinary intervention feasible in both primary and specialist care compared to routine care plus placebo in patients with hand OA.

Non-classical monocytes as mediators of tissue destruction in arthritis.

Objectives: Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive.

Methods: We investigated CCR2 mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage.

MicroRNA-146a governs fibroblast activation and joint pathology in arthritis.

Synovial fibroblasts are key cells orchestrating the inflammatory response in arthritis. Here we demonstrate that loss of miR-146a, a key epigenetic regulator of the innate immune response, leads to increased joint destruction in a TNF-driven model of arthritis by specifically regulating the behavior of synovial fibroblasts. Absence of miR-146a in synovial fibroblasts display a highly deregulated gene expression pattern and enhanced proliferation in vitro and in vivo.

Cartilage damage and bone erosion are more prominent determinants of functional impairment in longstanding experimental arthritis than synovial inflammation.

Chronic inflammation of articular joints causing bone and cartilage destruction consequently leads to functional impairment or loss of mobility in affected joints from individuals affected by rheumatoid arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes does not lead to full reversal of joint functionality, pointing to the crucial contribution of irreversibly damaged structural components, such as bone and cartilage, to restricted joint mobility. In this context, we investigated the impact of the distinct components, including synovial inflammation, bone erosion or cartilage damage, as well as the effect of blocking tumor necrosis factor (TNF) on functional impairment in human-TNF transgenic (hTNFtg) mice, a chronic inflammatory erosive animal model of RA.

Interface Management between General Practitioners and Rheumatologists-Results of a Survey Defining a Concept for Future Joint Recommendations.

Objective: To measure the views of general practitioners (GPs) and rheumatologists in a nationwide evaluation, so as to optimise their cooperation in managing patients with inflammatory rheumatic diseases.

Methods: A questionnaire covering aspects of collaboration was sent, both by mail and/or by email, to all GPs and rheumatologists in Austria. Topics covered were (i) examinations and interventions to be performed before referral, (ii) the spectrum of diseases to be referred, and (iii) the role of GPs in follow-up and continuous management of patients.

Phosphatase and tensin homolog (PTEN) in antigen-presenting cells controls Th17-mediated autoimmune arthritis.

Introduction: Autoreactive T cells are a central element in many systemic autoimmune diseases. The generation of these pathogenic T cells is instructed by antigen-presenting cells (APCs). However, signaling pathways in APCs that drive autoimmune diseases, such as rheumatoid arthritis, are not understood.

Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice.

Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-β (TGF-β) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene (Mstn) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration. However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone.

Effects of cilengitide in osteoclast maturation and behavior.

Bone metastasis is a common burden in many types of cancer and has a severe impact on the quality of life in patients. Hence, specific therapeutic strategies inhibiting tumor induced osteolysis are urgently needed. In this study, we aimed to interfere with integrin adhesion receptors, which are central players of the bone resorption process.

Nicotinic acetylcholine receptors modulate osteoclastogenesis.

Background: Our aim was to investigate the role of nicotinic acetylcholine receptors (nAChRs) in in-vitro osteoclastogenesis and in in-vivo bone homeostasis.

Methods: The presence of nAChR subunits as well as the in-vitro effects of nAChR agonists were investigated by ex vivo osteoclastogenesis assays, real-time polymerase chain reaction, Western blot and flow cytometry in murine bone marrow-derived macrophages differentiated in the presence of recombinant receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The bone phenotype of mice lacking various nAChR subunits was investigated by peripheral quantitative computed tomography and histomorphometric analysis.

Mechanisms of tissue damage in arthritis.

The destruction of articular structures in the course of inflammatory arthritides such as rheumatoid arthritis (RA) or seronegative spondyloarthropathies is the most serious direct consequence of these diseases. Indeed, joint damage constitutes the "organ damage" of RA and-just like in all other diseases with organ involvement-such damage will usually be irreversible, cause permanent loss of function and subsequent disability. Research has identified a number of mechanisms and mediators of damage to articular structures such as bone and cartilage, ranging from proinflammatory cytokines, signal transduction pathways and cells types, which will be discussed in this review.

