Immunomodulatory drugs thalidomide and lenalidomide affect osteoblast differentiation of human bone marrow stromal cells in vitro
| Autor: | Martin Schreder, Arnold Bolomsky, Niklas Zojer, Tobias Meißner, Heinz Ludwig, Dirk Hose, Sabine Pfeifer |
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| Přispěvatelé: | Hematology, Basic (bio-) Medical Sciences |
| Rok vydání: | 2014 |
| Předmět: |
musculoskeletal diseases
Cancer Research medicine.medical_specialty Stromal cell Bone disease In Vitro Techniques Pleiotrophin Bone remodeling Osteoblasts/drug effects Adjuvants Immunologic Adjuvants Immunologic/pharmacology Internal medicine Genetics medicine Humans Lenalidomide Molecular Biology Cells Cultured Osteoblasts Chemistry Bortezomib Cell Differentiation Mesenchymal Stem Cells Osteoblast Cell Biology Hematology medicine.disease Thalidomide/analogs & derivatives Thalidomide Mesenchymal Stem Cells/drug effects medicine.anatomical_structure Endocrinology DKK1 Cell Differentiation/drug effects oncology Cancer research medicine.drug |
| Zdroj: | Experimental Hematology. 42:516-525 |
| ISSN: | 0301-472X |
| DOI: | 10.1016/j.exphem.2014.03.005 |
| Popis: | Osteoblastic activity is severely impaired in active myeloma, contributing to the development of myeloma bone disease. Although several drugs reducing osteoclast-mediated bone degradation are in clinical use, approaches to specifically augment bone formation are at an early stage of development. Novel antimyeloma drugs not only directly act on myeloma cells, but impact on the microenvironment as well. Proteasome inhibitors were previously shown to have bone anabolic properties. Here we investigated the impact of immunomodulatory drugs (IMiDs) on bone formation. Treatment with thalidomide and lenalidomide significantly inhibited osteoblast development in vitro, as reflected by a reduction of alkaline phosphatase activity and matrix mineralization. The effects were upheld in combination with bortezomib. The IMiDs upregulated Dickkopf-1 (DKK1) and inhibin beta A, but blocking these molecules was not able to restore regular osteoblast development. We therefore performed gene expression profiling to reveal other osteoblast regulatory factors that might be involved in the IMiD-mediated effect on osteoblast development. Our data indicate that osteoblast inhibition is possibly an IMiD-class effect mediated by downregulation of major osteoblast regulators (e.g., runt-related transcription factor 2, distal-less homeobox 5, pleiotrophin) and concurrent induction of secreted inhibitors of osteoblast formation (e.g. DKK1, activin A, gremlin 1). Our results highlight the need for bone anabolic therapeutics in myeloma, counteracting the negative impact of prolonged IMiD exposure on bone metabolism. |
| Databáze: | OpenAIRE |
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