Suppressing angiogenesis regulates the irradiation‐induced stimulation on osteoclastogenesis in vitro

Abstract

Ionizing radiation-induced bone loss is a potential health concern in radiotherapy, occupational exposure, and astronauts. Although impaired bone vasculature and reduced proliferation of bone-forming osteoblasts has been implicated in this process, it has not been clearly characterized that whether radiation affects the growth of bone-resorbing osteoclasts. The molecular crosstalk between different cell populations in the skeletal system has not yet been elucidated in detail, especially between the increased bone resorption at early stage of post-irradiation and bone marrow-derived endothelial progenitor cells (BM-EPCs). In order to further understand the mechanisms involved in radiation-induced bone loss at the cellular level, we assessed the effects of irradiation on angiogenesis of BM-EPCs and osteoclastogenesis of receptor activator for nuclear factor-κB ligand (RANKL)-stimulated RAW 264.7 cells and crosstalk between these cell populations. We herein found significantly dysfunction of BM-EPCs in response to irradiation at a dose of 2 Gy, including inhibited proliferation, migration, tube-forming abilities, and downregulated expression of pro-angiogenesis vascular endothelial growth factors A (VEGF A). Meanwhile, we observed that irradiation promoted osteoclastogenesis of RANKL-stimulated RAW 264.7 cells directly or indirectly. These results provide quantitative evidences of irradiation induced osteoclastogenesis at a cellular level, and strongly suggest the involvement of osteoclastogenesis, angiogenesis and crosstalk between bone marrow cells in the radiation-induced bone loss. This study may provide new insights for the early diagnosis and intervention of bone loss post-irradiation.

Treatment‐related calvarial lesions in pediatric brain tumor survivors

“…RT‐induced osteitis and osteoradionecrosis result from altered blood supply to the bone and dysfunction of osteoblasts and osteoclasts 14 . Histopathology and pathogenesis of RT‐induced fibrosis is better studied in soft tissues than calvarial lesions.…”

Combination Use of BMP2 and VEGF165 Promotes Osseointegration and Stability of Titanium Implants in Irradiated Bone

“…But the combined use of BMP2/VEGF165 showed a much better effect in osseointegration, compared with HBO group, BMP2 group, and VEGF165 group. As discussed above, radiation would cause vascular damage, induce local microcirculation disorder, and decrease the expression of VEGF165 [15, 16, 29]. Schliephake reported that VEGF165 immobilized on the surface of titanium implants by using a modular binding system could enhance the contact rate between the bone and the implant surface to a certain extent [30].…”

“…VEGF165, a heparin-binding growth factor of VEGF family and the most active isoform of VEGF, acts as a mitogen of endothelial cells, a chemotactic mediator, and a vascular permeability inducer [14]. It plays a critical role in recruiting EPCs from the bone marrow, upregulating other angiogenic factors, promoting angiogenesis, and improving the formation of endothelium [15]. Evidence has shown that radiation treatment leads to vascular damage and reduces the expression of VEGF165.…”

“…Evidence has shown that radiation treatment leads to vascular damage and reduces the expression of VEGF165. Then the process of new blood vessel formation and the ability of vessels to deliver oxygen and nutrients to normal tissues would be seriously interfered, which inhibits the capacity of normal tissue healing and regenerating [15, 16]. BMP, a subfamily of the TGF-beta superfamily and one of the most promising growth factors to enhance bone regeneration, is a group of secreted, hydrophobic, acid glycoproteins that can induce the differentiation of osteoblasts and was originally named for its role in the induction of bone formation [17, 18].…”

Bench to Bedside: Animal Models of Radiation Induced Musculoskeletal Toxicity

“…Tong and colleagues hypothesized that the effects of RT on bone marrow-derived endothelial progenitor cells may also impact the resorption of bone after RT. In an in vitro study, they found that RT induced substantial dysfunction in endothelial progenitor cells, including the downregulation of vascular endothelial growth factor A (VEGF-A), which is a potent angiogenic agent [83]. However, angiogenesis is a critical part of tumor growth and metastasis, and abnormally upregulated angiogenesis, specifically VEGF, is a direct target of many commonly used systemic therapy agents, including bevacizumab [84].…”