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The research consortium Neuroimmunology and Pain (Neuroimpa) explores the importance of the relationships between the immune system and the nervous system in musculoskeletal diseases for the generation of pain and for the course of fracture healing and arthritis.The spectrum of methods includes analyses at the single cell level, in vivo models of arthritis and fracture healing, imaging studies on brain function in animals and humans and analysis of data from patients.Proinflammatory cytokines significantly contribute to the generation of joint pain through neuronal cytokine receptors. Immune cells release opioid peptides which activate opioid receptors at peripheral nociceptors and thereby evoke hypoalgesia. The formation of new bone after fractures is significantly supported by the nervous system. The sympathetic nervous system promotes the development of immune-mediated arthritis. The studies show a significant analgesic potential of the neutralization of proinflammatory cytokines and of opioids which selectively inhibit peripheral neurons. Furthermore, they show that the modulation of neuronal mechanisms can beneficially influence the course of musculoskeletal diseases.Interventions in the interactions between the immune system and the nervous system hold a great therapeutic potential for the treatment of musculoskeletal diseases and pain.

Objectives:The viral gene transfer of interleukin 1 receptor antagonist (IL1ra) and interleukin 10 (IL10) into rheumatoid arthritis (RA) synovial fibroblasts (RASFs) has shown protective effects on cartilage destruction in the severe combined immunodeficiency (SCID) mouse model of RA. Nevertheless, side effects of viral transduction are possible and a number of cytokines or cytokine inhibitors are not available encoded in viral vehicles. As the production of viruses coding for bioactive proteins is cost and time intensive, we established an in vivo long-term release model using osmotic minipumps in the SCID mouse model for RA.Methods:Isolated RASFs were cultured for four passages and coimplanted together with human cartilage and an Alzet osmotic miniature pump model 2004, containing 200 μl of IL10 and IL1ra for 40 days in SCID mice. Implants were removed after 40 days and evaluated histologically. The actual rates of IL10 and IL1ra in murine serum were measured by ELISA.Results:Release of IL10 and IL1ra by the pumps was effective as both could be measured in significant amounts in the serum of the mice. IL10 and IL1ra release showed protective effects towards the coimplanted cartilage, similar to the adenovirally IL10/IL1ra-transduced RASFs. The mean (SD) invasion scores for the implants with the osmotic pumps were: invasion 0.7 (0.5), degradation 0.5 (0.3) (all parameters significant vs controls, pConclusions:The results demonstrate that the combination of osmotic pumps with the SCID mouse model for RA can be used as approach for application and evaluation of cartilage-protective molecules. Furthermore, the effect of cartilage-protective cytokines is independent of the type of application.

Molecular imaging is a rapidly emerging field in biomedical research, aiming at the visualization, characterization and quantification of molecular and cellular processes non-invasively within intact living organisms. To sense biological processes such as gene expression, angiogenesis, apoptosis or cell trafficking in vivo, imaging reporter agents that interact specifically with molecular targets and appropriate imaging systems are currently under development. In rheumatoid arthritis, these novel tools will be used to evaluate physiological and pathophysiological processes, to facilitate diagnosis and monitor therapeutic regimens, to enable reliable prognosis and to support the development of new therapies. In this review, we summarize the basic principles of molecular imaging, such as the development of molecular imaging agents, the actual capabilities of different imaging modalities and the most recent advances in molecular imaging, demonstrating the potential of this technology. With regard to their applicability in rheumatic diseases, we discuss potential molecular targets, current experimental approaches and the future prospects for molecular imaging in rheumatoid arthritis.