TY  - JOUR
A1  - Franco-Obregon, Alfredo
A1  - Cambria, Elena
A1  - Greutert, Helen
A1  - Wernas, Timon
A1  - Hitzl, Wolfgang
A1  - Egli, Marcel
A1  - Sekiguchi, Miho
A1  - Boos, Norbert
A1  - Hausmann, Oliver
A1  - Ferguson, Stephen J.
A1  - Kobayashi, Hiroshi
A1  - Würtz-Kozak, Karin
T1  - TRPC6 in simulated microgravity of intervertebral disc cells
JF  - European Spine Journal
N2  - Purpose Prolonged bed rest and microgravity in space cause intervertebral disc (IVD) degeneration. However, the underlying molecular mechanisms are not completely understood. Transient receptor potential canonical (TRPC) channels are implicated in mechanosensing of several tissues, but are poorly explored in IVDs. Methods Primary human IVD cells from surgical biopsies composed of both annulus fibrosus and nucleus pulposus (passage 1-2) were exposed to simulated microgravity and to the TRPC channel inhibitor SKF-96365 (SKF) for up to 5days. Proliferative capacity, cell cycle distribution, senescence and TRPC channel expression were analyzed. Results Both simulated microgravity and TRPC channel antagonism reduced the proliferative capacity of IVD cells and induced senescence. While significant changes in cell cycle distributions (reduction in G1 and accumulation in G2/M) were observed upon SKF treatment, the effect was small upon 3days of simulated microgravity. Finally, downregulation of TRPC6 was shown under simulated microgravity. Conclusions Simulated microgravity and TRPC channel inhibition both led to reduced proliferation and increased senescence. Furthermore, simulated microgravity reduced TRPC6 expression. IVD cell senescence and mechanotransduction may hence potentially be regulated by TRPC6 expression. This study thus reveals promising targets for future studies.
KW  - Intervertebral disc
KW  - Simulated microgravity
KW  - Senescence
KW  - TRP channels
KW  - Mechanotransduction
KW  - Gene expression
Y1  - 2018
U6  - https://doi.org/10.1007/s00586-018-5688-8
SN  - 0940-6719
SN  - 1432-0932
VL  - 27
IS  - 10
SP  - 2621
EP  - 2630
PB  - Springer
CY  - New York
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  - 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  - Touli, Ermioni
A1  - Hitzl, Wolfgang
A1  - Greutert, Helen
A1  - Ferguson, Stephen J.
A1  - Würtz-Kozak, Karin
A1  - Hausmann, Oliver N.
T1  - Inflammaging in cervical and lumbar degenerated intervertebral discs
BT  - analysis of proinflammatory cytokine and TRP channel expression
JF  - European Spine Journal
N2  - To investigate and compare the occurrence of inflammatory processes in the sites of disc degeneration in the lumbar and cervical spine by a gene array and subsequent qPCR and to investigate the mechanistic involvement of transient receptor potential channels TRPC6 and TRPV4. The gene expression of inflammatory cytokines and TRP channels was measured in human disc samples obtained from patients undergoing discectomy at the cervical (n = 24) or lumbar (n = 27) spine for degenerative disc disease (DDD) and disc herniation (DH) and analyzed for differences with regard to spinal level, IVD degeneration grade, Modic grade, age, sex, disc region and surgical extent. Aside from genes with known implication in DDD and DH, four previously unreported genes from the interferon and TRP families (IFNA1, IFNA8, IFNB1, TRPC6) could be detected. A correlation between gene expression and age (IL-15) and IVD degeneration grade (IFNA1, IL-6, IL-15, TRPC6), but not Modic grade, was identified. Significant differences were detected between cervical and lumbar discs (IL-15), nucleus and annulus (IL-6, TNF-alpha, TRPC6), single-level and multi-level surgery (IL-6, IL-8) as well as DDD and DH (IL-8), while sex had no effect. Multiple gene-gene pair correlations, either between different cytokines or between cytokines and TRP channels, exist in the disc. This study supports the relevance of IL-6 and IL-8 in disc diseases, but furthermore points toward a possible pathological role of IL-15 and type I interferons, as well as a mechanistic role of TRPC6. With limited differences in the inflammatory profile of cervical and lumbar discs, novel anti-inflammatory or TRP-modulatory strategies for the treatment of disc pathologies may be applicable independent of the spinal region.
