B2 – Effects of sulfated glycosaminoglycans on bone regeneration through interactions with Wnt inhibitors

Aging societies face an increasing clinical need for biomaterials to repair and regenerate large bone defects. Ideally, new biomaterials fully integrate into the bone. Within the past two funding periods, we investigated the effect of sulfated glycosaminoglycans (GAG) on bone cell function in vitro and their regenerative potential in vivo. During the third funding period, we will test sulfated GAGs in a fracture model in vivo, using diabetic animals with impaired bone regeneration. We will study the underlying mechanisms of the pro-osteogenic effects of sulfated GAGs with a focus on Wnt-signaling and the Wnt-inhibitors sclerostin and dickkopf-1. The direct comparison of normal vs. compromised bone regeneration allows us to test the suitability of biomaterials for bone regeneration in vivo.

Publications

  1. Salbach-Hirsch J, Rauner M, Hofbauer C, Hofbauer LC. New insights into the role of glycosaminoglycans in the endosteal bone microenvironment. Biological Chemistry, vol. 402, no. 11, 2021, pp. 1415-1425. https://doi.org/10.1515/hsz-2021-0174.
  2. Gronbach M, Mitrach F, Lidzba V, Müller B, Möller S, Rother S, Salbach-Hirsch J, Hofbauer LC, Schnabelrauch M, Hintze V, Hacker MC, Schulz-Siegmund M. Scavenging of Dickkopf-1 by macromer-based biomaterials covalently decorated with sulfated hyaluronan displays pro-osteogenic effects. Acta Biomater. 2020 Sep 15;114:76-89. doi: 10.1016/j.actbio.2020.07.017. Epub 2020 Jul 13. PMID: 32673749.
  3. Colditz J, Picke AK, Hofbauer LC, Rauner M. Contributions of Dickkopf-1 to Obesity-Induced Bone Loss and Marrow Adiposity. JBMR Plus. 2020 Apr 28;4(6):e10364. doi: 10.1002/jbm4.10364. PMID: 2537550; PMCID: PMC7285751.
  4. Krieghoff J, Picke AK, Salbach-Hirsch J, Rother S, Heinemann C, Bernhardt R, Kascholke C, Möller S, Rauner M, Schnabelrauch M, Hintze V, Scharnweber D, Schulz-Siegmund M, Hacker MC, Hofbauer LC, Hofbauer C. Increased pore size of scaffolds improves coating efficiency with sulfated hyaluronan and mineralization capacity of osteoblasts. Biomater Res. 2019; 23:26. doi: 10.1186/s40824-019-0172-z.
  5. Rauner M, Baschant U, Roetto A, Pellegrino RM, Rother S, Salbach-Hirsch J, Weidner H, Hintze V, Campbell G, Petzold A, Lemaitre R, Henry I, Bellido T, Theurl I, Altamura S, Colucci S, Muckenthaler MU, Schett G, Komla-Ebri DSK, Bassett JHD, Williams GR, Platzbecker U, Hofbauer LC. Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signaling. Nature Metabolism. 2019; 1:111–24.
  6. Thiele S, Zimmer A, Göbel A, Rachner TD, Rother S, Fuessel S, Froehner M, Wirth MP, Muders MH, Baretton GB, Jakob F, Rauner M, Hofbauer LC. Role of WNT5A receptors FZD5 and RYK in prostate cancer cells. Oncotarget. 2018, 9:27293-304.
  7. Picke AK, Campbell GM, Blüher M, Krügel U, Schmidt FN, Tsourdi E, Winzer M, Rauner M, Vukicevic V, Busse B, Salbach-Hirsch J, Tuckermann JP, Simon JC, Anderegg U, Hofbauer LC, Saalbach A. Thy-1 (CD90) promotes bone formation and protects against obesity. Sci Transl Med. 2018; 10:eaao6806.
  8. Picke AK, Campbell GM, Schmidt FN, Busse B, Rauner M, Simon JC, Anderegg U, Hofbauer LC, Saalbach A. Thy-1 Deficiency Augments Bone Loss in Obesity by Affecting Bone Formation and Resorption. Front Cell Dev Biol 2018;6:127.
  9. Picke AK, Sylow L, Møller LLV, Kjøbsted R, Schmidt FN, Steejn MW, Salbach-Hirsch J, Hofbauer C, Blüher M, Saalbach A, Busse B, Rauner M, Hofbauer LC. Differential effects of high-fat diet and exercise training on bone and energy metabolism. Bone. 2018, 116:120-134.
