@article{LiedtkeHofmannJakobetal.2020, author = {Liedtke, Daniel and Hofmann, Christine and Jakob, Franz and Klopocki, Eva and Graser, Stephanie}, title = {Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease}, series = {Biomolecules}, volume = {10}, journal = {Biomolecules}, number = {12}, publisher = {MDPI}, issn = {2218-273X}, doi = {10.3390/biom10121648}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220096}, year = {2020}, abstract = {Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme's role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.}, language = {en} } @article{KemmlerKohlFroehlichetal.2020, author = {Kemmler, Wolfgang and Kohl, Matthias and Fr{\"o}hlich, Michael and Jakob, Franz and Engelke, Klaus and von Stengel, Simon and Schoene, Daniel}, title = {Effects of High-Intensity Resistance Training on Osteopenia and Sarcopenia Parameters in Older Men with Osteosarcopenia—One-Year Results of the Randomized Controlled Franconian Osteopenia and Sarcopenia Trial (FrOST)}, series = {Journal of Bone and Mineral Research}, volume = {35}, journal = {Journal of Bone and Mineral Research}, number = {9}, doi = {10.1002/jbmr.4027}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214609}, pages = {1634 -- 1644}, year = {2020}, abstract = {Dynamic resistance exercise (DRT) might be the most promising agent for fighting sarcopenia in older people. However, the positive effect of DRT on osteopenia/osteoporosis in men has still to be confirmed. To evaluate the effect of low-volume/high-intensity (HIT)-DRT on bone mineral density (BMD) and skeletal muscle mass index (SMI) in men with osteosarcopenia, we initiated the Franconian Osteopenia and Sarcopenia Trial (FrOST). Forty-three sedentary community-dwelling older men (aged 73 to 91 years) with osteopenia/osteoporosis and SMI-based sarcopenia were randomly assigned to a HIT-RT exercise group (EG; n = 21) or a control group (CG; n = 22). HIT-RT provided a progressive, periodized single-set DRT on machines with high intensity, effort, and velocity twice a week, while CG maintained their lifestyle. Both groups were adequately supplemented with whey protein, vitamin D, and calcium. Primary study endpoint was integral lumbar spine (LS) BMD as determined by quantitative computed tomography. Core secondary study endpoint was SMI as determined by dual-energy X-ray absorptiometry. Additional study endpoints were BMD at the total hip and maximum isokinetic hip-/leg-extensor strength (leg press). After 12 months of exercise, LS-BMD was maintained in the EG and decreased significantly in the CG, resulting in significant between-group differences (p < 0.001; standardized mean difference [SMD] = 0.90). In parallel, SMI increased significantly in the EG and decreased significantly in the CG (p < 0.001; SMD = 1.95). Total hip BMD changes did not differ significantly between the groups (p = 0.064; SMD = 0.65), whereas changes in maximum hip-/leg-extensor strength were much more prominent (p < 0.001; SMD = 1.92) in the EG. Considering dropout (n = 2), attendance rate (95\%), and unintended side effects/injuries (n = 0), we believe our HIT-RT protocol to be feasible, attractive, and safe. In summary, we conclude that our combined low-threshold HIT-RT/protein/vitamin D/calcium intervention was feasible, safe, and effective for tackling sarcopenia and osteopenia/osteoporosis in older men with osteosarcopenia.}, language = {en} } @article{ChaudryGrimmFriedbergeretal.2020, author = {Chaudry, Oliver and Grimm, Alexandra and Friedberger, Andreas and Kemmler, Wolfgang and Uder, Michael and Jakob, Franz and Quick, Harald H. and von Stengel, Simon and Engelke, Klaus}, title = {Magnetic Resonance Imaging and Bioelectrical Impedance Analysis to Assess Visceral and Abdominal Adipose Tissue}, series = {Obesity}, volume = {28}, journal = {Obesity}, number = {2}, doi = {10.1002/oby.22712}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213591}, pages = {277 -- 283}, year = {2020}, abstract = {Objective This study aimed to compare a state-of-the-art bioelectrical impedance analysis (BIA) device with two-point Dixon magnetic resonance imaging (MRI) for the quantification of visceral adipose tissue (VAT) as a health-related risk factor. Methods A total of 63 male participants were measured using a 3-T MRI scanner and a segmental, multifrequency BIA device. MRI generated fat fraction (FF) maps, in which VAT volume, total abdominal adipose tissue volume, and FF of visceral and total abdominal compartments were quantified. BIA estimated body fat mass and VAT area. Results Coefficients of determination between abdominal (r\(^{2}\) = 