@article{AltmannMutWolfetal.2021, author = {Altmann, Stephan and Mut, J{\"u}rgen and Wolf, Natalia and Meißner-Weigl, Jutta and Rudert, Maximilian and Jakob, Franz and Gutmann, Marcus and L{\"u}hmann, Tessa and Seibel, J{\"u}rgen and Ebert, Regina}, title = {Metabolic glycoengineering in hMSC-TERT as a model for skeletal precursors by using modified azide/alkyne monosaccharides}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {6}, issn = {1422-0067}, doi = {10.3390/ijms22062820}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259247}, year = {2021}, abstract = {Metabolic glycoengineering enables a directed modification of cell surfaces by introducing target molecules to surface proteins displaying new features. Biochemical pathways involving glycans differ in dependence on the cell type; therefore, this technique should be tailored for the best results. We characterized metabolic glycoengineering in telomerase-immortalized human mesenchymal stromal cells (hMSC-TERT) as a model for primary hMSC, to investigate its applicability in TERT-modified cell lines. The metabolic incorporation of N-azidoacetylmannosamine (Ac\(_4\)ManNAz) and N-alkyneacetylmannosamine (Ac\(_4\)ManNAl) into the glycocalyx as a first step in the glycoengineering process revealed no adverse effects on cell viability or gene expression, and the in vitro multipotency (osteogenic and adipogenic differentiation potential) was maintained under these adapted culture conditions. In the second step, glycoengineered cells were modified with fluorescent dyes using Cu-mediated click chemistry. In these analyses, the two mannose derivatives showed superior incorporation efficiencies compared to glucose and galactose isomers. In time-dependent experiments, the incorporation of Ac\(_4\)ManNAz was detectable for up to six days while Ac\(_4\)ManNAl-derived metabolites were absent after two days. Taken together, these findings demonstrate the successful metabolic glycoengineering of immortalized hMSC resulting in transient cell surface modifications, and thus present a useful model to address different scientific questions regarding glycosylation processes in skeletal precursors.}, language = {en} } @article{VogtGirschickSchweitzeretal.2020, author = {Vogt, Marius and Girschick, Hermann and Schweitzer, Tilmann and Benoit, Clemens and Holl-Wieden, Annette and Seefried, Lothar and Jakob, Franz and Hofmann, Christine}, title = {Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children}, series = {Orphanet Journal of Rare Diseases}, volume = {15}, journal = {Orphanet Journal of Rare Diseases}, doi = {10.1186/s13023-020-01500-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230505}, year = {2020}, abstract = {Background Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children's Hospital Wuerzburg, Germany over the last 25 years. Results The cohort comprises 4 (8\%) perinatal, 17 (34\%) infantile and 29 (58\%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88\%), low alkaline phosphatase (AP) activity (in 96\%), accumulating substrates of AP (in 58\%) and X-ray findings (in 48\%). Genetic analysis was performed in 48 patients (31 compound heterozygous, 15 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5 months (min. 0, max. 107), while median time to diagnosis was 13 months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78\%), impairment of mineralization (72\%), premature loss of teeth (64\%), musculoskeletal pain and craniosynostosis (each 64\%) and failure to thrive (62\%). Up to now 20 patients started medical treatment with Asfotase alfa. Conclusions Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options such as enzyme-replacement-therapy with Asfotase alfa in mind.}, language = {en} } @article{NedopilShekharHowelletal.2021, author = {Nedopil, Alexander J. and Shekhar, Adithya and Howell, Stephen M. and Hull, Maury L.