Abstract
Radiotherapy of head and neck squamous cell carcinoma can lead to long-term complications like osteoradionecrosis, resulting in severe impairment of the jawbone. Current standard procedures require a 6-month wait after irradiation before dental reconstruction can begin. A comprehensive characterization of the irradiation-induced molecular and functional changes in bone cells could allow the development of novel strategies for an earlier successful dental reconstruction in patients treated by radiotherapy. The impact of ionizing radiation on the bone-forming alveolar osteoblasts remains however elusive, as previous studies have relied on animal-based models and fetal or animal-derived cell lines. This study presents the first in vitro data obtained from primary human alveolar osteoblasts. Primary human alveolar osteoblasts were isolated from healthy donors and expanded. After X-ray irradiation with 2, 6 and 10 Gy, cells were cultivated under osteogenic conditions and analyzed regarding their proliferation, mineralization, and expression of marker genes and proteins. Proliferation of osteoblasts decreased in a dose-dependent manner. While cells recovered from irradiation with 2 Gy, application of 6 and 10 Gy doses not only led to a permanent impairment of proliferation, but also resulted in altered cell morphology and a disturbed structure of the extracellular matrix as demonstrated by immunostaining of collagen I and fibronectin. Following irradiation with any of the examined doses, a decrease of marker gene expression levels was observed for most of the investigated genes, revealing interindividual differences. Primary human alveolar osteoblasts presented a considerably changed phenotype after irradiation, depending on the dose administered. Mechanisms for these findings need to be further investigated. This could facilitate improved patient care by re-evaluating current standard procedures and investigating faster and safer reconstruction concepts, thus improving quality of life and social integrity.
Highlights
Radiotherapy of head and neck squamous cell carcinoma can lead to long-term complications like osteoradionecrosis, resulting in severe impairment of the jawbone
This is the first study employing primary human alveolar osteoblasts to investigate the impact of irradiation on this cell type, which is essential for the regeneration of bone
All three jawbone-derived human osteoblasts (JHOBs) cultures showed a dose-dependent decrease in proliferation after irradiation, with the cell culture from donor 3 presenting overall a significantly lower proliferation index (PI) (Supplementary Fig. S1a–c; Pdonor 1 vs. 3 = 0.0011, Pdonor 2 vs. 3 < 0.0001, Supplementary Table S2)
Summary
Radiotherapy of head and neck squamous cell carcinoma can lead to long-term complications like osteoradionecrosis, resulting in severe impairment of the jawbone. Previous in vitro studies have relied on osteoblastic murine cell lines like MC3T3-E1 or human fetal cell lines from skeletal bones[16,17,18,19,20,21] These models can only partially mimic the in vivo situation due to interspecies differences and the fact that alveolar osteoblasts behave differently than those derived from long bones, for example regarding their proliferation, mineralization and angiogenic p roperties[22,23]. This is the first study employing primary human alveolar osteoblasts to investigate the impact of irradiation on this cell type, which is essential for the regeneration of bone. Human alveolar osteoblasts were irradiated with 2, 6, and 10 Gy and compared to non-irradiated controls regarding their proliferation, morphology, mineralization, and expression of marker genes and proteins
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