Jochen Zwerina

Mechanisms of Disease: the link between RANKL and arthritic bone disease.

Chronic inflammation and bone loss are closely linked pathophysiologic events. The most typical example of inflammatory bone loss is seen in patients with rheumatoid arthritis who develop systemic osteopenia as well as local breakdown of bone in the direct vicinity of inflamed joints. Understanding the mechanisms of arthritic bone degradation is crucial for designing therapies that can specifically protect joints from structural damage. Since osteoclast differentiation and activity are key events in arthritic bone damage, the signals that trigger osteoclastogenesis are potential therapeutic targets. Receptor activator of nuclear factor-κB (RANK) is activated by its ligand, RANKL, an essential molecule for osteoclast development: in the absence of RANKL or RANK, osteoclast differentiation from monocyte precursors does not occur. RANKL is expressed on T cells and fibroblasts within the synovial inflammatory tissue of patients with RA and its expression is regulated by proinflammatory cytokines. In animal models of arthritis, blockade of RANKL–RANK interactions, or a genetic absence of RANKL or RANK, protects against joint damage despite the presence of joint inflammation. Therefore, inhibition of RANKL is regarded as a promising future strategy for inhibiting inflammatory bone loss in patients with chronic inflammatory arthritis.

Pathogenesis of Rheumatoid Arthritis: Targeting Cytokines

Abstract: Although considerable progress has been made by adequate treatment with traditional disease‐modifying antirheumatic drugs (DMARDs), therapy of rheumatoid arthritis (RA) still remains difficult. The discovery of the importance of cytokines such as tumor necrosis factor (TNF), interleukin‐1 (IL‐1), interleukin‐6 (IL‐6), and interleukin‐15 (IL‐15), which are also stimulated by consequences of autoimmune responses, has led to the development of anticytokine therapies (“biologicals”). Blocking TNF or also, to some extent, IL‐1 has proved beneficial in DMARD‐resistant RA patients in multiple clinical trials. Along with clinical improvement, TNF blockade has been shown to halt radiographic disease progression, a major risk factor for disability. Recently, clinical trials have shown a significant therapeutic benefit of biological inhibitors of IL‐6, and also of IL‐15, with an efficacy comparable to that of TNF blockers. All these agents are particularly efficacious when combined with methotrexate. Although clinical remission is difficult to achieve even with anticytokine treatment, these drugs offer the potential to decrease disease activity and improve quality of life in a majority of RA patients, and it is conceivable that combinations of biological therapies may pave the path to even better success, which ultimately is remission or even cure.

Heme oxygenase 1 (HO-1) regulates osteoclastogenesis and bone resorption

Heme oxygenase 1 (HO‐1) plays an important role in vascular disease, transplantation, and inflammation. In animal models of acute and chronic inflammation, induction of HO‐1 has anti‐inflammatory and cytoprotective properties. Since inflammation is an important trigger of osteoclastogenesis, we hypothesized that HO‐1 might influence osteoclastogenesis. We investigated the effects of induction of HO‐1 on osteoclast formation in vitro and in vivo. Furthermore, we addressed the role of HO‐1 in inflammatory bone loss in humans. When HO‐1 was induced by hemin in vitro, a significant dose‐dependent inhibition of osteoclastogenesis was observed. Up‐regulation of HO‐1 was mediated by activation of MAPK and primarily prevented differentiation of osteoclast precursors to osteoclasts, whereas it did not affect mature osteoclasts. Anti‐osteoclastogenic properties of hemin were based on a down‐regulation of c‐fms, RANK, TRAF‐6, and c‐fos. In addition, induction of HO‐1 inhibited TNF‐triggered osteoclast differentiation in vitro as well as LPS‐driven inflammatory bone loss in vivo. Furthermore, HO‐1 induction suppressed osteoclastogenesis and bone destruction in a TNF‐mediated arthritis. In line, assessment of synovial tissue from rheumatoid arthritis patients revealed that osteoclasts are usually HO‐1 negative. Moreover, serum levels of bilirubin, a metabolite of HO‐1, were elevated in rheumatoid arthritis patients without bone damage, suggesting HO‐1 affects bone loss in humans. In summary, these data indicate that HO‐1 negatively regulates osteoclastogenesis, leading to a positive net balance of bone.

Pro-inflammatory cytokines in rheumatoid arthritis: pathogenetic and therapeutic aspects.

Therapy of rheumatoid arthritis (RA) aims at interfering with the disease process, namely inflammation and destruction of the joints, and thus at preventing long-term disability. Proinflammatory cytokines play a decisive role in the generation of the inflammatory and destructive response. Aside from traditional disease-modifying anti-rheumatic drugs and tumor necrosis factor-blocking agents, a number of targeted therapies are currently in evaluation, such as abatacept (interfering with co-stimulation), rituximab (an anti-B-cell agent) and tocilizumab (an anti-interleukin-6 receptor antibody). In phase II trials, all these agents have resulted in significant clinical improvement, and phase III trials have been partly completed with similar results and are partly on the way. Because none of these agents lead to good clinical responses in all patients and many patients have only relatively low degrees of response, it will still be a challenge to find the best therapeutic paths to combat the “inflammatory house of cards” of RA.