}, title = {An insert with less than spherical medial conformity causes a loss of passive internal rotation after calipered kinematically aligned TKA}, series = {Archives of Orthopaedic and Trauma Surgery}, volume = {141}, journal = {Archives of Orthopaedic and Trauma Surgery}, number = {12}, issn = {1434-3916}, doi = {10.1007/s00402-021-04054-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266710}, pages = {2287-2294}, year = {2021}, abstract = {Introduction In total knee arthroplasty (TKA), the level of conformity, a medial stabilized (MS) implant, needs to restore native (i.e., healthy) knee kinematics without over-tensioning the flexion space when the surgeon chooses to retain the posterior cruciate ligament (PCL) is unknown. Whether an insert with a medial ball-in-socket conformity and lateral flat surface like the native knee or a less than spherical medial conformity restores higher and closer to native internal tibial rotation without anterior lift-off, an over-tension indicator, when implanted with calipered kinematic alignment (KA), is unknown. Methods and Materials Two surgeons treated 21 patients with calipered KA and a PCL retaining MS implant. Validated verification checks that restore native tibial compartment forces in passive flexion without release of healthy ligaments were used to select the optimal insert thickness. A goniometer etched onto trial inserts with the ball-in-socket and the less than spherical medial conformity measured the tibial rotation relative to the femoral component at extension and 90° and 120° flexion. The surgeon recorded the incidence of anterior lift-off of the insert. Results The insert with the medial ball-in-socket and lateral flat surface restored more internal tibial rotation than the one with less than spherical medial conformity, with mean values of 19° vs. 17° from extension to 90° flexion (p < 0.01), and 23° vs. 20°-120° flexion (p < 0.002), respectively. There was no anterior lift-off of the insert at 90° and 120° flexion. Conclusion An MS insert with a medial ball-in-socket and lateral flat surface that matches the native knee's spherical conformity restores native tibial internal rotation when implanted with calipered KA and PCL retention without over-tensioning the flexion space.}, language = {en} } @article{BorojevićJaukovićKukoljetal.2022, author = {Borojević, Ana and Jauković, Aleksandra and Kukolj, Tamara and Mojsilović, Slavko and Obradović, Hristina and Trivanović, Drenka and Živanović, Milena and Zečević, Željko and Simić, Marija and Gobeljić, Borko and Vujić, Dragana and Bugarski, Diana}, title = {Vitamin D3 stimulates proliferation capacity, expression of pluripotency markers, and osteogenesis of human bone marrow mesenchymal stromal/stem cells, partly through SIRT1 signaling}, series = {Biomolecules}, volume = {12}, journal = {Biomolecules}, number = {2}, issn = {2218-273X}, doi = {10.3390/biom12020323}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262203}, year = {2022}, abstract = {The biology of vitamin D3 is well defined, as are the effects of its active metabolites on various cells, including mesenchymal stromal/stem cells (MSCs). However, the biological potential of its precursor, cholecalciferol (VD3), has not been sufficiently investigated, although its significance in regenerative medicine — mainly in combination with various biomaterial matrices — has been recognized. Given that VD3 preconditioning might also contribute to the improvement of cellular regenerative potential, the aim of this study was to investigate its effects on bone marrow (BM) MSC functions and the signaling pathways involved. For that purpose, the influence of VD3 on BM-MSCs obtained from young human donors was determined via MTT test, flow cytometric analysis, immunocytochemistry, and qRT-PCR. Our results revealed that VD3, following a 5-day treatment, stimulated proliferation, expression of pluripotency markers (NANOG, SOX2, and Oct4), and osteogenic differentiation potential in BM-MSCs, while it reduced their senescence. Moreover, increased sirtuin 1 (SIRT1) expression was detected upon treatment with VD3, which mediated VD3-promoted osteogenesis and, partially, the stemness features through NANOG and SOX2 upregulation. In contrast, the effects of VD3 on proliferation, Oct4 expression, and senescence were SIRT1-independent. Altogether, these data indicate that VD3 has strong potential to modulate BM-MSCs' features, partially through SIRT1 signaling, although the precise mechanisms merit further investigation.