1. |
- Bersellini Farinotti, Alex, et al.
(author)
-
Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons
- 2019
-
In: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 216:8, s. 1904-1924
-
Journal article (peer-reviewed)abstract
- Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.
|
|
2. |
- Steinz, Maarten M, et al.
(author)
-
Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis
- 2019
-
In: JCI Insight. - : American Society for Clinical Investigation (ASCI). - 2379-3708 .- 2324-7703 .- 2325-4556. ; 4:9
-
Journal article (peer-reviewed)abstract
- Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here, we show that oxidative posttranslational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde (MDA) adduct modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located in 3 distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritic mice and patients with RA. Moreover, molecular dynamics simulations revealed that these areas, here coined "hotspots," are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and may provide novel leads for targeted therapeutic treatment to improve muscle function.
|
|
3. |
- Ängeby Möller, Kristina
(author)
-
Studies on the role of NGF in arthritis-induced pain transmission using gait and weight bearing as outcome measures
- 2019
-
Doctoral thesis (other academic/artistic)abstract
- Pain is one of the most common reasons for seeking healthcare, with approximately forty percent of those suffering from chronic pain having joint pain. Osteoarthritis is the most common cause of joint pain, but currently there are few treatments available. The search for new, effective pain treatment has been mostly unsuccessful, in spite of the discovery of mechanisms that are involved in the transmission of nociceptive signals from the periphery to the central nervous system where pain is experienced. This work focuses on the evaluation of rodent joint pain models, the behavioural manifestations of the injuries, and the possibility to detect treatment effects in these models. Three models have been evaluated in rats; intra-articular injection of carrageenan, Freund´s complete adjuvant (CFA), and monoiodoacetate (MIA) into one hind leg. In mice, two models have been evaluated; intra-articular injection of CFA, and the surgical model of anterior cruciate ligament transection (ACLT). Carrageenan injection resulted in an acute, robust inflammation, CFA injection caused a more long-lasting strong joint inflammation, and MIA injection resulted in an almost complete loss of joint cartilage after a few weeks. The model more resembling osteoarthritis was the surgical model, ACLT, which gave severe cartilage degeneration, osteophytes, and pathophysiological changes in synovia and ligaments. Gait and weight bearing during locomotion have been tested in all models. The degree of weight bearing reduction in the affected limb was largest in the CFA- and carrageenan-induced model, followed by the MIA model and least effect was seen in the ACLT surgical model. Thus the ACLT model was not possible to use for pharmacological evaluation of drugs, whereas carrageenan- and CFA-induced monoarthritis resulted in a big enough difference between animals with monoarthritis and those without, to test drugs commonly used for pain as well as those under investigation for effects on pain. Conventional pain relieving drugs such as non-stereoidal anti-inflammatory drugs (NSAIDs) and opioids were able to normalize effects on weight bearing caused by both the carrageenan- and the CFA-induced monoarthritis, as were treatments based on inhibiting the NGF-TrkA pathway; an anti-NGF antibody and two pan-Trk compounds. However, an antagonist of the TRPV1 receptor lacked effect. We also investigated mice with a mutation in the R100 NGFß gene (hR100E), in comparison with mice possessing a human wild-type NGF (hWT), similar but not exactly like the one found in a hereditary sensory and autonomic neuropathy type V (HSAN V) disorder. This disorder leads to insensitivity to deep pain in homozygous patients, with sensory and autonomic functions remaining almost normal. In mice with the hR100E mutation, we found similar behavioural outcome; normal peripheral sensory functions but less pain-like behaviour when assessing joint pain with gait and weight bearing. In summary, this work shows that in order to detect translatable effects on joint pain, models need to be robust enough, especially for pharmacological testing, but more important, the methods of testing need to be relevant for the study aim.
|
|