[Rheumatoid arthritis]. / Rheumatoide Arthritis.

Rheumatoid arthritis (RA) is a chronic and progressive systemic disease of the connective tissue, which is particularly manifested with destructive alterations to the joints. Inflammatory reactions in the synovium lead to the influx of peripheral inflammatory cells as well as the activation of local cells. Released growth factors, chemokines and especially cytokines play a key role in chronic inflammatory responses. In addition to the central lymphocytes, the T and B cells and their subpopulations, locally resident cells, such as neutrophils, macrophages and fibroblasts as well as cells of bone metabolism are activated by the inflammatory milieu and contribute to and drive inflammation and tissue damage. The destruction of cartilage and bone substance by local tissue cells, synovial fibroblasts and osteoclasts is characteristic for this disease. Untreated, the local inflammatory and destructive processes as well as systemic inflammatory factors lead to progressive and irreversible joint destruction. Cellular and immunological processes in RA are closely interwoven; therefore, besides the general inhibition of immunological processes, specific inhibition of central key molecules can reduce or completely stop the inflammatory destructive processes; however, a high heterogeneity can be observed among RA patients and disease progression. Therefore, an expansion of the therapeutic options is desirable as not all patients are able to equally benefit from the therapeutic treatment. It is important to characterize new molecular mechanisms, which could lead to the development of new therapeutic options. Some of the more recent insights are summarized in this overview.

Visfatin alters the cytokine and matrix-degrading enzyme profile during osteogenic and adipogenic MSC differentiation.

OBJECTIVES: Age-related bone loss is associated with bone marrow adiposity. Adipokines (e.g., visfatin, resistin, leptin) are adipocyte-derived factors with immunomodulatory properties and might influence differentiation of bone marrow-derived mesenchymal stem cells (MSC) in osteoarthritis (OA) and osteoporosis (OP). Thus, the presence of adipokines and MMPs in bone marrow and their effects on MSC differentiation were analyzed. METHODS: MSC and ribonucleic acid (RNA) were isolated from femoral heads after hip replacement surgery of OA or osteoporotic femoral neck fracture (FF) patients. Bone structural parameters were evaluated by microcomputed tomography (µCT). MSC were differentiated towards adipocytes or osteoblasts with/without adipokines. Gene expression (adipokines, bone marker genes, MMPs, TIMPs) and cytokine production was evaluated by realtime-polymerase chain reaction (realtime-PCR) and enzyme-linked immunosorbent assay (ELISA). Matrix mineralization was quantified using Alizarin red S staining. RESULTS: µCT showed an osteoporotic phenotype of FF compared to OA bone (reduced trabecular thickness and increased ratio of bone surface vs volume of solid bone). Visfatin and leptin were increased in FF vs OA. Visfatin induced the secretion of IL-6, IL-8, and MCP-1 during osteogenic and adipogenic differentiation. In contrast to resistin and leptin, visfatin increased MMP2 and MMP13 during adipogenesis. In osteogenically differentiated cells, MMPs and TIMPs were reduced by visfatin. Visfatin significantly increased matrix mineralization during osteogenesis, whereas collagen type I expression was reduced. CONCLUSION: Visfatin-mediated increase of matrix mineralization and reduced collagen type I expression could contribute to bone fragility. Visfatin is involved in impaired bone remodeling at the adipose tissue/bone interface through induction of proinflammatory factors and dysregulated MMP/TIMP balance during MSC differentiation.

[Inflammation and bone : Osteoimmunological aspects]. / Entzündung und Knochen : Osteoimmunologische Aspekte.

Microscopic fractures (so-called microcracks) or traumatic macrofractures require bone, as the basic scaffold of the human body, to have a high regenerative capability. In order to be able to provide this regenerative capability, bone is in a constant process of remodeling. This finely tuned homeostasis of bone formation and degradation can become disrupted, which leads to osteoporosis or other bone disorders. It has been shown that the immune system is substantially involved in the regulation of bone homeostasis and that chronic inflammation in particular can disturb this balance; therefore, this article reviews the osteoimmunological aspects contributing to osteoporosis and other diseases associated with bone degradation.