}, language = {en} } @article{AchenbachKleinLuigetal.2021, author = {Achenbach, Leonard and Klein, Christian and Luig, Patrick and Bloch, Hendrik and Schneider, Dominik and Fehske, Kai}, title = {Collision with opponents - but not foul play - dominates injury mechanism in professional men's basketball}, series = {BMC Sports Science Medicine and Rehabilitation}, volume = {13}, journal = {BMC Sports Science Medicine and Rehabilitation}, doi = {10.1186/s13102-021-00322-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261765}, year = {2021}, abstract = {Background To identify injury patterns and mechanisms in professional men's basketball by means of video match analysis. Methods In Germany, injuries are registered with the statutory accident insurance for professional athletes (VBG) by clubs or club physicians as part of occupational accident reporting. Moderate and severe injuries (absence of > 7 days) sustained during basketball competition in one of four seasons (2014-2017 and 2018-2019) in the first or second national men's league in Germany were prospectively analyzed using a newly developed standardized observation form. Season 2017-2018 was excluded because of missing video material. Results Video analysis included 175 (53\%) of 329 moderate and severe match injuries. Contact patterns categorized according to the different body sites yielded eight groups of typical injury patterns: one each for the head, shoulders, and ankles, two for the thighs, and three for the knees. Injuries to the head (92\%), ankles (76\%), shoulders (70\%), knees (47\%), and thighs (32\%) were mainly caused by direct contact. The injury proportion of foul play was 19\%. Most injuries (61\%) occurred in the central zone below the basket. More injuries occurred during the second (OR 1.8, p = 0.018) and fourth quarter (OR 1.8, p = 0.022) than during the first and third quarter of the match. Conclusion The eight identified injury patterns differed substantially in their mechanisms. Moderate and severe match injuries to the head, shoulders, knees, and ankles were mainly caused by collision with opponents and teammates. Thus, stricter rule enforcement is unlikely to facilitate safer match play.}, language = {en} } @article{SchmalzlPlumhoffGilbertetal.2019, author = {Schmalzl, J. and Plumhoff, P. and Gilbert, F. and Gohlke, F. and Konrads, C. and Brunner, U. and Jakob, F. and Ebert, R. and Steinert, AF}, title = {The inflamed biceps tendon as a pain generator in the shoulder: A histological and biomolecular analysis}, series = {Journal of Orthopaedic Surgery}, volume = {27}, journal = {Journal of Orthopaedic Surgery}, number = {1}, doi = {10.1177/2309499018820349}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228611}, pages = {1-10}, year = {2019}, abstract = {Introduction: The long head of the biceps (LHB) is often resected in shoulder surgery. However, its contribution to inflammatory processes in the shoulder remains unclear. In the present study, inflamed and noninflamed human LHBs were comparatively characterized for features of inflammation. Materials and methods: Twenty-two resected LHB tendons were classified into inflamed (n = 11) and noninflamed (n = 11) samples. For histological examination, samples were stained with hematoxylin eosin, Azan, van Gieson, and Masson Goldner trichrome. Neuronal tissue was immunohistochemically visualized. In addition, specific inflammatory marker gene expression of primary LHB-derived cell cultures were analyzed. Results: Features of tendinopathy, such as collagen disorganization, infiltration by inflammatory cells, neovascularization, and extensive neuronal innervation were found in the tendinitis group. Compared to noninflamed samples, inflamed LHBs showed a significantly increased inflammatory marker gene expression Conclusion: Structural and biomolecular differences of both groups suggest that the LHB tendon acts as an important pain generator in the shoulder joint. These findings can, on the one hand, contribute to the understanding of the biomolecular genesis of LHB tendinitis and, on the other hand, provide possibilities for new therapeutic approaches.}, language = {en} } @article{ShekharHowellNedopiletal.2022, author = {Shekhar, Adithya and Howell, Stephen M. and Nedopil, Alexander J. and Hull, Maury L.