Group uncovers why osteosarcoma often develops near the knee during adolescence

The research group of Professor Yasuhiro Yamada and Graduate Student Masato Saito of the Graduate School of Medicine, University of Tokyo, in collaboration with Keio University, Kyoto University, and RIKEN, elucidated why osteosarcoma tends to occur near the knee during puberty. They focused on the cell cycle regulator "p21," which is an indicator of DNA damage response, and analyzed the pathology by reproducing it in mice. Active bone proliferation and protective mechanisms of DNA damage response coexist at the epiphysis during the growth period. Disruption of this balance was found to cause osteosarcoma. The finding is expected to lead to the development of new treatments. The results were published in Nature Communications on July 15.

Osteosarcoma has the highest incidence among rare cancers, and the number of new cases in Japan is estimated to be about 200 per year. The prognosis has improved with the introduction of chemotherapy, but there have been no major changes in treatment results of metastatic or recurrent cases in the past 30 years, requiring development of new treatments.

Since cancer develops due to accumulated DNA damage, the incidence rate of cancer generally increases with aging. In contrast, osteosarcoma occurs frequently around puberty, when bone growth is particularly active. It is also characterized by frequent occurrence at the metaphyseal area near the knee, but the reason has been unknown for such tendency. Cancer-associated DNA mutations have also been identified, but the causal relationship with these mutations is not well understood.

The research group has previously focused on p21, which is an indicator of DNA damage and cellular aging, in their research on aging. p21 works to stop cell cycle proliferation, and its expression is induced by activation of p53 in response to cellular stress.

This time, the research group developed and analyzed a mouse model that visualizes p21 in the body. They discovered a phenomenon where p21 expression increases at the metaphyseal area of the long bone during the growth period and the expression is lost when bone growth stops.

Next, they investigated the properties of p21 expressing cells and clarified that these cells are immature osteoblasts that are actively proliferating. Despite its inhibitory effect on cell proliferation, p21 was expressed in actively proliferating osteoblasts in the growth period, with DNA damage response also observed. Following this, they investigated epiphyseal cells in the growth period by single cell RNA sequencing and found that the hedgehog signaling pathway is involved in this cell proliferation. It was confirmed that inhibition of this signaling markedly reduced p21 expressing cells.

This finding clarified that osteoblasts at the metaphyseal area in the growth period promote normal bone growth by working on both accelerator and brake for cell proliferation in a balanced manner. Furthermore, in order to examine possible involvement of these osteoblasts as the cause of osteosarcoma, they reproduced activation of cell proliferation by c-Myc gene as found in osteosarcoma. This manipulation also strongly activated DNA damage at the same time, further activating the downstream mechanism for proliferative suppression to stop proliferation. Osteosarcoma did not develop by c-Myc alone.

Next, they manipulated osteoblasts to enable the accelerator and disable the brake by activating c-Myc and making p53 non-functional at the same time. One month later, they confirmed the development of osteosarcoma along with lung metastasis, which is common in this disease.

This study clarified the presence of actively proliferating osteoblasts at the metaphyseal area of the long bone during the growth period as well as the physiological mechanism by which the cells proliferate normally by using brakes as appropriate.

Yamada said, "This time, we were able to obtain knowledge about why osteosarcoma occurs at the metaphyseal area of the long bone during the growth period. I think this is an achievement that can also explain genetic mutations found in osteosarcoma specimens. In the future, I intend to explore treatment targets for osteosarcoma. I also expect that our mouse model of osteosarcoma that can be generated in a short period will become a good model for evaluating treatment effects."

Journal Information
Publication: Nature Communications
Title: Inherent tissue homeostasis of the juvenile metaphysis provides a foundation for osteosarcoma development
DOI: 10.1038/s41467-026-74929-6