0.75) and visceral compartments (r\(^{2}\) = 0.78) were similar for both groups, but slopes differed by a factor of two. The ratio of visceral to total abdominal FF was increased in older men compared with younger men. This difference was not detected with BIA. MRI and BIA measurements of the total abdominal volume correlated moderately (r\(^{2}\) = 0.31-0.56), and visceral measurements correlated poorly (r\(^{2}\) = 0.13-0.44). Conclusions Visceral BIA measurements agreed better with MRI measurements of the total abdomen than of the visceral compartment, indicating that BIA visceral fat area assessment cannot differentiate adipose tissue between visceral and abdominal compartments in young and older participants.}, language = {en} } @article{LiedertNemitzHaffnerLuntzeretal.2020, author = {Liedert, Astrid and Nemitz, Claudia and Haffner-Luntzer, Melanie and Schick, Fabian and Jakob, Franz and Ignatius, Anita}, title = {Effects of estrogen receptor and Wnt signaling activation on mechanically induced bone formation in a mouse model of postmenopausal bone loss}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {21}, issn = {1422-0067}, doi = {10.3390/ijms21218301}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285487}, year = {2020}, abstract = {In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/β-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/β-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss. We demonstrated that both pathways interact in the regulation of bone mass adaption in response to mechanical loading and that the activation of Wnt/β-catenin signaling considerably increased mechanically induced bone formation, whereas the effects of estrogen treatment strictly depended on the estrogen status in the mice.}, language = {en} } @article{HorasvanHerckMaieretal.2020, author = {Horas, Konstantin and van Herck, Ulrike and Maier, Gerrit S. and Maus, Uwe and Harrasser, Norbert and Jakob, Franz and Weissenberger, Manuel and Arnholdt, J{\"o}rg and Holzapfel, Boris M. and Rudert, Maximilian}, title = {Does vitamin D deficiency predict tumour malignancy in patients with bone tumours? Data from a multi-center cohort analysis}, series = {Journal of Bone Oncology}, volume = {25}, journal = {Journal of Bone Oncology}, doi = {10.1016/j.jbo.2020.100329}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230314}, year = {2020}, abstract = {Vitamin D deficiency is a global health concern that is estimated to afflict over one billion people globally. The major role of vitamin D is that of a regulator of calcium and phosphate metabolism, thus, being essential for proper bone mineralisation. Concomitantly, vitamin D is known to exert numerous extra-skeletal actions. For example, it has become evident that vitamin D has direct anti-proliferative, pro-differentiation and pro-apoptotic actions on cancer cells. Hence, vitamin D deficiency has been associated with increased cancer risk and worse prognosis in several malignancies. We have recently demonstrated that vitamin D deficiency promotes secondary cancer growth in bone. These findings were partly attributable to an increase in bone remodelling but also through direct effects of vitamin D on cancer cells. To date, very little is known about vitamin D status of patients with bone tumours in general. Thus, the objective of this study was to assess vitamin D status of patients with diverse bone tumours. Moreover, the aim was to elucidate whether or not there is an association between pre-diagnostic vitamin D status and tumour malignancy in patients with bone tumours. In a multi-center analysis, 25(OH)D, PTH and calcium levels of 225 patients that presented with various bone tumours between 2017 and 2018 were assessed. Collectively, 76\% of all patients had insufficient vitamin D levels with a total mean 25(OH)D level of 21.43 ng/ml (53.58 nmol/L). In particular, 52\% (117/225) of patients were identified as vitamin D deficient and further 24\% of patients (55/225) were vitamin D insufficient. Notably, patients diagnosed with malignant bone tumours had significantly lower 25(OH)D levels than patients diagnosed with benign bone tumours [19.3 vs. 22.75 ng/ml (48.25 vs. 56.86 nmol/L); p = 0.04). In conclusion, we found a widespread and distressing rate of vitamin D deficiency and insufficiency in patients with bone tumours. However, especially for patients with bone tumours sufficient vitamin D levels seem to be of great importance. Thus, we believe that 25(OH)D status should routinely be monitored in these patients. Collectively, there should be an increased awareness for physicians to assess and if necessary correct vitamin D status of patients with bone tumours in general or of those at great risk of developing bone tumours.