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Hyaluronan Hydrogels Delivering BMP-6 for Local Targeting of Malignant Plasma Cells and Osteogenic Differentiation of Mesenchymal Stromal Cells

26 Pages Posted: 10 Apr 2019 First Look: Accepted

See all articles by Anna Luise Grab

Anna Luise Grab

Heidelberg University - Laboratory for Myeloma Research; Heidelberg University - Institute of Physical Chemistry; Max Planck Institute for Medical Research - Department of Cellular Biophysics; Max Planck Institute for Medical Research - Cellular Biotechnology

Anja Seckinger

Heidelberg University - Laboratory for Myeloma Research

Patrick Horn

Heidelberg University - Medical Clinic V

Dirk Hose

Heidelberg University - Laboratory for Myeloma Research

Elisabetta Ada Cavalcanti-Adam

Heidelberg University - Institute of Physical Chemistry; Max Planck Institute for Medical Research - Department of Cellular Biophysics; Max Planck Institute for Medical Research - Cellular Biotechnology

Abstract

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 Smad1/5 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 prevent disease relapse or fractures.

Keywords: BMP-6, hyaluronan hydrogel, multiple myeloma, osteogenic differentiation, BMP/ Smad signaling

Suggested Citation

Grab, Anna Luise and Seckinger, Anja and Horn, Patrick and Hose, Dirk and Cavalcanti-Adam, Elisabetta Ada, Hyaluronan Hydrogels Delivering BMP-6 for Local Targeting of Malignant Plasma Cells and Osteogenic Differentiation of Mesenchymal Stromal Cells (April 9, 2019). Available at SSRN: https://ssrn.com/abstract=3368806

Anna Luise Grab (Contact Author)

Heidelberg University - Laboratory for Myeloma Research

Im Neuenheimer Feld 410
Heidelberg, 69120
Germany

Heidelberg University - Institute of Physical Chemistry

Im Neuenheimer Feld 253
Heidelberg, 69120
Germany

Max Planck Institute for Medical Research - Department of Cellular Biophysics

Heidelberg
Germany

Max Planck Institute for Medical Research - Cellular Biotechnology

Jahnstr. 29
Heidelberg, 69120
Germany

Anja Seckinger

Heidelberg University - Laboratory for Myeloma Research

Im Neuenheimer Feld 410
Heidelberg, 69120
Germany

Patrick Horn

Heidelberg University - Medical Clinic V

Im Neuenheimer Feld 350
Heidelberg, 69120
Germany

Dirk Hose

Heidelberg University - Laboratory for Myeloma Research ( email )

Im Neuenheimer Feld 410
Heidelberg, 69120
Germany

Elisabetta Ada Cavalcanti-Adam

Heidelberg University - Institute of Physical Chemistry ( email )

Im Neuenheimer Feld 253
Heidelberg, 69120
Germany

Max Planck Institute for Medical Research - Department of Cellular Biophysics ( email )

Heidelberg
Germany

Max Planck Institute for Medical Research - Cellular Biotechnology ( email )

Jahnstr. 29
Heidelberg, 69120
Germany

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