Aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 5 (ADAMTS-5) is crucial for the breakdown of cartilage matrix during osteoarthritis, a degenerative joint disease that leads to the progressive destruction of articular structures. The mechanisms of ADAMTS-5 activation and their links to the pathogenesis of osteoarthritis remain poorly understood, but syndecans have been shown to be involved in the activation of ADAMTS-4 (ref. 3). Here we show that syndecan-4 is specifically induced in type X collagen-producing chondrocytes both in human osteoarthritis and in murine models of the disease. The loss of syndecan-4 in genetically modified mice and intra-articular injections of syndecan-4-specific antibodies into wild-type mice protect from proteoglycan loss and thereby prevent osteoarthritic cartilage damage in a surgically induced model of osteoarthritis. The occurrence of less severe osteoarthritis-like cartilage destruction in both syndecan-4-deficient mice and syndecan-4-specific antibody-treated wild-type mice results from a marked decrease in ADAMTS-5 activity. Syndecan-4 controls the activation of ADAMTS-5 through direct interaction with the protease and through regulating mitogen-activated protein kinase (MAPK)-dependent synthesis of matrix metalloproteinase-3 (MMP-3). Our data suggest that strategies aimed at the inhibition of syndecan-4 will be of great value for the treatment of cartilage damage in osteoarthritis.
The small ubiquitin-like modifier (SUMO)-1 is an important posttranslational regulator of different signaling pathways and involved in the formation of promyelocytic leukemia (PML) protein nuclear bodies (NBs). Overexpression of SUMO-1 has been associated with alterations in apoptosis, but the underlying mechanisms and their relevance for human diseases are not clear. Here, we show that the increased expression of SUMO-1 in rheumatoid arthritis (RA) synovial fibroblasts (SFs) contributes to the resistance of these cells against Fas-induced apoptosis through increased SUMOylation of nuclear PML protein and increased recruitment of the transcriptional repressor DAXX to PML NBs. We also show that the nuclear SUMO-protease SENP1, which is found at lower levels in RA SFs, can revert the apoptosis-inhibiting effects of SUMO-1 by releasing DAXX from PML NBs. Our findings indicate that in RA SFs overexpression of SENP1 can alter the SUMO-1-mediated recruitment of DAXX to PML NBs, thus influencing the proapoptotic effects of DAXX. Accumulation of DAXX in PML NBs by SUMO-1 may, therefore, contribute to the pathogenesis of inflammatory disorders.inflammation ͉ autoimmunity ͉ DAXX ͉ SENP
The data suggest that lower expression of surface Fas, but higher levels of apoptosis-inhibiting sFas, contribute to the resistance of fibroblasts in lung fibrosis against apoptosis, to increased cellularity and also to increased formation and deposition of extracellular matrix.
Background
Due to its bone preserving philosophy, short-stem total hip arthroplasty (THA) has primarily been recommended for young and active patients. However, there may be benefits for elderly patients given a less invasive operative technique due to the short curved implant design. The purpose of this study was to compare the clinical and radiological outcomes as well as perioperative complications of a calcar-guided short stem between a young (< 60 years) and a geriatric (> 75 years) population.
Methods
Data were collected in a total of 5 centers, and 400 short-stems were included as part of a prospective multicentre observational study between 2010 and 2014 with a mean follow-up of 49.2 months. Preoperative femur morphology was analysed using the Dorr classification. Clinical and radiological outcomes were assessed in both groups as well as perioperative complications, rates and reasons for stem revision.
Results
No differences were found for the mean visual analogue scale (VAS) values of rest pain, load pain, and satisfaction, whereas Harris Hip Score (HHS) was slightly better in the young group. Comparing both groups, none of the radiological parameters that were assessed (stress-shielding, cortical hypertrophy, radiolucency, osteolysis) reached differences of statistical significance. While in young patients aseptic loosening is the main cause of implant failure, in the elderly group particularly postoperative periprosthetic fractures due to accidental fall have to be considered to be of high risk. The incidence of periprosthetic fractures was found to be 0% in Dorr type A femurs, whereas in Dorr types B and C fractures occurred in 2.1 and 22.2% respectively.
Conclusions
Advanced age alone is not necessarily to be considered as contra-indications for calcar-guided short-stem THA, although further follow-up is needed. However, markedly reduced bone quality with femur morphology of Dorr type C seems to be associated with increased risk for postoperative periprosthetic fractures, thus indication should be limited to Dorr types A and B.
Trial registration
German Clinical Trials Register;
DRKS00012634
, 07.07.2017 (retrospectively registered).
Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease with systemic involvement that affects about 1% of the Western population. The progressive destruction of affected joints is a major characteristic of the disease and distinguishes RA from other acute and chronic arthritides. The etiology of RA is unknown, and a variety of genetic and environmental factors are being discussed as potential causes of the disease. However, in contrast to our incomplete understanding of the etiology, the knowledge about molecular mechanisms leading to joint destruction has advanced considerably over the past years. Thus, a large number of studies have investigated the presence and interplay of several types of cells in rheumatoid synovium, such as lymphocytes, macrophages and fibroblasts. They have led to the understanding that cells in the rheumatoid synovium form a network, which interacts through direct cell-to cell contacts as well as the release of a multitude of cytokines. The use of novel molecular techniques together with the development of new animal models has revised our concept on the pathogenesis of RA and specifically on the role of fibroblasts in initiation and progression of joint destruction. This article will review current data and hypotheses on disease mechanisms by which fibroblasts are involved in the destruction of joints in RA.
Conclusion. The data demonstrate that an antisense RNA expression construct against MT1-MMP can be generated and expressed in RASFs for at least 60 days. Inhibition of MT1-MMP significantly reduces the cartilage degradation by RASFs.Membrane-type matrix metalloproteinases (MTMMPs) are cell membrane-anchored MMPs that have been associated with both normal tissue remodeling and various diseases. Six different MT-MMPs have thus far been described, of which membrane type 1 MMP (MT1-MMP) has been studied most intensively. MT1-MMP (also called MMP-14) has a specific structural organization that is characterized by a hydrophobic transmembrane domain and a short cytoplasmic tail. It also contains a recognition site for furin-like proprotein convertases, which, by furin-dependent cleavage, activate MT1-MMP intracellularly (1). MT1-MMP digests interstitial collagens as well as other extracellular matrix components, including fibronectin, laminin, aggrecan,
Introduction The rheumatoid arthritis (RA) synovium is characterised by the presence of an aggressive population of activated synovial fibroblasts (RASFs) that are prominently involved in the destruction of articular cartilage and bone. Accumulating evidence suggests that RASFs are relatively resistant to Fas-ligand (FasL)-induced apoptosis, but the data concerning tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) have been conflicting. Here, we hypothesise that the susceptibility of RASFs to receptor-mediated apoptosis depends on the proliferation status of these cells and therefore analysed the cell cycle dependency of FasL-and TRAIL-induced programmed cell death of RASFs in vitro.
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