  10. Szulc P, Chapurlat R, Hofbauer LC. Prediction of fractures and major cardiovascular events in men using serum osteoprotegerin levels: The prospective STRAMBO study. J Bone Miner Res. 2017;32:2288-96.
  11. Tsourdi E, Lademann F, Ominsky MS, Rijntjes E, Köhrle J, Misof BM, Roschger P, Klaushofer K, Hofbauer LC, Rauner M. Sclerostin blockade and zoledronic acid improve bone mass and strength in male mice with exogenous hyperthyroidism. Endocrinology. 2017;158:3765-77.
  12. Schulz MC, Kowald J, Estenfelder S, Jung R, Kuhlisch E, Eckelt U, Mai R, Hofbauer LC, Stroszczynski C, Stadlinger B. Site-specific variations in bone mineral density under systemic conditions inducing osteoporosis in minipigs. Front Physiol. 2017;8:426.
  13. Khosla S, Hofbauer LC. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol. 2017;5:898-907.
  14. Campbell GM, Tiwari S, Hofbauer C, Picke AK, Rauner M, Huber G, Peña JA, Damm T, Barkmann R, Morlock MM, Hofbauer LC, Glüer CC. Effects of parathyroid hormone on cortical porosity, non-enzymatic glycation and bone tissue mechanics in rats with type 2 diabetes mellitus. Bone. 2016, 82:116-21.
  15. Förster Y, Schmidt JR, Wissenbach DK, Pfeiffer SEM, Baumann S, Hofbauer LC, von Bergen M, Kalkhof S, Rammelt S. Microdialysis sampling from wound fluids enables quantitative assessment of cytokines, proteins, and metabolites reveals bone defect-specific molecular profiles. PLoS One. 2016;11:e0159580.
  16. Picke AK, Salbach-Hirsch J, Hintze V, Rother S, Rauner M, Kascholke C, Möller S, Bernhardt R, Rammelt S, Pisabarro MT, Ruiz-Gómez G, Schnabelrauch M, Schulz-Siegmund M, Hacker MC, Scharnweber D, Hofbauer C, Hofbauer LC. Sulfated hyaluronan improves bone regeneration of diabetic rats by binding sclerostin and enhancing osteoblast function. Biomaterials. 2016;96:11-23.
  17. Picke AK, Gordaliza Alaguero I, Campbell GM, Glüer CC, Salbach-Hirsch J, Rauner M, Hofbauer LC, Hofbauer C. Bone defect regeneration and cortical bone parameters of type 2 diabetic rats are improved by insulin therapy. Bone. 2015; pii: S8756-3282(15)00236-7.
  18. Rother S, Salbach-Hirsch J, Moeller S, Seemann T, Schnabelrauch M, Hofbauer LC, Hintze V, Scharnweber D. Bioinspired collagen/glycosaminoglycan-based cellular microenvironments for tuning osteoclastogenesis. ACS Appl Mater Interfaces. 2015;7:23787-97.
  19. Scharnweber D, Hübner L, Rother S, Hempel U, Anderegg U, Samsonov SA, Pisabarro MT, Hofbauer LC, Schnabelrauch M, Franz S, Simon J, Hintze V. Glycosaminoglycan derivatives: promising candidates for the design of functional biomaterials. J Mater Sci Mater Med. 2015;26:232
  20. Salbach-Hirsch J, Samsonov SA, Hintze V, Picke AK, Rauner M, Gehrcke JP, Moeller S, Schnabelrauch M, Scharnweber D, Pisabarro MT, Hofbauer LC. Structural and functional insights into sclerostin-glycosaminoglycan interactions in bone. Biomaterials. 2015 Jul 15;67:335-345.
  21. Hempel U, Preissler C, Vogel S, Möller S, Hintze V, Becher J, Schnabelrauch M, Rauner M, Hofbauer LC, Dieter P. Artificial extracellular matrices with oversulfated glycosaminoglycan derivatives promote the differentiation of osteoblast-precursor cells and premature osteoblasts. Biomed Res Int.2014;2014:938368
  22. Hamann C, Picke AK, Campbell GM, Balyura M, Rauner M, Bernhardt R, Huber G, Morlock MM, Günther KP, Bornstein SR, Glüer CC, Ludwig B, Hofbauer LC. Effects of parathyroid hormone on bone mass, bone strength, and bone regeneration in male rats with type 2 diabetes mellitus. Endocrinology. 2014 Apr;155(4):1197-206.
