TY - GEN A1 - Krupkova, Olga A1 - Sadowska, Aleksandra A1 - Kameda, Takuya A1 - Hitzl, Wolfgang A1 - Hausmann, Oliver Nic A1 - Klasen, Jürgen A1 - Wuertz-Kozak, Karin T1 - p38 MaPK facilitates crosstalk between endoplasmic reticulum stress and IL-6 release in the intervertebral Disc T2 - Postprints der Universität Potsdam : Humanwissenschaftliche Reihe N2 - Degenerative disc disease is associated with increased expression of pro-inflammatory cytokines in the intervertebral disc (IVD). However, it is not completely clear how inflammation arises in the IVD and which cellular compartments are involved in this process. Recently, the endoplasmic reticulum (ER) has emerged as a possible modulator of inflammation in age-related disorders. In addition, ER stress has been associated with the microenvironment of degenerated IVDs. Therefore, the aim of this study was to analyze the effects of ER stress on inflammatory responses in degenerated human IVDs and associated molecular mechanisms. Gene expression of ER stress marker GRP78 and pro-inflammatory cytokines IL-6, IL-8, IL-1 beta, and TNF-alpha was analyzed in human surgical IVD samples (n = 51, Pfirrmann grade 2-5). The expression of GRP78 positively correlated with the degeneration grade in lumbar IVDs and IL-6, but not with IL-1 beta and TNF-alpha. Another set of human surgical IVD samples (n = 25) was used to prepare primary cell cultures. ER stress inducer thapsigargin (Tg, 100 and 500 nM) activated gene and protein expression of IL-6 and induced phosphorylation of p38 MAPK. Both inhibition of p38 MAPK by SB203580 (10 mu M) and knockdown of ER stress effector CCAAT-enhancer-binding protein homologous protein (CHOP) reduced gene and protein expression of IL-6 in Tg-treated cells. Furthermore, the effects of an inflammatory microenvironment on ER stress were tested. TNF-alpha (5 and 10 ng/mL) did not activate ER stress, while IL-1 beta (5 and 10 ng/mL) activated gene and protein expression of GRP78, but did not influence [Ca2+](i) flux and expression of CHOP, indicating that pro-inflammatory cytokines alone may not induce ER stress in vivo. This study showed that IL-6 release in the IVD can be initiated following ER stress and that ER stress mediates IL-6 release through p38 MAPK and CHOP. Therapeutic targeting of ER stress response may reduce the consequences of the harsh microenvironment in degenerated IVD. T3 - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 705 KW - intervertebral disc KW - inflammation KW - endoplasmic reticulum stress KW - p38 MAPK KW - CHOP KW - GADD153 KW - GRP78 KW - IL-6 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-468698 SN - 1866-8364 IS - 705 ER - TY - GEN A1 - Sadowska, Aleksandra A1 - Kameda, Takuya A1 - Krupkova, Olga A1 - Würtz-Kozak, Karin T1 - Osmosensing, osmosignalling and inflammation BT - how intervertebral disc cells respond to altered osmolarity T2 - Postprints der Universität Potsdam : Humanwissenschaftliche Reihe N2 - Intervertebral disc (IVD) cells are naturally exposed to high osmolarity and complex mechanical loading, which drive microenvironmental osmotic changes. Age- and degeneration-induced degradation of the IVD's extracellular matrix causes osmotic imbalance, which, together with an altered function of cellular receptors and signalling pathways, instigates local osmotic stress. Cellular responses to osmotic stress include osmoadaptation and activation of pro-inflammatory pathways. This review summarises the current knowledge on how IVD cells sense local osmotic changes and translate these signals into physiological or pathophysiological responses, with a focus on inflammation. Furthermore, it discusses the expression and function of putative membrane osmosensors (e.g. solute carrier transporters, transient receptor potential channels, aquaporins and acid-sensing ion channels) and osmosignalling mediators [e.g. tonicity responseelement-binding protein/nuclear factor of activated T-cells 5 (TonEBP/NFAT5), nuclear factor kappa-lightchain-enhancer of activated B cells (NF-kappa B)] in healthy and degenerated IVDs. Finally, an overview of the potential therapeutic targets for modifying osmosensing and osmosignalling in degenerated IVDs is provided. T3 - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 693 KW - intervertebral disc degeneration KW - degenerative disc disease KW - osmolarity KW - hyper-osmolarity KW - hypo-osmolarity KW - osmotic KW - inflammatory KW - transient receptor potential channel KW - aquaporin KW - tonicity-responsive enhancer binding protein Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-469080 SN - 1866-8364 IS - 693 ER - TY - GEN A1 - Sadowska, Aleksandra A1 - Hausmann, Oliver Nic A1 - Wuertz-Kozak, Karin T1 - Inflammaging in the intervertebral disc T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - Degeneration of the intervertebral disc – triggered by ageing, mechanical stress, traumatic injury, infection, inflammation and other factors – has a significant role in the development of low back pain. Back pain not only has a high prevalence, but also a major socio-economic impact. With the ageing population, its occurrence and costs are expected to grow even more in the future. Disc degeneration is characterized by matrix breakdown, loss in proteoglycans and thus water content, disc height loss and an increase in inflammatory molecules. The accumulation of cytokines, such as interleukin (IL)-1 , IL-8 or tumor necrosis factor (TNF)-, together with age-related immune deficiency, leads to the so-called inflammaging – low-grade, chronic inflammation with a crucial role in pain development. Despite the relevance of these molecular processes, current therapies target symptoms, but not underlying causes. This review describes the biological and biomechanical changes that occur in a degenerated disc, discusses the connection between disc degeneration and inflammaging, highlights factors that enhance the inflammatory processes in disc pathologies and suggests future research avenues. T3 - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 519 KW - Intervertebral disc KW - chronic inflammation KW - inflammaging KW - senescence KW - mechanical loading KW - matrix fragmentation KW - obesity KW - Propionibacterium acnes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-414081 IS - 519 ER -