Figure 1.

Osteoclasts in the osteosarcoma microenvironment. Osteosarcoma cells and osteoblasts in the tumor microenvironment affect osteoclasts through direct and indirect ways, leading to changes in osteoclasts. Osteoclasts produce related factors, which in turn regulate osteosarcoma cells and osteoblasts, and then activated or stimulated osteosarcoma cells and osteoblasts affect osteoclasts in a direct or indirect way, forming a vicious cycle. Osteosarcoma cells and tumor-associated fibroblasts melt in the osteosarcoma microenvironment and undergo multi-nucleated osteoclast-like changes. The myeloid-derived suppressor cells produce high levels of HIF-1 in hypoxia environment, thus producing NO-mediated osteoclast differentiation, and NO can also mediate HIF-1 increase through PI3K and AKT pathways, thus forming a positive feedback.