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Boerckel Laboratory

Annemarie Lang, Ph.D.

Post-doctoral Fellow

Home country: Germany

Education

State exam and approbation in Veterinary Medicine | Freie Universität (FU) Berlin, Germany | 02/2012

Dr. med. vet., Immunology and Molecular Biology | Freie Universität (FU) Berlin, Germany | 03/2016

Ph.D., Biomedical Sciences | Charité-Universitätsmedizin Berlin and FU Berlin, Germany | 11/2019

Postdoctoral, Rheumatology | Prof. Frank Buttgereit’s Group, Charité-Universitätsmedizin Berlin, Germany | since 2016

Postdoctoral, Mechanobiology | Joel D. Boerckel’s Group, University of Pennsylvania, PA, US | since 2021

Areas of Interest

I am a veterinarian by training and have dedicated my postgraduate life to science. Within my current work, I aim to uncover fundamental mechanisms that i) control endochondral ossification in fracture repair and ii) maintain cartilage homeostasis in the knee joint by state-of-the-art in vivo and in vitro models to develop sophisticated therapies for musculoskeletal disorders.

My curiosity for scientific questions in a translational context was boosted during my veterinary training, when I developed a gene therapy to treat osteoarthritis in parallel to my studies (Dr. med. vet.). My Ph.D. work focused on fundamental mechanisms of HIF-stabilizers as therapeutics for fracture healing disorders which is currently being tested for clinical translation. In my current research, I investigate the mechanisms of HIF1-YAP/TAZ crosstalk in fracture repair. Moreover, I have a passion for the implementation of the 3R principle (replace, reduce, refine animal experiments) using bioengineering approaches, so in parallel to my in vivo studies, I developed sophisticated in vitro models to mimic i) osteoarthritis, ii) the immunopathogenesis of arthritis or iii) the initial phase of fracture healing including the appropriate microenvironment (e.g., hypoxia) and complex cellular crosstalk (e.g. bone and immune cells).

Annemarie joined McKay Orthopedic Research Lab in spring 2021 and is working towards completing her post-doc work. Annemarie came with her dog “Mephisto” and loves to explore Philadelphia with him.

 

Selected Publications

Publications as first or last author and short summary on scientific significance and own contribution – *authors contributed equally

  1. Lang, A., Stefanowski, J., Pfeiffenberger, M., Wolter, A., Damerau, A., Hemmati-Sadeghi, S., Haag, R., Hauser, A.-E., Löhning, M., Perka, C., Duda, G.N., Hoff, P., Schmidt-Bleek, K.*, Gaber, T.* Buttgereit, F.* (2022) MIF does only marginally enhance the pro-regenerative capacities of DFO in a mouse-osteotomy-model of compromised bone healing conditions. Bone. Jan; 154:116247 - Link: https://pubmed.ncbi.nlm.nih.gov/34743042/ ~ This study provides evidence that the application of potent HIF-stabilizers during the initial phase of fracture healing might be a promising preventive strategy to accelerate fracture healing to finally help minimizing bone healing disorders. Based this my data, we successfully received a BMBF-Grant (PROOF-DESFERAL) for the clinical translation of my findings (PI Prof Buttgereit). This project strengthened my interest in studying the role of hypoxia and related pathways more in-depth.

  2. Wolter, A.*, Rapp, A.E.*, Durst, M., Hildebrand, L., Löhning, L., Buttgereit, F., Schmidt-Bleek, K., Jirkof, P., Lang, A. (2021) Systematic review on the reporting accuracy of experimental details in publications using mouse femoral fracture models. Bone. Nov; 152: 116088. Link: https://pubmed.ncbi.nlm.nih.gov/34175502/ ~ Here, we systematically show that the reporting accuracy in mouse femoral fracture model studies is partly insufficient and that compliance with ARRIVE guidelines may help to improve reporting in the field. I initiated and supervised the study to create awareness for good reporting practice ensuring scientific integrity and increasing reproducibility.