}, language = {en} } @article{OhlebuschBorstFrankenbachetal.2020, author = {Ohlebusch, Barbara and Borst, Angela and Frankenbach, Tina and Klopocki, Eva and Jakob, Franz and Liedtke, Daniel and Graser, Stephanie}, title = {Investigation of alpl expression and Tnap-activity in zebrafish implies conserved functions during skeletal and neuronal development}, series = {Scientific Reports}, volume = {10}, journal = {Scientific Reports}, doi = {10.1038/s41598-020-70152-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230024}, year = {2020}, abstract = {Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissue-nonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish (Danio rerio) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. Additionally, we determined functional consequences of Tnap inhibition on neural and skeletal development in zebrafish. We show that expression of alpl is present during embryonic stages and in adult neuronal tissues. Analyses of enzyme function reveal zones of pronounced Tnap-activity within the telencephalon and the mesencephalon. Treatment of zebrafish embryos with chemical Tnap inhibitors followed by axonal and cartilage/mineralized tissue staining imply functional consequences of Tnap deficiency on neuronal and skeletal development. Based on the results from neuronal and skeletal tissue analyses, which demonstrate an evolutionary conserved role of this enzyme, we consider zebrafish as a promising species for modeling HPP in order to discover new potential therapy strategies in the long-term.}, language = {en} } @article{SchmalzlPlumhoffGilbertetal.2019, author = {Schmalzl, Jonas and Plumhoff, Piet and Gilbert, Fabian and Gohlke, Frank and Konrads, Christian and Brunner, Ulrich and Jakob, Franz and Ebert, Regina and Steinert, Andre F.}, title = {Tendon-derived stem cells from the long head of the biceps tendon}, series = {Bone \& Joint Research}, volume = {8}, journal = {Bone \& Joint Research}, number = {9}, doi = {10.1302/2046-3758.89.BJR-2018-0214.R2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200370}, pages = {414-424}, year = {2019}, abstract = {Objectives The long head of the biceps (LHB) is often resected in shoulder surgery and could therefore serve as a cell source for tissue engineering approaches in the shoulder. However, whether it represents a suitable cell source for regenerative approaches, both in the inflamed and non-inflamed states, remains unclear. In the present study, inflamed and native human LHBs were comparatively characterized for features of regeneration. Methods In total, 22 resected LHB tendons were classified into inflamed samples (n = 11) and non-inflamed samples (n = 11). Proliferation potential and specific marker gene expression of primary LHB-derived cell cultures were analyzed. Multipotentiality, including osteogenic, adipogenic, chondrogenic, and tenogenic differentiation potential of both groups were compared under respective lineage-specific culture conditions. Results Inflammation does not seem to affect the proliferation rate of the isolated tendon-derived stem cells (TDSCs) and the tenogenic marker gene expression. Cells from both groups showed an equivalent osteogenic, adipogenic, chondrogenic and tenogenic differentiation potential in histology and real-time polymerase chain reaction (RT-PCR) analysis. Conclusion These results suggest that the LHB tendon might be a suitable cell source for regenerative approaches, both in inflamed and non-inflamed states. The LHB with and without tendinitis has been characterized as a novel source of TDSCs, which might facilitate treatment of degeneration and induction of regeneration in shoulder surgery.}, language = {en} } @article{MuellerDeubertSeefriedKrugetal.2017, author = {M{\"u}ller-Deubert, Sigrid and Seefried, Lothar and Krug, Melanie and Jakob, Franz and Ebert, Regina}, title = {Epidermal growth factor as a mechanosensitizer in human bone marrow stromal cells}, series = {Stem Cell Research}, volume = {24}, journal = {Stem Cell Research}, doi = {10.1016/j.scr.2017.08.012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170247}, pages = {69-76}, year = {2017}, abstract = {Epidermal growth factors (EGFs) e.g. EGF, heparin-binding EGF and transforming growth factor alpha and their receptors e.g. EGFR and ErbB2 control proinflammatory signaling and modulate proliferation in bone marrow stromal cells (BMSC). Interleukin-6 and interleukin-8 are EGF targets and participate in the inflammatory phase of bone regeneration via