Patients with spasticity typically present with an increased muscle tone that is at least partly caused by an exaggerated stretch reflex. However, intrinsic changes in the skeletal muscles, such as altered mechanical properties of the extracellular matrix or the cytoskeleton, have been reported in response to spasticity and could contribute to hypertonia, although the underlying mechanisms are poorly understood. Here we examined the vastus lateralis muscles from spinal cord-injured patients with spasticity (n = 7) for their passive mechanical properties at three different levels of structural organization, in comparison to healthy controls (n = 7). We also assessed spasticity-related alterations in muscle protein expression and muscle ultrastructure. At the whole-muscle level in vivo, we observed increased passive tension (PT) in some spasticity patients particularly at long muscle lengths, unrelated to stretch reflex activation. At the single-fibre level, elevated PT was found in cells expressing fast myosin heavy chain (MyHC) isoforms, especially MyHC-IIx, but not in those expressing slow MyHC. Type IIx fibres were present in higher than normal proportions in spastic muscles, whereas type I fibres were proportionately reduced. At the level of the isolated myofibril, however, there were no differences in PT between patients and controls. The molecular size of the giant protein titin, a main contributor to PT, was unchanged in spasticity, as was the titin : MyHC ratio and the relative desmin content. Electron microscopy revealed extensive ultrastructural changes in spastic muscles, especially expanded connective tissue, but also decreased mitochondrial volume fraction and appearance of intracellular amorphous material. Results strongly suggest that the global passive muscle stiffening in spasticity patients is caused to some degree by elevated PT of the skeletal muscles themselves. We conclude that this increased PT component arises not only from extracellular matrix remodelling, but also from structural and functional adaptations inside the muscle cells, which alter their passive mechanical properties in response to spasticity in a fibre type-dependent manner.

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ERK = extracellular signal-related kinase; IL = interleukin; JNK = c-Jun N-terminal kinase; MAPK = mitogen-activated protein kinase; MMP = matrix metalloproteinase; RA = rheumatoid arthritis; TNF = tumour necrosis factor. Available online http://arthritis-research.com/content/7/5/177 AbstractMitogen-activated protein kinases (MAPKs) have been associated with the pathogenesis of rheumatoid arthritis (RA), but the individual contributions of the three MAPK family members are incompletely understood. Although previous data have established a role for c-Jun N-terminal kinase (JNK) and extracellular signalrelated kinase (ERK) in different animal models of arthritis, most recent data indicate that the stable activation of p38 MAPK and in part of ERK significantly contributes to destructive arthritis in mice transgenic for human tumour necrosis factor-α. These data highlight the complexity of MAPK signalling in arthritis and provide a basis for the design of novel strategies to treat human RA.

Purpose Four-and-a-half LIM 2 (FHL2) is a mediator of protein interactions involved in cellular processes that are of relevance for the activation of mesenchymal cells. It interacts with integrins, focal adhesion-and mitogen-activated kinases, transcription factor AP-1 and is involved in TRAF6-dependent signalling. We analysed the function of FHL2 in chronic infl ammatory arthritis. Methods The expression of FHL2 in synovial tissues from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and in destructive arthritis of human tumour necrosis factor transgenic (hTNFtg) mice was analysed by immunohistochemistry. Fibroblast-like synoviocytes from patients with RA (RA-FLS), from hTNFtg mice and appropriate controls were isolated and FHL2 levels were determined by immunoblot after stimulation with cytokines. Knock down of FHL2 was performed by RNA interference and the expression of matrix metalloproteinases (MMPs) was determined by western blot analysis and ELISA. The invasiveness of FLS was analysed using our established matrix-associated transepithelial resistance invasion (MATRIN) assay. FHL2-mediated signalling pathways were also studied. hTNFtg mice were crossbred with FHL2-/-mice and clinical parameters of arthritis as well as histomorphometric parameters of joint destruction and MMP expression in wild-type, hTNFtg, FHL2-/-and FHL2+/-/ hTNFtg animals were analysed. Results Although there was a signifi cantly higher expression of FHL2 in RA than in OA, only transforming growth on 11 May 2018 by guest. Protected by copyright.