  3. Sunkara, V., Heinz, G.A., Heinrich, F.F., Durek, P., Mobasheri, A., Mashreghi, M.-F.*, Lang, A.* (2021). Combining segmental bulk- and single-cell RNA-sequencing to define the chondrocyte gene expression signature in the murine knee joint. Osteoarthritis and Cartilage. Jun 01; 29(6): 905–914. Link: https://pubmed.ncbi.nlm.nih.gov/33762205/ ~ This manuscript describes a novel strategy to precisely delineate the chondrocyte transcriptome from murine joint cartilage without dissociation-induced artifacts. It strongly underlines my ability to work in interdisciplinary teams and my independent/innovative thinking. V. Sunkara (mathematician) and I jointly conducted the project from the beginning including wet and dry lab methods as well as big data analysis. 

  4. Pfeiffenberger, M., Damerau, A., Ponomarev, I., Bucher, C.H., Chen, Y., Barnewitz, D., Thöne-Reineke, C., Hoff, P., Buttgereit, F., Gaber, T., Lang, A. (2021) Functional scaffold-free bone equivalents induce osteogenic and angiogenic processes in a human in vitro fracture hematoma model. Journal of Bone Mineral Research. Jun 01; 26(6): 1189–1201. Link: https://pubmed.ncbi.nlm.nih.gov/33534144/ ~ Based on my in vivo experiences, I developed a concept to simulate the initial phase of bone regeneration in vitro. Here, we describe this up-to-date in vitro system recapitulating cellular and humoral interactions in a controlled physicochemical microenvironment to study the interaction between bone and immune cells in the fracture gap.

  5. Damerau, A., Pfeiffenberger, M., Weber, M.-C., Burmester, G.-R., Buttgereit, F., Gaber, T.*, Lang, A.* (2021). Mimicking cytokine-induced key features of arthritis in a human in vitro 3D osteo-chondral tissue model. International Journal of Molecular Sciences. Dec 24; 22(1): 128. Link: https://pubmed.ncbi.nlm.nih.gov/33374446/ ~ We here provide evidence that a newly developed human in vitro 3D osteochondral tissue model mimics cytokine-induced cell- and matrix-related changes-key features of arthritis and may serve as a preclinical tool for the evaluation of both new targets and potential drugs in a more translational setup. I closely supervised this project and outlined the whole experimental setup.

  6. Weber, M.-C.*, Fischer, L.*, Damerau, A., Ponomarev, I., Pfeiffenberger, M., Gaber, T., Götschel, S., Lang, J., Röblitz, S., Buttgereit, F., Ehrig, R., Lang, A. (2020) Macroscale mesenchymal condensation to study cytokine-driven cellular and matrix-related changes during cartilage degradation. Biofabrication. Aug 10; 12(4):045016. Link: https://pubmed.ncbi.nlm.nih.gov/32598334/ ~ I designed the project based on the idea to develop a combined in vitro and in silico model to simulate matrix degrading process during the onset of osteoarthritis in close collaboration with mathematicians. Besides setting up, managing, and supervising the collaborative effort, I significantly contributed to the acquisition of funding.

  7. Jirkof, P.*, Durst, M.*, Klopfleisch, R., Palme, R., Thöne-Reineke, C., Buttgereit, F., Schmidt-Bleek, K., Lang, A. (2019) Administration of Tramadol or Buprenorphine via the drinking water for post-operative analgesia in a mouse-osteotomy model. Scientific Reports. Jul 24; 9(1):10749. Link: https://pubmed.ncbi.nlm.nih.gov/31341225/ ~ When I started with animal experiments during my PhD, I recognized that evidence for appropriate pain management especially in the mouse-osteotomy-model was missing. Thus, I teamed up with an expert (P. Jirkof) and precisely assessed the pain management in our model using general wellbeing and model-specific pain parameters. We also show that increasing the concentration of pain medication does not further relief pain but rather negatively affects animal wellbeing.

