Hyaluronan Hydrogels Delivering BMP-6 for Local Targeting of Malignant Plasma Cells and Osteogenic Differentiation of Mesenchymal Stromal Cells
| Autor: | Dirk Hose, Patrick Horn, Elisabetta Ada Cavalcanti-Adam, Anja Seckinger, Anna Luise Grab |
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| Přispěvatelé: | Hematology, Basic (bio-) Medical Sciences |
| Rok vydání: | 2019 |
| Předmět: |
Bone disease
Bone Morphogenetic Protein 6 Mesenchymal Stem Cells/metabolism 0206 medical engineering Biomedical Engineering 02 engineering and technology Biochemistry Biomaterials chemistry.chemical_compound Drug Delivery Systems Osteogenesis Hyaluronic acid Tumor Cells Cultured medicine Humans Hyaluronic Acid Bone Morphogenetic Protein 6/chemistry Molecular Biology Multiple myeloma Multiple Myeloma/metabolism hematology Mesenchymal stem cell Cell Differentiation Hydrogels Mesenchymal Stem Cells General Medicine Hydrogels/chemistry 021001 nanoscience & nanotechnology medicine.disease 020601 biomedical engineering Osteogenesis/drug effects Resorption Bone morphogenetic protein 6 medicine.anatomical_structure Hyaluronic Acid/chemistry chemistry Cell Differentiation/drug effects Self-healing hydrogels Cancer research Sclerostin Bone marrow Multiple Myeloma 0210 nano-technology Biotechnology |
| Zdroj: | Acta Biomaterialia |
| ISSN: | 1556-5068 |
| DOI: | 10.2139/ssrn.3368806 |
| Popis: | Multiple myeloma is a malignant disease characterized by accumulation of clonal plasma cells in the bone marrow. Uncoupling of bone formation and resorption by myeloma cells leads to osteolytic lesions. These are prone to fracture and represent a possible survival space for myeloma cells under treatment causing disease relapse. Here we report on a novel approach suitable for local treatment of multiple myeloma based on hyaluronic acid (HA) hydrogels mimicking the physical properties of the bone marrow. The HA hydrogels are complexed with heparin to achieve sustained presentation and controlled release of bone morphogenetic protein 6 (BMP-6). Others and we have shown that BMP-6 induces myeloma cell apoptosis and bone formation. Using quartz crystal microbalance and enzyme-linked immunosorbent assay, we measured an initial surface density of 400 ng BMP6/cm2, corresponding to two BMP-6 per heparin molecule, with 50% release within two weeks. HA-hydrogels presenting BMP-6 enhanced the phosphorylation of Smad 1/5 while reducing the activity of BMP-6 antagonist sclerostin. These materials induced osteogenic differentiation of mesenchymal stromal cells and decreased the viability of myeloma cell lines and primary myeloma cells. BMP-6 functionalized HA-hydrogels represent a promising material for local treatment of myeloma-induced bone disease and residual myeloma cells within lesions to minimize disease relapse or fractures. Statement of Significance Multiple myeloma is a hematological cancer characterized by the accumulation of clonal plasma cells in the bone marrow and local suppression of bone formation, resulting in osteolytic lesions and fractures. Despite recent advances in systemic treatment of multiple myeloma, it is rare to achieve a targeted suppression of myeloma cells and healing of bone lesions. Here we present hydrogels which mimic the physico-chemical properties of the bone marrow, consisting of hyaluronic acid with crosslinked heparin for the controlled presentation of bioactive BMP-6. The hydrogels decrease the viability of myeloma cell lines and primary myeloma cells and induces osteogenic differentiation of mesenchymal stromal cells. The presentation of BMP-6 in the hyaluronan hydrogels enhances the phosphorylation of Smad1/5 while reducing the activity of the BMP-6 antagonist sclerostin. As such, BMP-6 functionalized hyaluronan hydrogels represent a promising material for the localized eradication of myeloma cells. |
| Databáze: | OpenAIRE |
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