}, title = {Excellent and good results treating stiffness with early and late manipulation after unrestricted caliper-verified kinematically aligned TKA}, series = {Journal of Personalized Medicine}, volume = {12}, journal = {Journal of Personalized Medicine}, number = {2}, issn = {2075-4426}, doi = {10.3390/jpm12020304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262094}, year = {2022}, abstract = {Manipulation under anesthesia (MUA) for stiffness within 6 to 12 weeks after mechanically aligned total knee arthroplasty (TKA) generally yields better outcome scores than an MUA performed later. However, the timing of MUA after unrestricted, caliper-verified, kinematically aligned (KA) TKA remains uncertain. A retrospective review identified 82 of 3558 (2.3\%) KA TKA patients treated with an MUA between 2010 and 2017. Thirty patients treated with an MUA within 3 months of the TKA (i.e., early) and 24 in the late group (i.e., >3 months) returned a questionnaire after a mean of 6 years and 5 years, respectively. Mean outcome scores for the early vs. late group were 78 vs. 62 for the Forgotten Joint Score (FJS) (p = 0.023) and 42 vs. 39 for the Oxford Knee Score (OKS) (p = 0.037). Subjectively, the early vs. late group responses indicated that 83\% vs. 67\% walked without a limp, 73\% vs. 54\% had normal extension, and 43\% vs. 25\% had normal flexion. An MUA within 3 months after unrestricted KA TKA provided excellent FJS and OKS at final follow-up relative to a late MUA. A late MUA performed after 3 months is worth consideration because of the good FJS and OKS scores, albeit with a risk of a persistent limp and limitation in knee extension and flexion.}, language = {en} } @article{WagenbrennerHeinzHorasetal.2020, author = {Wagenbrenner, Mike and Heinz, Tizian and Horas, Konstantin and Jakuscheit, Axel and Arnholdt, J{\"o}rg and Hermann, Marietta and Rudert, Maximilian and Holzapfel, Boris M. and Steinert, Andre F. and Weißenberger, Manuel}, title = {The human arthritic hip joint is a source of mesenchymal stromal cells (MSCs) with extensive multipotent differentiation potential}, series = {BMC Musculoskeletal Disorders}, volume = {21}, journal = {BMC Musculoskeletal Disorders}, number = {1}, doi = {10.1186/s12891-020-03340-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229497}, year = {2020}, abstract = {Background While multiple in vitro studies examined mesenchymal stromal cells (MSCs) derived from bone marrow or hyaline cartilage, there is little to no data about the presence of MSCs in the joint capsule or the ligamentum capitis femoris (LCF) of the hip joint. Therefore, this in vitro study examined the presence and differentiation potential of MSCs isolated from the bone marrow, arthritic hyaline cartilage, the LCF and full-thickness samples of the anterior joint capsule of the hip joint. Methods MSCs were isolated and multiplied in adherent monolayer cell cultures. Osteogenesis and adipogenesis were induced in monolayer cell cultures for 21 days using a differentiation medium containing specific growth factors, while chondrogenesis in the presence of TGF-ss1 was performed using pellet-culture for 27 days. Control cultures were maintained for comparison over the same duration of time. The differentiation process was analyzed using histological and immunohistochemical stainings as well as semiquantitative RT-PCR for measuring the mean expression levels of tissue-specific genes. Results This in vitro research showed that the isolated cells from all four donor tissues grew plastic-adherent and showed similar adipogenic and osteogenic differentiation capacity as proven by the histological detection of lipid droplets or deposits of extracellular calcium and collagen type I. After 27 days of chondrogenesis proteoglycans accumulated in the differentiated MSC-pellets from all donor tissues. Immunohistochemical staining revealed vast amounts of collagen type II in all differentiated MSC-pellets, except for those from the LCF. Interestingly, all differentiated MSCs still showed a clear increase in mean expression of adipogenic, osteogenic and chondrogenic marker genes. In addition, the examination of an exemplary selected donor sample revealed that cells from all four donor tissues were clearly positive for the surface markers CD44, CD73, CD90 and CD105 by flow cytometric analysis. Conclusions This study proved the presence of MSC-like cells in all four examined donor tissues of the hip joint. No significant differences were observed during osteogenic or adipogenic differentiation depending on the source of MSCs used. Further research is necessary to fully determine the tripotent differentiation potential of cells isolated from the LCF and capsule tissue of the hip joint.}, language = {en} } @article{HowellGillSheltonetal.2022, author = {Howell, Stephen M. and Gill, Manpreet and Shelton, Trevor J. and Nedopil, Alexander J.