KW  - Cervical and lumbar discs
KW  - Degenerative disc disease (DDD) and disc herniation (DH)
KW  - Inflammaging
KW  - Inflammation
KW  - Intervertebral disc
KW  - Transient receptor potential (TRP) channel
Y1  - 2017
U6  - https://doi.org/10.1007/s00586-017-5360-8
SN  - 0940-6719
SN  - 1432-0932
VL  - 27
IS  - 3
SP  - 564
EP  - 577
PB  - Springer
CY  - New York
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  - Wuertz-Kozak, Karin
A1  - Roszkowski, Martin
A1  - Cambria, Elena
A1  - Block, Andrea
A1  - Kuhn, Gisela A.
A1  - Abele, Thea
A1  - Hitzl, Wolfgang
A1  - Drießlein, David
A1  - Müller, Ralph
A1  - Rapp, Michael A.
A1  - Mansuy, Isabelle M.
A1  - Peters, Eva M. J.
A1  - Wippert, Pia-Maria
T1  - Effects of Early Life Stress on Bone Homeostasis in Mice and Humans
JF  - International Journal of Molecular Sciences
N2  - Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies.
KW  - psychosocial stress
KW  - bone pathologies
KW  - osteoporosis
KW  - bone mineral density
KW  - childhood
KW  - neuroendocrine
Y1  - 2020
U6  - https://doi.org/10.3390/ijms21186634
SN  - 1422-0067
VL  - 21
IS  - 18
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  - 
TY  - JOUR
A1  - Mehren, Christoph
A1  - Heider, Franziska
A1  - Sauer, Daniel
A1  - Kothe, Ralph
A1  - Korge, Andreas
A1  - Hitzl, Wolfgang
A1  - Würtz-Kozak, Karin
T1  - Clinical and radiological outcome of a new total cervical disc replacement design
JF  - Spine
N2  - Study Design. A nonrandomized, prospective, and single- center clinical trial of the ProDisc Vivo prosthesis. Objective. The aim of this study was to investigate the clinical and radiological results of a refined total cervical disc replacement (cTDR), the ProDisc Vivo, with two years of follow-up (FU). The incidence of implant-related complications was recorded as a secondary outcome variable. Summary of Background Data. Previous generations of the ProDisc artificial cervical disc replacement generate high primary stability due to keel-based designs with opening of the anterior cortex during the implantation and subsequent high rates of heterotopic ossifications. Methods. Clinical outcome scores included the Neck Disability Index (NDI), Visual Analogue Scale (VAS), arm and neck pain self-assessment questionnaires. The radiological outcome included the range of motion (ROM) and the occurrence of heterotopic ossifications. The incidence of implant-related complications with new implant design was recorded as a secondary outcome variable. Results. A total of 55 patients received a single-level treatment with the ProDisc Vivo cTDR between C3/4 and C6/7, with a follow-up rate of 78%. The clinical outcome scores improved in all parameters significantly (P 1/4 0.0001) (NDI: 68.3 -> 17.4; VAS arm: 6.3 -> 1.4; VAS neck: 4.9 -> 1.6). The ROM of the indexsegment did not show a significant change (P 1/4 0.26) (7.9 degrees -> 9.2 degrees). Heterotopic ossifications at the index segment was found as grade 0 in 5%, grade 1 in 22%, grade 2 in 10%, grade 3 (with functional impairment of the prosthesis) in 7%, and grade 4 in 3% of the cases. We observed three implant-related complications (5.5%), with two implant dislocations anteriorly and one low-grade infect. Conclusion. cTDR with ProDisc Vivo demonstrated a significant and sustained improvement of all clinical outcome parameters. A less invasive implantation mechanism with lower primary stability of the cTDR might be a reason for a higher dislocation rate than the keel-based previous generation ProDisc C.
KW  - heterotopic ossifications
KW  - implant-related complications
KW  - outcomes
KW  - ProDisc Vivo
KW  - total disc arthroplasty
KW  - total disc replacement
Y1  - 2018
U6  - https://doi.org/10.1097/BRS.0000000000002799
SN  - 0362-2436
SN  - 1528-1159
VL  - 44
IS  - 4
SP  - E202
EP  - E210
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  -