[Inflammation and bone metabolism]. / Entzündung und Knochenmetabolismus.

A finely balanced relationship between bone resorption and bone formation is characteristic for a healthy bone metabolism. Osteoblasts are responsible for bone formation and osteoclasts for bone resorption. In general inflammatory and in particular chronic inflammatory processes influence osteoblast and osteoclast function directly or via indirect mechanisms. Bone metabolism can be influenced by the interaction of cytokines, hormones and growth factors with bone cells. A central factor involved in bone metabolism is the receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, which is influenced by different inflammatory processes. Usually, (chronic) inflammation results in increased bone loss. The molecular mechanisms and pathophysiological pathways of bone metabolism under the influence of inflammation are summarized in this review.

[Intracellular signaling transduction pathways. Potential targets in the treatment of rheumatic diseases]. / Intrazelluläre Signaltransduktionswege. Potenzielle Angriffspunkte für rheumatologische Therapeutika.

Even though biologics, frequently combined with conventional DMARD therapy, represent a significant advance in the treatment of rheumatic diseases, they have disadvantages such as high costs of production and parenteral administration. Therefore, oral small-molecule drugs are a potential alternative. Major targets for such small-molecule therapeutics are intracellular signaling molecules. This article will briefly discuss potential intracellular targets for therapeutics in the field of rheumatic diseases. How therapeutic signaling inhibitors will be used in clinical practice will depend on a number of factors: their overall effectiveness, their effectiveness in patients who did not or insufficiently respond to conventional DMARD therapy and/or treatment with biologics, their effectiveness when combined with other therapeutics, their side effects, and their cost-benefit ratio.The English full-text version of this article is available at SpringerLink (under "Supplemental").

Expression and function of ETA and ETB receptors in SSc.

Endothelin (ET) receptors are widely expressed within the human body with one of their major functions being regulation of the vascular tone. Pulmonary arterial hypertension and other complications associated with SSc are related to the function and or dysregulation of these receptors. As ET receptors also play a crucial role in SSc, this review will discuss the expression and physiological functions of ET receptors in the human organism, their signalling pathways, the complications of diseases they are associated with and their importance as a therapeutic target in SSc.

A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy.

OBJECTIVE: To investigate the analgesic efficacy of lamotrigine in the treatment of painful HIV-associated distal sensory polyneuropathy (DSP). BACKGROUND: The pathogenesis of HIV-associated DSP is unknown and there is no effective treatment. A novel anticonvulsant, lamotrigine, blocks voltage-sensitive sodium channels and inhibits the release of glutamate and aspartate. There have been anecdotal reports of efficacy of lamotrigine in the treatment of painful neuropathy and trigeminal neuralgia. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study, lamotrigine was initiated at 25 mg per day and slowly titrated over 7 weeks to 300 mg per day. Study duration was 14 weeks. The primary outcome measure was change in pain on the modified Gracely scale with secondary outcome measures including change in neurologic examination, use of concomitant analgesic medications, and global pain relief. RESULTS: Of 42 enrolled subjects, 13 did not complete the 14-week study endpoint. In five of these, rash was the cause for dropout. In the remaining 29 evaluable subjects, 20 patients received placebo and 9 received lamotrigine. The pain scores at baseline were not significantly different. The reduction in average pain from baseline to week 14 was greater (p = 0.03) in the lamotrigine group (-0.55) than in the placebo group (-0.18), adjusting for baseline levels of pain. There was no difference between the groups on the change in peak worst pain. CONCLUSIONS: In this small trial, lamotrigine showed promise in the treatment of pain associated with HIV-related DSP. The frequency of rash was greater than in lamotrigine studies in epilepsy. A larger controlled study of lamotrigine is warranted.