}, title = {Reoperations are few and confined to the most valgus phenotypes 4 years after unrestricted calipered kinematically aligned TKA}, series = {Knee Surgery, Sports Traumatology, Arthroscopy}, volume = {30}, journal = {Knee Surgery, Sports Traumatology, Arthroscopy}, number = {3}, doi = {10.1007/s00167-021-06473-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265291}, pages = {948-957}, year = {2022}, abstract = {Purpose The present study determined the postoperative phenotypes after unrestricted calipered kinematically aligned (KA) total knee arthroplasty (TKA), whether any phenotypes were associated with reoperation, implant revision, and lower outcome scores at 4 years, and whether the proportion of TKAs within each phenotype was comparable to those of the nonarthritic contralateral limb. Methods From 1117 consecutive primary TKAs treated by one surgeon with unrestricted calipered KA, an observer identified all patients (N = 198) that otherwise had normal paired femora and tibiae on a long-leg CT scanogram. In both legs, the distal femur-mechanical axis angle (FMA), proximal tibia-mechanical axis angle (TMA), and the hip-knee-ankle angle (HKA) were measured. Each alignment angle was assigned to one of Hirschmann's five FMA, five TMA, and seven HKA phenotype categories. Results Three TKAs (1.5\%) underwent reoperation for anterior knee pain or patellofemoral instability in the subgroup of patients with the more valgus phenotypes. There were no implant revisions for component loosening, wear, or tibiofemoral instability. The median Forgotten Joint Score (FJS) was similar between phenotypes. The median Oxford Knee Score (OKS) was similar between the TMA and HKA phenotypes and greatest in the most varus FMA phenotype. The phenotype proportions after calipered KA TKA were comparable to the contralateral leg. Conclusion Unrestricted calipered KA's restoration of the wide range of phenotypes did not result in implant revision or poor FJS and OKS scores at a mean follow-up of 4 years. The few reoperated patients had a more valgus setting of the prosthetic trochlea than recommended for mechanical alignment. Designing a femoral component specifically for KA that restores patellofemoral kinematics with all phenotypes, especially the more valgus ones, is a strategy for reducing reoperation risk.}, language = {en} } @article{KemmlerKohlJakobetal.2020, author = {Kemmler, Wolfgang and Kohl, Matthias and Jakob, Franz and Engelke, Klaus and Stengel, Simon von}, title = {Effects of high intensity dynamic resistance exercise and whey protein supplements on osteosarcopenia in older men with low bone and muscle mass. Final results of the randomized controlled FrOST study}, series = {Nutrients}, volume = {12}, journal = {Nutrients}, number = {8}, issn = {2072-6643}, doi = {10.3390/nu12082341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-211108}, year = {2020}, abstract = {The present study aimed to evaluate the effect of high intensity dynamic resistance exercise (HIT-DRT) and whey protein supplementation (WPS) on bone mineral density (BMD) and sarcopenia parameters in osteosarcopenic men. Men ≥ 72 years with osteosarcopenia (n = 43) were randomly assigned to a HIT-RT (HIT-RT: n = 21) or a non-training control group (n = 22). Supervised HIT-RT twice/week was applied for 18 months, while the control group maintained their habitual lifestyle. Supplying WPS, total protein intake amounted to 1.5-1.6 (HIT-RT) and 1.2 g/kg/body mass/d (control). Both groups were supplied with calcium and vitamin D. Primary study outcomes were BMD and the sarcopenia Z-score. After adjusting for multiplicity, we observed significant positive effects for sarcopenia Z-score (standardized mean difference (SMD): 1.40), BMD at lumbar spine (SMD: 0.72) and total hip (SMD: 0.72). In detail, effect sizes for skeletal muscle mass changes were very pronounced (1.97, p < 0.001), while effects for functional sarcopenia parameters were moderate (0.87, p = 0.008; handgrip strength) or low (0.39, p = 0.209; gait velocity). Apart from one man who reported short periods of temporary worsening of existing joint pain, no HIT-RT/WPS-related adverse effects or injuries were reported. We consider HIT-RT supported by whey protein supplementation as a feasible, attractive, safe and highly effective option to fight osteosarcopenia in older men.}, language = {en} }