  23. Salbach-Hirsch J, Ziegler N, Thiele S, Moeller S, Schnabelrauch M, Hintze V, Scharnweber D, Rauner M, Hofbauer LC. Sulfated glycosaminoglycans support osteoblast fubctions and concurrently suppress osteoclasts. J Cell Biochem. 2014 Jun;115(6):1101-11
  24. Neumann T, Hofbauer LC, Rauner M, Lodes S, Kästner B, Franke S, Kiehntopf M, Lehmann T, Müller UA, Wolf G, Hamann C, Sämann A. Clinical and endocrine correlates of circulating sclerostin levels in patients with type 1 diabetes mellitus. Clin Endocrinol (Oxf). 2014 May;80(5):649-55.
  25. Goettsch C, Babelova A, Trummer O, Erben RG, Rauner M, Rammelt S, Weissmann N, Weinberger V, Benkhoff S, Kampschulte M, Obermayer-Pietsch B, Hofbauer LC, Brandes RP, Schröder K. NADPH oxidase 4 limits bone mass by promoting osteoclastogenesis. J Clin Invest. 2013 Nov 1;123(11):4731-8.
  26. Salbach-Hirsch J, Kraemer J, Rauner M, Samsonov SA, Pisabarro MT, Moeller S, Schnabelrauch M, Scharnweber D, Hofbauer LC, Hintze V. The promotion of osteoclastogenesis by sulfated hyaluronan through interference with osteoprotegerin and receptor activator of NF-?B ligand/osteoprotegerin complex formation. Biomaterials. 2013 Oct;34(31):7653-61
  27. Hofbauer LC, Hamann C. Deconstructing vitamin D deficiency. Sci Transl Med. 2013 Jul 10;5(193):193fs27
  28. Szulc P, Boutroy S, Vilayphiou N, Schoppet M, Rauner M, Chapurlat R, Hamann C, Hofbauer LC. Correlates of bone microarchitectural parameters and serum sclerostin levels in men: the STRAMBO study. J Bone Miner Res. 2013 Aug;28(8):1760-70.
  29. Förster Y, Gao W, Demmrich A, Hempel U, Hofbauer LC, Rammelt S. Monitoring of the first stages of bone healing with microdialysis. Acta Orthop. 2013 Feb;84(1):76-81
  30. Hamann C, Rauner M, Höhna Y, Bernhardt R, Mettelsiefen J, Goettsch C, Günther KP, Stolina M, Han CY, Asuncion FJ, Ominsky MS, Hofbauer LC. Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus. J Bone Miner Res. 2013;28:627-38. Salbach J, Kliemt S, Rauner M, Rachner TD, Goettsch C, Kalkhof S, von Bergen M, Möller S, Schnabelrauch M, Hintze V, Scharnweber D, Hofbauer LC. The effect of the degree of sulfation of glycosaminoglycans on osteoclast function and signaling pathways. Biomaterials. 2012;33:8418-29.
  31. Salbach J, Rachner TD, Rauner M, Hempel U, Anderegg U, Franz S, Simon JC, Hofbauer LC. Regenerative potential of glycosaminoglycans for skin and bone. J Mol Med (Berl). 2012;90:625-35.
  32. Hamann C, Kirschner S, Günther KP, Hofbauer LC. Bone, sweet bone–osteoporotic fractures in diabetes mellitus. Nat Rev Endocrinol. 2012;17;8(5):297-305.
  33. Hamann C, Goettsch C, Mettelsiefen J, Henkenjohann V, Rauner M, Hempel U, Bernhardt R, Fratzl-Zelman N, Roschger P, Rammelt S, Günther KP, Hofbauer LC. Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function. Am J Physiol Endocrinol Metab. 2011;301:E1220-8.

Contact

Prof. Dr. med. Lorenz Hofbauer

Professor of Endocrinology, Diabetology and Bone Diseases
University Hospital “Carl Gustav Carus” of the TU Dresden
Medical Clinic III
Fetscherstraße 47, 01307 Dresden

Phone: +49 (0)351 458-3173
E-Mail: lorenz.hofbauer@uniklinikum-dresden.de
Website: bone-lab.de

 

Dr. med. Christine Hofbauer (geb. Hamann)

Chief Physician and Head of Section
University Hospital of the TU Dresden
Clinic and Polyclinic for Orthopaedics
Tumor Orthopedics Division
Fetscherstraße 74, 01307 Dresden

Phone: +49 (0)351 458 13323
E-Mail: Christine.Hofbauer@uniklinikum-dresden.de