  8. Pfeiffenberger, M.*, Bartsch, J.*, Hoff, P., Ponomarev, I., Barnewitz, D., Thöne-Reineke, C., Buttgereit, F., Gaber, T.*, Lang, A.* (2019) Hypoxia and mesenchymal stromal cells as key drivers of initial fracture healing in an equine in vitro fracture hematoma model. PlosONE. Apr 4; 14(4):e0214276. Link: https://pubmed.ncbi.nlm.nih.gov/30947253/ ~ Detailed knowledge on processes in equine fracture healing in general and on the initial phase in particular is apparently very limited. Therefore, we generated equine in vitro fracture hematoma models (FH models) to study time-dependent changes in cell composition and RNA-expression for the most prominent cells under conditions most closely adapted to the in vivo situation (hypoxia). This project was particularly close to my heart, as I decided against equine medicine and in favor of research during my veterinary studies. Moreover, I am certain that considering animals as suitable comparative patient and not only as research tools would have a major impact on translational medicine in the future.

  9. Stefanowski, J.*, Lang, A.*, Rauch, A., Aulich, L., Köhler, M., Buttgereit, F., Schmidt-Bleek, K., Niesner, R., Gaber, T., Hauser, A. (2019) Spatial Distribution of Macrophages during Callus Formation and Maturation Reveals Close Crosstalk between Macrophages and Newly Forming Vessels. Frontiers Immunology. Nov 26; 10:2588. Link: https://pubmed.ncbi.nlm.nih.gov/31956322/ ~ Within this study, we analyzed the initial phase of vascular regeneration during fracture repair and provide evidence for its dependence on the presence of macrophages. We specifically focused on the early regeneration events where a close crosstalk of blood vessels with macrophages is most prominent (d1–d7) and compared this to the bone remodeling phase (d14–d21). Jonathan and I jointly designed this project based on the same but independent observations.

  10. Lang, A., Kirchner, M., Stefanowski, J., Durst, M., Weber, M.-C., Pfeiffenberger, M., Damerau, A., Hauser, A.E., Hoff, P., Duda, G.N., Buttgereit, F., Schmidt-Bleek, K.*, Gaber, T.* (2019) Col I-based Scaffolds Negatively Impact Fracture Healing in a Mouse-Osteotomy-Model Although Used Routinely in Clinical Application. Acta Biomaterialia. Mar 1; 86:171–184. Link: https://pubmed.ncbi.nlm.nih.gov/30616076/ ~ As a side finding of my PhD study on HIF stabilizers, I observed a delayed fracture healing when applying a clinically approved bovine collagen-I based scaffold as carrier system. In this study, I precisely describe this unexpected finding and therefore pave the way for new more sophisticated delivery systems.

  11. Lang, A., Neuhaus, J., Pfeiffenberger, M., Schröder, E., Weber,Y., Ponomarev, I., Gaber, T. & M.F.G. Schmidt (2014) Optimization of a non-viral transfection system to evaluate Cox-2 controlled IL-4 expression for osteoarthritis gene therapy in vitro. Journal of Gene Medicine. Nov–Dec; 16(11–12): 352–63. Link: https://pubmed.ncbi.nlm.nih.gov/25382123/ ~ Here, I tested a new gene therapeutic approach in an equine cell culture system. To avoid continuous overexpression, we developed a controlled, self-limiting and inflammation-dependent expression of therapeutic transgenes. Therefore, a genetically switchable plasmid was developed by placing the Cox-2 promoter in front of the chosen transgene IL-4.

  12. Lang, A., De Vries, M., Feineis, S., Müller, E, Osterrieder, N. & A.M. Damiani (2013) Development of a peptide ELISA for discrimination between serological responses to equine herpesvirus type 1 and 4. Journal of Virological Methods. 193: 667– 673. Link: https://pubmed.ncbi.nlm.nih.gov/23928223/ ~ Different peptides for equine herpesvirus type 1 (EHV-1) and 4 (EHV-4) were tested and evaluated   to be used in a robust ELISA assay to detect EHV-1/-4 outbreaks. My work contributed to the installation of an ELISA-based assay in the Institute for Virology (Freie Universität Berlin) as reliable and cost-effective alternative to current methods for serological EHV-1 and EHV-4 diagnosis.

