TY - GEN A1 - Krupkova, Olga A1 - Smolders, Lucas A1 - Wuertz-Kozak, Karin A1 - Cook, James A1 - Pozzi, Antonio T1 - The pathobiology of the meniscus BT - a comparison between the human and dog T2 - Frontiers in Veterinary Science N2 - Serious knee pain and related disability have an annual prevalence of approximately 25% on those over the age of 55 years. As curative treatments for the common knee problems are not available to date, knee pathologies typically progress and often lead to osteoarthritis (OA). While the roles that the meniscus plays in knee biomechanics are well characterized, biological mechanisms underlying meniscus pathophysiology and roles in knee pain and OA progression are not fully clear. Experimental treatments for knee disorders that are successful in animal models often produce unsatisfactory results in humans due to species differences or the inability to fully replicate disease progression in experimental animals. The use of animals with spontaneous knee pathologies, such as dogs, can significantly help addressing this issue. As microscopic and macroscopic anatomy of the canine and human menisci are similar, spontaneous meniscal pathologies in canine patients are thought to be highly relevant for translational medicine. However, it is not clear whether the biomolecular mechanisms of pain, degradation of extracellular matrix, and inflammatory responses are species dependent. The aims of this review are (1) to provide an overview of the anatomy, physiology, and pathology of the human and canine meniscus, (2) to compare the known signaling pathways involved in spontaneous meniscus pathology between both species, and (3) to assess the relevance of dogs with spontaneous meniscal pathology as a translational model. Understanding these mechanisms in human and canine meniscus can help to advance diagnostic and therapeutic strategies for painful knee disorders and improve clinical decision making. T3 - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 677 KW - meniscus KW - inflammation KW - oxidative stress KW - pain KW - dog Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-460868 SN - 1866-8364 IS - 677 ER - TY - GEN A1 - Wippert, Pia-Maria A1 - Rector, Michael V. A1 - Kuhn, Gisela A1 - Wuertz-Kozak, Karin T1 - Stress and Alterations in Bones BT - An Interdisciplinary Perspective N2 - Decades of research have demonstrated that physical stress (PS) stimulates bone remodeling and affects bone structure and function through complex mechanotransduction mechanisms. Recent research has laid ground to the hypothesis that mental stress (MS) also influences bone biology, eventually leading to osteoporosis and increased bone fracture risk. These effects are likely exerted by modulation of hypothalamic–pituitary–adrenal axis activity, resulting in an altered release of growth hormones, glucocorticoids and cytokines, as demonstrated in human and animal studies. Furthermore, molecular cross talk between mental and PS is thought to exist, with either synergistic or preventative effects on bone disease progression depending on the characteristics of the applied stressor. This mini review will explain the emerging concept of MS as an important player in bone adaptation and its potential cross talk with PS by summarizing the current state of knowledge, highlighting newly evolving notions (such as intergenerational transmission of stress and its epigenetic modifications affecting bone) and proposing new research directions. T3 - Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe - 323 KW - biomechanics KW - bone–brain–nervous system interactions KW - endocrine pathways KW - exercise KW - osteoporosis Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-395866 ER - TY - JOUR A1 - Wippert, Pia-Maria A1 - Rector, Michael V. A1 - Kuhn, Gisela A1 - Wuertz-Kozak, Karin T1 - Stress and Alterations in Bones BT - An Interdisciplinary Perspective JF - Frontiers in endocrinology N2 - Decades of research have demonstrated that physical stress (PS) stimulates bone remodeling and affects bone structure and function through complex mechanotransduction mechanisms. Recent research has laid ground to the hypothesis that mental stress (MS) also influences bone biology, eventually leading to osteoporosis and increased bone fracture risk. These effects are likely exerted by modulation of hypothalamic–pituitary–adrenal axis activity, resulting in an altered release of growth hormones, glucocorticoids and cytokines, as demonstrated in human and animal studies. Furthermore, molecular cross talk between mental and PS is thought to exist, with either synergistic or preventative effects on bone disease progression depending on the characteristics of the applied stressor. This mini review will explain the emerging concept of MS as an important player in bone adaptation and its potential cross talk with PS by summarizing the current state of knowledge, highlighting newly evolving notions (such as intergenerational transmission of stress and its epigenetic modifications affecting bone) and proposing new research directions. KW - biomechanics KW - bone–brain–nervous system interactions KW - endocrine pathways KW - osteoporosis KW - exercise Y1 - 2017 U6 - https://doi.org/10.3389/fendo.2017.00096 SN - 1664-2392 VL - 8 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Wuertz-Kozak, Karin A1 - Bleisch, Dominique A1 - Nadi, Najia A1 - Proemmel, Peter A1 - Hitzl, Wolfgang A1 - Kessler, Thomas M. M. A1 - Gautschi, Oliver P. A1 - Hausmann, Oliver N. T1 - Sexual and urinary function following anterior lumbar surgery in females JF - Neurourology and urodynamics N2 - Aims Anterior lumbar interbody fusion procedures (ALIF) and total disc replacement (TDR) with anterior exposure of the lumbar spine entail a risk of a vascular injury and dysfunction of the sympathetic and parasympathetic nerves due to disturbance