FHL2 regulates the resolution of tissue damage in chronic inflammatory arthritis.

Objective: We analysed the role of the adaptor molecule four-and-a-half Lin11, Isl-1 & Mec-3 (LIM) domain protein 2 (FHL2) in the activation of fibroblast-like synoviocytes in human rheumatoid arthritis (RA) and tumour necrosis factor α (TNFα)-dependent animal models of the disease.

Methods: Synovial tissues of patients with RA and osteoarthritis (OA) as well as hind paw sections from arthritic human TNFα transgenic (hTNFtg) mice and synovial fibroblasts from these were analysed. The effects of cytokines on the expression of FHL2 and disease-relevant matrixmetalloproteases (MMPs) were determined.

Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells.

Objective: Local bone destruction in rheumatic diseases, which often leads to disability and severely reduced quality of life, is almost exclusively mediated by osteoclasts. Therefore, it is important to understand pathways regulating the generation of osteoclasts. Here, we analysed the impact of the Phosphoinositide-3-Kinase (PI3K)/Phosphatase and tensin homolog (PTEN) axis on osteoclast generation and bone biology under basal and inflammatory conditions.

Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force.

Background: Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA).

Objective: To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy.

Tumor necrosis factor-inhibiting therapy preferentially targets bone destruction but not synovial inflammation in a tumor necrosis factor-driven model of rheumatoid arthritis.

Objective: To investigate how tumor necrosis factor (TNF)-inhibiting therapy affects bone destruction and inflammation in a TNF-driven mouse model of rheumatoid arthritis.

Methods: In order to evaluate the influence of TNF on osteoclastogenesis in vitro, different concentrations of TNF were added to spleen cell-derived monocytes in the absence or presence of different concentrations of RANKL. In addition, the effects of TNF inhibition on osteoclast precursors as well as local bone destruction in vivo were assessed by treating TNF-transgenic mice with different doses of adalimumab.

Economic burden of osteoporotic fractures in Austria.

Objective: Osteoporotic fractures impose a huge economic burden on society. Though several cost of illness studies from other countries exist, no equivalent study has been conducted in Austria. Our study aims at assessing costs resulting from osteoporotic fractures in Austria in the year 2008 from a societal perspective.

Relationship between inflammation, bone destruction, and osteoproliferation in the HLA-B27/human β2 -microglobulin-transgenic rat model of spondylarthritis.

Objective: Inhibition of inflammation and destruction, but not of osteoproliferation, in patients with spondylarthritis (SpA) treated with anti-tumor necrosis factor raises the question of how these three processes are interrelated. This study was undertaken to analyze this relationship in a rat model of SpA.

Methods: Histologic spine and joint samples from HLA-B27/human β(2) -microglobulin (hβ(2) m)-transgenic rats were analyzed for signs of spondylitis and destructive arthritis and semiquantitatively scored as showing mild, moderate, or severe inflammation.

Targeting TNF receptors in rheumatoid arthritis.

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine that signals through two distinct receptors, TNFR1 and TNFR2. TNF is essentially involved in the pathogenesis of various inflammatory and autoimmune diseases. Blocking TNF, in turn, has been proven to be highly effective in treating a variety of diseases.

The pathogenesis of rheumatoid arthritis: new insights from old clinical data?

Despite their different targets, biologic agents used for blockade of TNF and IL-6, inhibition of T-cell co-stimulation and B-cell depletion all have similar beneficial effects on the outcome of rheumatoid arthritis (RA). This observation raises questions as to whether the targets of these therapies might all be involved in a common pathogenetic pathway. However, blockade of TNF and IL-6 has a similar inhibitory effect on joint damage progression in patients with either early or late disease.

Inflammatory bone loss: pathogenesis and therapeutic intervention.

Bone is a tissue undergoing continuous building and degradation. This remodelling is a tightly regulated process that can be disturbed by many factors, particularly hormonal changes. Chronic inflammation can also perturb bone metabolism and promote increased bone loss.