Publications in peer-reviewed scientific journals as co-author

  1. Pfeiffenberger, M., Hoff, P., Thöne-Reineke, C., Buttgereit, F., Lang, A., Gaber, T. (2020) The in vitro human fracture hematoma model – a tool for preclinical drug testing. ALTEX. Oct 20; 37(4):561–578.

  2. Gaber, T., Brinkman, A.C.K., Pienczikowski, J., Diesing, K., Damerau, K., Pfeiffenberger, M., Lang, A., Ohrndorf, S., Burmester, G.-R., Buttgereit, F., Hoff, P. (2020) Impact of janus kinase (Jak) inhibition with tofacitinib on fundamental processes of bone healing. International Journal of Molecular Sciences. Jan 29; 21(3):865.

  3. Gaber, T., Schönbeck, K., Hoff, H., Tran, C.L., Strehl, C., Lang, A., Ohrndorf, S., Pfeiffenberger, M., Röhner, E., Matziolis, G., Burmester, G.R., Buttgereit, F., Hoff, P. (2018) CTLA-4 Mediates Inhibitory Function of Mesenchymal Stem/Stromal Cells. International Journal of Molecular Sciences. Aug 7; 19(8). 

  4. Hoff, P., Gaber, T., Strehl, C., Jakstadt, M., Hoff, H., Schmidt-Bleek, K., Lang, A., Röhner, E., Huscher, D., Matziolis, G., Burmester, G.R., Schmidmaier, G., Perka, C., Duda, G.N., Buttgereit, F. (2017) A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients. International Journal of Molecular Sciences. Mar 8; 18(3). pii: E583. 

  5. Hoff, P., Gaber, T., Strehl, C., Schmidt-Bleek, K., Lang, A., Huscher, D., Burmester, G.R., Schmidmaier, G., Perka, C., Duda, G.N., Buttgereit, F. (2016) Immunological characterization of the early human fracture hematoma. Immunologic Research. Sep 14; 64(5–6): 1195–1206. 

  6. Hoff, P., Belavý, D.L., Huscher, D., Lang, A., Hahne, M., Kuhlmey, A., Maschmeyer, P., Armbrecht, G., Fitzner, R., Perschel, F.H., Gaber, T., Burmester, G.R., Straub, R.H., Felsenberg, D., Buttgereit, F. (2015) Effects of 60-days bed rest with and without exercise on cellular and humoral immunological parameters. Cellular & Molecular Immunology. Nov 14; 12(4):483–92. 

  7. Röhner, E., Hoff,P. , Gaber, T., Lang, A., Vörös, P., Buttgereit, F., Perka, C., Windisch, C., Matziolis, G. (2015) Cytokine expression in human osteoblast after antiseptic treatment with polyhexanide but not chlorhexidine. Journal of Investigative Surgery. Aug 5; 28(1):1–7.

Reviews, preprint publications, workshop reports, editorials, monographs & book chapters

  1. Pfeiffenberger, M., Damerau, A., Lang, A., Buttgereit, F., Hoff, P., Gaber, T. (2021) Fracture Healing Research—Shift towards In Vitro Modeling? Biomedicines. 9 (748).

  2. Mobasheri, A., Kapoor, M., Ali, S. A., Lang, A., Madry, H. (2021) The future of deep phenotyping in osteoarthritis: how can high throughput omics technologies advance our understanding of the cellular and molecular taxonomy of the disease? Osteoarthritis and Cartilage Open – in press.

  3. Marx-Stoelting, […], Lang, A., […] & R. Solecki (2020) 25th anniversary of the Berlin workshop on developmental toxicology: DevTox database update, challenges in risk assessment of developmental neurotoxicity and alternative methodologies in bone development and growth. Reproductive Toxicology – in press.

  4. Lang, A., Czech, L. & A. Probst (2020) Die Leiden der jungen Wissenschaftler. Biospektrum 26, 572–576.

  5. A. Lang (2019) HIF-stabilization to accelerate fracture healing – Evaluation of a new therapeutic strategy to treat delayed bone regeneration. Inaugural-Dissertation PhD. Freie Universität Berlin. In: Mensch und Buch Verlag. Berlin, Germany. ISBN 978-3-96729-026-4. Monography.