of the inferior and superior hypogastric plexus. While retrograde ejaculation is a known complication of the anterior spinal approach in males, post-operative sexual as well as urinary function in females has not yet been thoroughly investigated and was hence the aim of this study. Methods Fifteen female patients documented their sexual and urinary function preoperatively, 3 months and 6 months postoperatively, using the validated questionnaires FSFI (Female Sexual Function Index) and ICIQ (International Consultation of Incontinence Questionnaire). Randomization tests were used to statistically analyze expectation values over time (two-sided, P < 0.05). Results While no statistically significant change in the total FSFI score occurred over time, a significant increase in FSFI desire score was noted between preoperative (2.95 +/- 0.8) and 6 months follow-up (3.51 +/- 0.6, P = 0.02). Urinary continence remained unchanged over time. Conclusion In summary, ALIF and lumbar TDR do not seem to negatively influence sexual and urinary function in females. In contrast, increased sexual desire was noted, likely secondary to post-surgical pain relief. KW - ALIF KW - dysfunction KW - FSFI KW - ICIQ KW - questionnaire KW - TDR KW - women Y1 - 2018 U6 - https://doi.org/10.1002/nau.23874 SN - 0733-2467 SN - 1520-6777 VL - 38 IS - 2 SP - 632 EP - 636 PB - Wiley CY - Hoboken ER - 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 - JOUR 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 JF - Frontiers in Immunology 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. KW - intervertebral disc KW - inflammation KW - endoplasmic reticulum stress KW - p38 MAPK KW - CHOP KW - GADD153 KW - GRP78 KW - IL-6 Y1 - 2018 U6 - https://doi.org/10.3389/fimmu.2018.01706 SN - 1664-3224 VL - 9 PB - Frontiers Research Foundation CY - Lausanne ER - TY - JOUR A1 - Sadowska, Aleksandra A1 - Kameda, Takuya A1 - Krupkova, Olga A1 - Wuertz-Kozak, Karin T1 - Osmosensing, osmosignalling and inflammation BT - how intervertebral disc cells respond to altered osmolarity JF - European cells & materials 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 response-element-binding protein/nuclear factor of activated T-cells 5 (TonEBP/NFAT5), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)] in healthy and degenerated IVDs. Finally, an overview of the potential therapeutic targets for modifying osmosensing and osmosignalling in degenerated IVDs is provided. 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 - 2018 U6 - https://doi.org/10.22203/eCM.v036a17 SN - 1473-2262 VL - 36 SP - 231 EP - 250 PB - Ao research institute davos-Ari CY - Davos 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 - TY - JOUR A1 - Mehren, Christoph A1 - Wuertz-Kozak, Karin A1 - Sauer, Daniel A1 - Hitzl, Wolfgang A1 - Pehlivanoglu, Tuna A1 - Heider, Franziska T1 - Implant Design and the Anchoring Mechanism Influence the Incidence of Heterotopic Ossification in Cervical Total Disc Replacement at 2-year Follow-up JF - Spine N2 - Study Design. A nonrandomized, prospective, and single-center clinical trial. Objective. The aim of this study was to determine whether the prosthesis design, and especially changes in the primary anchoring mechanism between the keel-based ProDisc C and the spike-based ProDisc Vivo, affects the frequency of heterotopic ossification (HO) formation over time. Summary of Background Data. The occurrence of motion-restricting HO as well as underlying risk factors has so far been a widely discussed, but not well understand phenomenon. The anchoring mechanism and the opening of the anterior cortex may be possible causes of this unwanted complication. Methods. Forty consecutive patients treated with the ProDisc C and 42 consecutive patients treated with the ProDisc Vivo were compared with respect to radiological and clinical outcome, with 2 years of follow-up. Clinical outcome scores included the Neck Disability Index (NDI), Visual Analogue Scale (VAS), and arm and neck pain self-assessment questionnaires. Radiological outcomes included the segmental lordosis and range of motion (ROM) of the index-segment as well as the occurrence of HO. Results. The clinical outcome parameters improved in both groups significantly. [ProDisc C: VAS arm and neck pain from 6.3 and 6.2 preoperatively to 0.7 and 1.3; NDI from 23.0 to 3.7; ProDisc Vivo: VAS arm and neck pain from 6.3 and 4.9 to 1.4 and 1.6, NDI from 34.1 to 8.7; 2-year follow-up (FU)]. The ProDisc Vivo cohort demonstrated a significantly lower incidence of HO than the ProDisc C group at 1-year FU (P = 0.0005) and 2-year FU (P = 0.005). Specifically, high-grade HO occurred in 9% versus 31%. Conclusion. These findings demonstrate that prosthesis designs that allow primary anchoring without violation of the cortical surface help to reduce the incidence of severe ossification, possibly affecting the functionality and mobility of the artificial disc device over of time. KW - anchoring mechanism KW - cervical artificial disc replacement KW - heterotopic ossification (HO) KW - implant design KW - ProDisc C KW - ProDisc Vivo KW - total disc replacement Y1 - 2019 U6 - https://doi.org/10.1097/BRS.0000000000003098 SN - 0362-2436 SN - 1528-1159 VL - 44 IS - 21 SP - 1471 EP - 1480 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Wu, Yabin A1 - Stoddart, Martin J. A1 - Wuertz-Kozak, Karin A1 - Grad, Sibylle A1 - Alini, Mauro A1 - Ferguson, Stephen J. T1 - Hyaluronan supplementation as a mechanical regulator of cartilage tissue development under joint-kinematic-mimicking loading JF - Interface : journal of the Royal Society KW - synovial fluid KW - cartilage tissue engineering KW - mechanical loading KW - non-Newtonian fluid KW - hyaluronic acid supplementation Y1 - 2017 U6 - https://doi.org/10.1098/rsif.2017.0255 SN - 1742-5689 SN - 1742-5662 VL - 14 PB - Royal Society CY - London ER -