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Three-Dimensional Bone Extracellular Matrix Model for Osteosarcoma
Published on: April 12, 2019
Imatinib mesylate and nilotinib decrease synthesis of bone matrix in vitro
Lysann Michaela Kroschwald1,2, Josephine Tabea Tauer3, Sonja Ingrid Kroschwald4,5
1Department of Dermatology, Medical Faculty, Technical University Dresden, D-01307 Dresden, Germany.
Abstract:
Tyrosine kinase inhibitors (TKIs), such as imatinib (IMA) and nilotinib (NIL), are the cornerstone of chronic myeloid leukemia (CML) treatment via the blockade of the oncogenic BCR-ABL1 fusion protein. However, skeletal side effects are commonly observed in pediatric patients receiving long-term treatment with IMA. Additionally, in vitro studies have shown that IMA and NIL alter vitamin D metabolism, which may further impair bone metabolism. To determine whether TKIs directly affect bone cell function, the present study treated the human osteoblastic cell line SaOS-2 with IMA or NIL and assessed effects on their mineralization capacity as well as mRNA expression of receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG), two cytokines that regulate osteoclastogenesis. Both TKIs significantly inhibited mineralization and downregulated osteoblast marker genes, including alkaline phosphatase, osteocalcin, osterix, as well as genes associated with the pro-osteogenic Wnt signaling pathway; NIL was more potent than IMA. In addition, both TKIs increased the RANKL/OPG ratio, which is known to stimulate osteoclastogenesis. The present results suggested that the TKIs IMA and NIL directly inhibited osteoblast differentiation and directly promoted a pro-osteoclastogenic environment through the RANKL-OPG signaling axis. Thus, we propose that future work is required to determine whether the bone health of CML patients undergoing TKI-treatment should be routinely monitored.
Insights
Tyrosine kinase inhibitors (TKIs) like imatinib and nilotinib used for chronic myeloid leukemia (CML) treatment directly harm bone cells. These TKIs inhibit osteoblast function and promote bone breakdown, suggesting a need for bone health monitoring in CML patients.
Area of Science:
- Biochemistry
- Oncology
- Cell Biology
Background:
- Tyrosine kinase inhibitors (TKIs), including imatinib (IMA) and nilotinib (NIL), are vital for treating chronic myeloid leukemia (CML) by inhibiting the BCR-ABL1 fusion protein.
- Pediatric patients on long-term IMA treatment often experience skeletal side effects, and in vitro studies indicate TKIs disrupt vitamin D metabolism, potentially worsening bone health.
Purpose of the Study:
- To investigate the direct impact of TKIs (IMA and NIL) on the function of human osteoblastic cells.
- To assess the effects of TKIs on osteoblast mineralization and the expression of key genes regulating bone metabolism and osteoclastogenesis.
Main Methods:
- Human osteoblastic SaOS-2 cells were treated with imatinib (IMA) or nilotinib (NIL).
- Assessed effects on mineralization capacity.
- Measured mRNA expression of osteoblast markers, Wnt signaling pathway genes, receptor activator of nuclear factor κB ligand (RANKL), and osteoprotegerin (OPG).
Main Results:
- Both IMA and NIL significantly inhibited SaOS-2 cell mineralization.
- TKIs downregulated osteoblast differentiation markers (alkaline phosphatase, osteocalcin, osterix) and Wnt signaling pathway genes.
- Nilotinib (NIL) demonstrated greater potency than imatinib (IMA).
- Both TKIs increased the RANKL/OPG ratio, favoring osteoclastogenesis.
Conclusions:
- TKIs IMA and NIL directly inhibit osteoblast differentiation and function.
- TKIs promote a pro-osteoclastogenic environment via the RANKL-OPG axis.
- Routine monitoring of bone health in CML patients undergoing TKI therapy is warranted.
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