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Bevacizumab and sunitinib mediate osteogenic and pro-inflammatory molecular changes in primary human alveolar
Elena Hofmann1,2, Benedikt Eggers3, Nils Heim3
1Department of Oral, Maxillofacial and Plastic Surgery, University Hospital Bonn, Welschnonnenstr 17, 53111, Bonn, Germany. Elena.hofmann@uni-bonn.de.
Abstract:
Antiangiogenic medications target the de novo blood vessel formation in tumorigenesis. However, these novel drugs have been linked to the onset of medication-related osteonecrosis of the jaw (MRONJ). The aim of this in vitro study was to examine the effects of the vascular endothelial growth factor A (VEGFA) antibody bevacizumab (BEV) and the receptor tyrosine kinase inhibitor (RTKI) sunitinib (SUN) on primary human osteoblasts derived from the alveolar bone. Primary human alveolar osteoblasts (HAOBs) were treated with BEV or SUN for 48 h. Cellular metabolic activity was examined by XTT assay. Differentially regulated genes were identified by screening of 22 selected osteogenic and angiogenic markers by quantitative real-time reverse transcriptase polymerase chain reaction (qRT2-PCR). Protein levels of alkaline phosphatase (ALP), collagen type 1, α1 (COL1A1) and secreted protein acidic and cysteine rich (SPARC) were examined by enzyme-linked immunoassay (ELISA). Treatment with BEV and SUN did not exhibit direct cytotoxic effects in HAOBs as confirmed by XTT assay. Of the 22 genes examined by qRT2-PCR, four genes were significantly regulated after BEV treatment and eight genes in the SUN group as compared to the control group. Gene expression levels of ALPL, COL1A1 and SPARC were significantly downregulated by both drugs. Further analysis by ELISA indicated the downregulation of protein levels of ALP, COL1A1 and SPARC in the BEV and SUN groups. The effects of BEV and SUN in HAOBs may be mediated by alterations to osteogenic and catabolic markers. Therapeutic or preventive strategies in MRONJ may address drug-induced depression of osteoblast differentiation.
Insights
Antiangiogenic drugs like bevacizumab and sunitinib do not directly harm human osteoblasts. However, they significantly reduce key bone-forming gene and protein levels, potentially contributing to medication-related osteonecrosis of the jaw (MRONJ).
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Antiangiogenic medications are crucial in cancer therapy by inhibiting new blood vessel formation.
- These drugs are associated with medication-related osteonecrosis of the jaw (MRONJ), a serious side effect.
- The precise mechanisms by which these drugs affect bone cells remain under investigation.
Purpose of the Study:
- To investigate the in vitro effects of bevacizumab (BEV) and sunitinib (SUN) on primary human alveolar osteoblasts (HAOBs).
- To assess the impact of these drugs on osteoblast metabolic activity, gene expression, and protein production.
Main Methods:
- Primary human alveolar osteoblasts were treated with BEV or SUN for 48 hours.
- Cellular metabolic activity was measured using the XTT assay.
- Gene expression of 22 osteogenic and angiogenic markers was analyzed by qRT2-PCR.
- Protein levels of alkaline phosphatase (ALP), collagen type 1 (COL1A1), and SPARC were quantified by ELISA.
Main Results:
- Neither BEV nor SUN demonstrated direct cytotoxicity to HAOBs.
- BEV and SUN significantly downregulated the expression of ALPL, COL1A1, and SPARC genes.
- Protein levels of ALP, COL1A1, and SPARC were also significantly reduced following treatment with both drugs.
Conclusions:
- Bevacizumab and sunitinib do not directly kill osteoblasts but impair their function by downregulating critical osteogenic markers.
- These drug-induced alterations in osteoblast differentiation and function may underlie the development of MRONJ.
- Targeting these drug-induced changes could lead to new therapeutic or preventive strategies for MRONJ.
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