  6. Scheinpflug, J.*, Pfeiffenberger, M.*, Damerau, A., Schwarz, F., Textor, M., Lang, A., Schulze, F. (2018) Journey into human bone models – A review. Genes. 9 (5).

  7. Lang, A. et al. (2018) In silico methods – Computational alternatives to animal testing. ALTEX 35, 124–126. Workshop report.

  8. Lang, A., Schulz, A., Ellinghaus, A., Schmidt-Bleek, K. (2016) Osteotomy models – the current status on pain scoring and management in small rodents. Laboratory animals, 50(6): 433–441.

  9. A. Lang (2016) Reviewing Challenges in Osteoarthritis Gene Therapy and Introduction of a Molecular Therapeutic Approach in an Equine Model System. Inaugural-Dissertation Dr. med. vet. Freie Universität Berlin. In: Mensch und Buch Verlag. Berlin, Germany. ISBN 978-3-86387-707-1. Monography. 

  10. Amann, A., Lang, A., Hoff, P., Buttgereit, F. (2014) Effekte der Glukokortikoide auf den Knochen. Osteologie; 23(03): 179–186. DOI: 10.1055/s-0037-1622016. 

  11. Rai, M.F., Lang, A., Sieber, M., Schmidt, M.F.G. (2011) Conditioning and Scaffolding of Chondrocytes: Smart Steps towards Osteoarthritis Gene Therapy. In: Chunsheng Kang (ed.), Gene Therapy Application. In: Tech Open Access Publisher. Rijeka, Croatia. ISBN 978-953-307-541-9. Book chapter.

Selected conference abstracts
  1. Lang, A., Heinz, G.A., Heinrich, F.R., Durek, P., Mobasheri, A., Mashreghi, M.-F., Sunkara. V. Evaluation of a pipeline for chondrocyte dissociation from murine articular cartilage for single cell sequencing without altering the transcriptome. OARSI World Congress 2021 – virtual Poster presentation

  2. Lang, A., Benn, A., Damerau, A., Boerckel, J., Kerckhofs, G., Zwijsen, A. BMP-SMAD1/5 Signaling Is Required for Adequate Coupling of Angiogenesis and Osteogenesis in Long Bones. ORS Congress 2021 – virtual Podium presentation – NIRA Award

  3. Lang, A., Diesing, K., Damerau, A., Pfeiffenberger, M., Gaber, T., Buttgereit, F. First Steps Towards the Establishment of an In Vitro Trabecular Human Bone Model. ORS Congress 2021 – virtual Podium presentation – finalist for 3R Award of the ORS Preclinical Model Section & NIRA Awardee

  4. Pfeiffenberger, M., Damerau, A., Hoff, P., Buttgereit, F., Gaber, T., Lang, A. A preclinical testing tool: The in vitro fracture gap model. ORS Congress 2021 – virtual Poster presentation 

  5. Damerau, A., Pfeiffenberger, M., Buttgereit, F., Gaber, T., Lang, A. Three-dimensional human osteochondral tissue as a novel in vitro model of arthritis and preclinical drug screening platform. ORS Congress 2021 – virtual Poster presentation

  6. Lang, A., Diesing, K., Damerau, A., Pfeiffenberger, M., Gaber, T., Buttgereit, F. Development of an In Vitro Trabecular Human Bone Model to Recapitulate Features of Glucocorticoid-induced Osteoporosis. EULAR Congress 2020 – virtual Poster presentation

  7. Lang, A., Cai, L., Kuppe, A., Gaber, T., Guilak, F., Buttgereit, F., Rai, M.F. Characterization of a disease-inducible interleukin-4 gene therapy in murine articular chondrocytes. OARSI World Congress 2020 - https://doi.org/10.1016/j.joca.2020.02.797 – Abstract publication due to Covid19

