@misc{KrupkovaSmoldersWuertzKozaketal.2018, author = {Krupkova, Olga and Smolders, Lucas and Wuertz-Kozak, Karin and Cook, James and Pozzi, Antonio}, title = {The pathobiology of the meniscus}, series = {Frontiers in Veterinary Science}, journal = {Frontiers in Veterinary Science}, number = {677}, issn = {1866-8364}, doi = {10.25932/publishup-46086}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-460868}, pages = {17}, year = {2018}, abstract = {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.}, language = {en} } @misc{WippertRectorKuhnetal.2017, author = {Wippert, Pia-Maria and Rector, Michael V. and Kuhn, Gisela and Wuertz-Kozak, Karin}, title = {Stress and Alterations in Bones}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-395866}, pages = {7}, year = {2017}, abstract = {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.}, language = {en} } @article{WippertRectorKuhnetal.2017, author = {Wippert, Pia-Maria and Rector, Michael V. and Kuhn, Gisela and Wuertz-Kozak, Karin}, title = {Stress and Alterations in Bones}, series = {Frontiers in endocrinology}, volume = {8}, journal = {Frontiers in endocrinology}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-2392}, doi = {10.3389/fendo.2017.00096}, pages = {7}, year = {2017}, abstract = {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.}, language = {en} } @article{WuertzKozakBleischNadietal.2018, author = {Wuertz-Kozak, Karin and Bleisch, Dominique and Nadi, Najia and Proemmel, Peter and Hitzl, Wolfgang and Kessler, Thomas M. M. and Gautschi, Oliver P. and Hausmann, Oliver N.}, title = {Sexual and urinary function following anterior lumbar surgery in females}, series = {Neurourology and urodynamics}, volume = {38}, journal = {Neurourology and urodynamics}, number = {2}, publisher = {Wiley}, address = {Hoboken}, issn = {0733-2467}, doi = {10.1002/nau.23874}, pages = {632 -- 636}, year = {2018}, abstract = {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.}, language = {en} } @misc{KrupkovaSadowskaKamedaetal.2018, author = {Krupkova, Olga and Sadowska, Aleksandra and Kameda, Takuya and Hitzl, Wolfgang and Hausmann, Oliver Nic and Klasen, J{\"u}rgen and Wuertz-Kozak, Karin}, title = {p38 MaPK facilitates crosstalk between endoplasmic reticulum stress and IL-6 release in the intervertebral Disc}, series = {Postprints der Universit{\"a}t Potsdam : Humanwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Humanwissenschaftliche Reihe}, number = {705}, issn = {1866-8364}, doi = {10.25932/publishup-46869}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-468698}, pages = {16}, year = {2018}, abstract = {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.}, language = {en} } @article{KrupkovaSadowskaKamedaetal.2018, author = {Krupkova, Olga and Sadowska, Aleksandra and Kameda, Takuya and Hitzl, Wolfgang and Hausmann, Oliver Nic and Klasen, J{\"u}rgen and Wuertz-Kozak, Karin}, title = {p38 MaPK Facilitates crosstalk Between endoplasmic reticulum stress and IL-6 release in the intervertebral Disc}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, publisher = {Frontiers Research Foundation}, address = {Lausanne}, issn = {1664-3224}, doi = {10.3389/fimmu.2018.01706}, pages = {14}, year = {2018}, abstract = {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.}, language = {en} } @article{SadowskaKamedaKrupkovaetal.2018, author = {Sadowska, Aleksandra and Kameda, Takuya and Krupkova, Olga and Wuertz-Kozak, Karin}, title = {Osmosensing, osmosignalling and inflammation}, series = {European cells \& materials}, volume = {36}, journal = {European cells \& materials}, publisher = {Ao research institute davos-Ari}, address = {Davos}, issn = {1473-2262}, doi = {10.22203/eCM.v036a17}, pages = {231 -- 250}, year = {2018}, abstract = {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.}, language = {en} } @misc{SadowskaHausmannWuertzKozak2018, author = {Sadowska, Aleksandra and Hausmann, Oliver Nic and Wuertz-Kozak, Karin}, title = {Inflammaging in the intervertebral disc}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe}, number = {519}, doi = {10.25932/publishup-41408}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-414081}, pages = {9}, year = {2018}, abstract = {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.}, language = {en} } @article{MehrenWuertzKozakSaueretal.2019, author = {Mehren, Christoph and Wuertz-Kozak, Karin and Sauer, Daniel and Hitzl, Wolfgang and Pehlivanoglu, Tuna and Heider, Franziska}, title = {Implant Design and the Anchoring Mechanism Influence the Incidence of Heterotopic Ossification in Cervical Total Disc Replacement at 2-year Follow-up}, series = {Spine}, volume = {44}, journal = {Spine}, number = {21}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0362-2436}, doi = {10.1097/BRS.0000000000003098}, pages = {1471 -- 1480}, year = {2019}, abstract = {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.}, language = {en} } @article{WuStoddartWuertzKozaketal.2017, author = {Wu, Yabin and Stoddart, Martin J. and Wuertz-Kozak, Karin and Grad, Sibylle and Alini, Mauro and Ferguson, Stephen J.}, title = {Hyaluronan supplementation as a mechanical regulator of cartilage tissue development under joint-kinematic-mimicking loading}, series = {Interface : journal of the Royal Society}, volume = {14}, journal = {Interface : journal of the Royal Society}, publisher = {Royal Society}, address = {London}, issn = {1742-5689}, doi = {10.1098/rsif.2017.0255}, pages = {9}, year = {2017}, language = {en} }