non-canonical wnt signaling. BMSC differentiation is also influenced by mechanical strain-related activation of ERK1/2 and AP-1, but the role of EGFR signaling in mechanotransduction is unclear. We investigated the effects of EGFR signaling in telomerase-immortalized BMSC, transfected with a luciferase reporter, comprising a mechanoresponsive AP1 element, using ligands, neutralizing antibodies and EGFR inhibitors on mechanotransduction and we found that EGF via EGFR increased the response to mechanical strain. Results were confirmed by qPCR analysis of mechanoresponsive genes. EGF-responsive interleukin-6 and interleukin-8 were synergistically enhanced by EGF stimulation and mechanical strain. We show here in immortalized and primary BMSC that EGFR signaling enhances mechanotransduction, indicating that the EGF system is a mechanosensitizer in BMSC. Alterations in mechanosensitivity and -adaptation are contributors to age-related diseases like osteoporosis and the identification of a suitable mechanosensitizer could be beneficial. The role of the synergism of these signaling cascades in physiology and disease remains to be unraveled.}, language = {en} } @article{DotterweichSchlegelmilchKelleretal.2016, author = {Dotterweich, Julia and Schlegelmilch, Katrin and Keller, Alexander and Geyer, Beate and Schneider, Doris and Zeck, Sabine and Tower, Robert J. J. and Ebert, Regina and Jakob, Franz and Sch{\"u}tze, Norbert}, title = {Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells-implications for myeloma bone disease}, series = {Bone}, volume = {93}, journal = {Bone}, doi = {10.1016/j.bone.2016.08.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186688}, pages = {155-166}, year = {2016}, abstract = {Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors. To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA6 cell attachment. This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage.}, language = {en} } @article{WittmannSiebervonStengeletal.2016, author = {Wittmann, Katharina and Sieber, Cornel and von Stengel, Simon and Kohl, Matthias and Freiberger, Ellen and Jakob, Franz and Lell, Michael and Engelke, Klaus and Kemmler, Wolfgang}, title = {Impact of whole body electromyostimulation on cardiometabolic risk factors in older women with sarcopenic obesity: the randomized controlled FORMOsA-sarcopenic obesity study}, series = {Clinical Interventions in Aging}, volume = {11}, journal = {Clinical Interventions in Aging}, doi = {10.2147/CIA.S116430}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164930}, pages = {1697—1706}, year = {2016}, abstract = {Background: Sarcopenic obesity (SO) is characterized by a combination of low muscle and high fat mass with an additive negative effect of both conditions on cardiometabolic risk. The aim of the study was to determine the effect of whole-body electromyostimulation (WB-EMS) on the metabolic syndrome (MetS) in community-dwelling women aged ≥70 years with SO. Methods: The study was conducted in an ambulatory university setting. Seventy-five community-dwelling women aged ≥70 years with SO living in Northern Bavaria, Germany, were randomly allocated to either 6 months of WB-EMS application with (WB-EMS\&P) or without (WB-EMS) dietary supplementation (150 kcal/day, 56\% protein) or a non-training control group (CG). WB-EMS included one session of 20 min (85 Hz, 350 µs, 4 s of strain-4 s of rest) per week with moderate-to-high intensity. The primary study endpoint was the MetS Z-score with the components waist circumference (WC), mean arterial pressure (MAP), triglycerides, fasting plasma glucose, and high-density lipoprotein cholesterol (HDL-C); secondary study endpoints were changes in these determining variables. Results: MetS Z-score decreased in both groups; however, changes compared with the CG were significant (P=0.001) in the WB-EMS\&P group only. On analyzing the components of the MetS, significant positive effects for both WB-EMS groups (P≤0.038) were identified for MAP, while the WB-EMS group significantly differed for WC (P=0.036), and the WB-EMS\&P group significantly differed for HDL-C (P=0.006) from the CG. No significant differences were observed between the WB-EMS groups. Conclusion: The study clearly confirms the favorable effect of WB-EMS application on the MetS in community-dwelling women aged ≥70 years with SO. However, protein-enriched supplements did not increase effects of WB-EMS alone. In summary, we considered this novel technology an effective and safe method to prevent cardiometabolic risk factors and diseases in older women unable or unwilling to exercise conventionally.}, language = {en} }