  8. Lang, A., Fischer, L., Weber, M.C., Damerau, A., Gaber, T., Götschel, S., Ehrig, R., Röblitz, S., Buttgereit, F. Combining in vitro and in silico modelling to simulate cartilage degradation during osteoarthritis. EUSAAT Congress 2019, Linz, Austria – Podium presentation

  9. Lang, A., Fischer, L., Weber, M.-C., Gaber, T., Ehrig, R., Röblitz, S., Buttgereit, F. Combining in vitro simulation and in silico modelling towards a sophisticated human osteoarthritis model. OARSI World Congress 2019, Toronto, Canada – Poster presentation

  10. Sunkara, V., Lang, A. Systems biology pipeline for precise extraction of the chondrocyte transcriptome in a whole tissue approach. OARSI World Congress 2019, Toronto, Canada – Poster presentation

  11. Lang, A., Pfeiffenberger, M., Damerau, A., Buttgereit, F., Gaber, T. Mimicking the First Phase of Fracture Healing In Vitro. ORS Meeting 2019, Austin, Texas, US – Poster presentation

  12. Lang, A., Gaber, T., Hoff, P., Schmidt-Bleek, K., Buttgereit, F. Application of HIF-Stabilizers Enhances Bone Regeneration in a Mouse Model of Compromised Conditions. ORS Meeting 2019, Austin, Texas, US – Poster presentation

  13. Lang, A., Damerau, A., Weber, M.-C., Buttgereit, F., Gaber, T. First steps towards the in vitro simulation of an arthritic joint. OARSI World Congress 2018, Liverpool, UK – Poster presentation

  14. Lang, A., Gaber, T., Schmidt-Bleek, K., Buttgereit, F. Bovine Col I-based scaffold inhibits bone healing in a mouse-osteotomy-model – Time to rethink delivery systems. Bone-tec, München, 2017, Deutschland – Podium presentation

  15. Lang, A., Weber, M.-C., Pfeiffenberger, M., Gaber, T., Buttgereit, F. Simulating osteoarthritis in vitro with human scaffold-free 3D cartilage transplants.10th World Congress on Alternatives and Animal Use in the Life Sciences (WC10), 2017, Seattle, US – Podium presentation

  16. Lang, A., Durst, M., Buttgereit, F., Schmidt-Bleek, K., Jirkof, P. Dosage matters - Tramadol applied via the drinking water for pain management in bone-linked mice models. 10th World Congress on Alternatives and Animal Use in the Life Sciences (WC10), 2017, Seattle, US - Podium presentation

  17. Lang, A., Pfeiffenberger, M., Neuhaus, J., Ponomarev, I., Barnewitz, D., Buttgereit, F., Gaber, T. Modelling musculoskeletal disorders in vitro – Comprising complex processes in convincing systems. Pan-American Conference on Alternative to Animal Testing, 2016, Baltimore, US – Podium presentation 

Further Scientific Activities

  • Member of the OARSI Young Investigator Committee (Osteoarthritis Research Society International)
  • Board member of EUSAAT (European Society for Alternatives to Animal Testing)
  • Elected member of the Charité3R board - Representative EARA & EU3Rnet 
  • Editor-in-Chief for Laboratory Animals
  • Associate Guest Editor - OAC Open Special Themed Issue on Current advances in high throughput omics technologies for deep phenotyping in osteoarthritis

Awards/Fellowships

  • ORS/ON Education Grant 2022
  • New Investigator Recognition Award 2021 (NIRA) - Orthopedic Research Society (ORS) 
  • DFG Research Fellowship for stay at UPenn 
  • Award for Alternative Methods from Berlin State
  • Add-on Fellowship for Systems Biology - Joachim Herz Foundation 
  • OARSI Belt and Road Scholarship funded by the Beijing Joint Care Foundation 
  • DAAD Postdoctoral Travel Award (2017, 2019) 

Collaborations at UPenn/CHOP

Riccardo Gottardi (CHOP) - An in vitro toolset to study endochondral ossification (3DEndOs) -Research Grant by Alternatives Research and Development Foundation (ARDF) - PI: Joel D. Boerckel

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