Imbalance of local bone metabolism in inflammatory arthritis and its reversal upon tumor necrosis factor blockade: direct analysis of bone turnover in murine arthritis

Chronic arthritis typically leads to loss of periarticular bone, which results from an imbalance between bone formation and bone resorption. Recent research has focused on the role of osteoclastogenesis and bone resorption in arthritis. Bone resorption cannot be observed isolated, however, since it is closely linked to bone formation and altered bone formation may also affect inflammatory bone loss. To simultaneously assess bone resorption and bone formation in inflammatory arthritis, we developed a histological technique that allows visualization of osteoblast function by in-situ hybridization for osteocalcin and osteoclast function by histochemistry for tartrate-resistant acid phosphatase. Paw sections from human tumor necrosis factor transgenic mice, which develop an erosive arthritis, were analyzed at three different skeletal sites: subchondral bone erosions, adjacent cortical bone channels, and endosteal regions distant from bone erosions. In subchondral bone erosions, osteoclasts were far more common than osteoblasts. In contrast, cortical bone channels underneath subchondral bone erosions showed an accumulation of osteoclasts but also of functional osteoblasts resembling a status of high bone turnover. In contrast, more distant skeletal sites showed only very low bone turnover with few scattered osteoclasts and osteoblasts. Within subchondral bone erosions, osteoclasts populated the subchondral as well as the inner wall, whereas osteoblasts were almost exclusively found along the cortical surface. Blockade of tumor necrosis factor reversed the negative balance of bone turnover, leading to a reduction of osteoclast numbers and enhanced osteoblast numbers, whereas the blockade of osteoclastogenesis by osteoprotegerin also abrogated the osteoblastic response. These data indicate that bone resorption dominates at skeletal sites close to synovial inflammatory tissue, whereas bone formation is induced at more distant sites attempting to counter-regulate bone resorption.

An Incidentally Found Inflamed Uterine Myoma Causing Low Abdominal Pain, Using Tc-99m-Tektrotyd Single Photon Emission Computed Tomography-CT Hybrid Imaging

We report the case of a 50-year-old woman presented with a history of right hemicolectomy due to an ileocecal neuroendocrine tumor and left breast metastasis. Owing to a slightly elevated chromogranin A-level and lower abdominal pain, single photon emission computed tomography-computer tomography (SPECT-CT) was performed. There were no signs of recurrence on the SPECT-CT scan, but the patient was incidentally found to have an inflamed intramural myoma. We believe that the slightly elevated chromogranin A-level was caused by the hypertension that the patient presented. In the clinical context, this is a report of an inflamed uterine myoma seen as a false positive result detected by TC-99m-Tc-EDDA/HYNIC-Tyr3-Octreotide (Tektrotyd) SPECT-CT hybrid imaging.

Acoustic Structure Quantification Analysis of the Thyroid in Patients with Diffuse Autoimmune Thyroid Disease

The aim of this study was to assess whether acoustic structure quantification (ASQ) can differentiate normal from pathological thyroid parenchyma in patients with diffuse autoimmune thyroid disease (AITD). We evaluated 83 subjects (72 [87%] women and 11 [13%] men) aged 19 to 94 years with a mean age of 53 years. We performed a prospective study (from March 2011 to November 2014) that included 43 (52%) patients with chronic autoimmune thyroiditis (CAT), 22 (26%) patients with Graves’ disease (GD), and 18 (22%) healthy volunteers. The ASQ values were significantly lower in normal subjects than in subjects with CAT and GD (p < 0.001). In contrast, the differences between the GD and the CAT patients (p = 0.23) were not statistically significant. The optimal cutoff ASQ value for which the sum of sensitivity and specificity was the highest for the prediction of diffuse thyroid pathology was 103 (95% confidence interval = [0.79, 0.95]). At this cutoff value, the sensitivity was 83% and the specificity was 89%. Our findings suggest that ASQ is a useful method for the assessment of the thyroid in patients with AITD.

Arthritis induces lymphocytic bone marrow inflammation and endosteal bone formation

UNLABELLED Arthritis can destroy the cortical bone barrier and expose bone marrow to synovial tissue. This study examines bone marrow changes in arthritis and its effects on cortical bone remodeling. Bone marrow next to arthritic lesions exhibits B-lymphocyte-rich infiltrates, which express BMPs and stimulate endosteal bone formation. Thus, bone marrow actively participates in the arthritic process. INTRODUCTION Imaging studies have shown that bone marrow changes occur in patients with rheumatoid arthritis (RA). To examine whether bone marrow is affected during arthritis, human TNF transgenic (hTNFtg) mice, which constitute an established animal model of human RA, were examined for bone marrow changes. MATERIALS AND METHODS The hind paws (tarsal area) of 22 untreated hTNFtg mice, 5 hTNFtg mice treated with anti-TNF (infliximab), and 5 wildtype (WT) mice were examined histologically, immunohistochemically, and by means of mRNA in situ hybridization. RESULTS AND CONCLUSIONS All untreated hTNFtg mice with moderate (n = 10) and severe (n = 7) disease developed inflammatory bone marrow lesions during the course of disease, whereas no such lesions appeared in hTNFtg mice with mild disease (n = 5) and WT mice. Bone marrow infiltrates were almost exclusively composed of lymphocytes, and the overwhelming proportion (>80%) was B-cells. Presence and extent of bone marrow infiltrates were closely linked to severity of arthritis. In addition, blockade of TNF effectively reduced bone marrow inflammation. Interestingly, osteoblast numbers were increased at the endosteal surface in the vicinity of these lesions. Moreover, osteoid deposition; expression of bone matrix proteins, such as osteocalcin and osteopontin; and mineralization were enhanced, suggesting that inflammatory bone marrow infiltrates induce bone formation. Indeed, B-lymphocytes of these lesions expressed bone morphogenetic protein (BMP)-6 and -7, which are important stimulators of new bone formation. Thus, we conclude that bone marrow actively participates in destructive arthritis by generating B-lymphocyte-rich bone marrow lesions and inducing endosteal bone formation.