Figure 1.

The vicious cycle between tumor and bone cells during osteosarcoma development. Osteosarcoma cells produce soluble osteolytic factors such as receptor activator of nuclear factor kappa-B ligand (RANKL), interleukin-11 (IL-11), IL-6, and tumor necrosis factor-α (TNF-α) that directly activate osteoclastogenesis, leading to bone degradation. Osteosarcoma cells also produce soluble factors, such as bone morphogenetic protein (BMP) or parathyroid hormone-related protein (PTHrP), which stimulate the production of RANKL by osteoblasts and therefore increase osteoclast activity. Osteoblasts are derived from mesenchymal stem cell in response to transcriptional factors such as Runx2 and osterix. Following bone degradation, the growth factors trapped in the bone matrix, such as transforming growth factor-βs (TGF-βs), are released into the bone microenvironment and stimulate both tumor growth and metastatic progression.