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

Prof. Dr. Lorenz Hofbauer, Dr. Christine Hofbauer, PD Dr. Martina Rauner, Dr. Juliane Salbach-Hirsch, Dr. Ulrike Baschant, Nicole Pacyna, Dorit Surek, cand. med. dent. Mario Lüttwitz, cand. med. Romy Riffel, Ishwarya Balu

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.

Project-related Publications

  1. 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 regen-eration of diabetic rats by binding sclerostin and enhancing osteoblast function. Biomaterials. 2016;96:11-23.
  2. 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.
  3. 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.
  4. 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
  5. 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.
  6. 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
  7. 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.
  8. 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
  9. 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.
  10. 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.
  11. 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 
  12. Hofbauer LC, Hamann C. Deconstructing vitamin D deficiency. Sci Transl Med. 2013 Jul 10;5(193):193fs27
  13. 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.
  14. 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
  15. 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.
  16. 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.
  17. 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.
  18. 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.