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Updated: May 1, 2026
Pan-myeloid Differentiation of Human Cord Blood Derived CD34+ Hematopoietic Stem and Progenitor Cells
Published on: August 9, 2019
Immunomodulatory drugs thalidomide and lenalidomide affect osteoblast differentiation of human bone marrow stromal
Arnold Bolomsky1, Martin Schreder1, Tobias Meißner2
1Wilhelminen Cancer Research Institute, First Department of Medicine, Center for Oncology and Hematology, Wilhelminenhospital, Vienna, Austria.
Abstract:
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.
Insights
Immunomodulatory drugs (IMiDs) like thalidomide and lenalidomide impair bone formation by inhibiting osteoblast development. This highlights the need for bone-building therapies to counteract IMiD effects in myeloma patients.
Area of Science:
- * Biomedical research
- * Cancer biology
- * Bone metabolism
Background:
- * Multiple myeloma often leads to myeloma bone disease, characterized by impaired osteoblastic activity.
- * Current treatments primarily target osteoclast activity, with limited options for enhancing bone formation.
- * Novel anti-myeloma drugs can influence the tumor microenvironment, including bone metabolism.
Purpose of the Study:
- * To investigate the impact of immunomodulatory drugs (IMiDs) on osteoblast development and bone formation.
- * To identify molecular mechanisms underlying IMiD-induced effects on osteoblasts.
- * To assess the potential for IMiDs to negatively affect bone metabolism in multiple myeloma.
Main Methods:
- * In vitro studies using thalidomide and lenalidomide to assess osteoblast development.
- * Measurement of alkaline phosphatase activity and matrix mineralization.
- * Gene expression profiling to identify regulatory factors involved in IMiD effects.
- * Combination studies with bortezomib.
Main Results:
- * Thalidomide and lenalidomide significantly inhibited osteoblast development in vitro.
- * IMiD treatment reduced alkaline phosphatase activity and matrix mineralization, effects sustained with bortezomib.
- * IMiDs upregulated Dickkopf-1 (DKK1) and inhibin beta A; blocking these did not restore osteoblast development.
- * Gene expression profiling revealed downregulation of key osteoblast regulators (e.g., RUNX2, DLX5) and induction of inhibitors (e.g., DKK1, activin A, gremlin 1).
Conclusions:
- * Immunomodulatory drugs (IMiDs) exhibit a class effect of inhibiting osteoblast development.
- * IMiD-induced osteoblast inhibition is mediated by altering the expression of critical osteoblast regulators and inducers.
- * The findings underscore the necessity for developing bone anabolic therapeutics to address the detrimental effects of prolonged IMiD exposure on bone metabolism in multiple myeloma.
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