Inherent tissue homeostasis of the juvenile metaphysis provides a foundation for osteosarcoma development
- Masato Saito
- Fumie Nakasuka
- Nao Sankoda
- Yihan Wang
- Jumpei Taguchi
- Sho Ohta
- Yosuke Yamada
- Manabu Ozawa
- Satoko Sakurai
- Atsushi Kondo
- Tetsuo Ushiku
- Robert Nakayama
- Masaya Nakamura
- Hiroshi Takayanagi
- Atsushi Shibata
- Takuya Yamamoto
- Yasuhiro Yamada
2026-06-26
Osteosarcomas preferentially arise in the metaphysis of juvenile long bones, near the growth plate, unlike most cancers, whose incidence increases with age. Here, we show that p21, a negative regulator of the cell cycle, is induced in proliferating juvenile metaphyseal osteoblasts in response to DNA replication-associated damage. Single-cell RNA sequencing defines a differentiation hierarchy from multipotent progenitors to mature osteoblasts and identifies immature osteoblasts enriched for proliferation and replication stress responses. p21-positive metaphyseal osteoblasts associate with growth plate Indian hedgehog expression and decline after growth plate maturation or Hedgehog inhibition. c-Myc induction selectively promotes juvenile osteoblast proliferation despite p53 activation, but this proliferative response remains Hedgehog-dependent and ceases after growth plate maturation. By contrast, p53 inactivation enables sustained Hedgehog-independent proliferation of c-Myc -induced osteoblasts and lung metastasis. These findings reveal juvenile metaphyseal tissue homeostasis as a potential basis for the age of onset, anatomical specificity, and mutational profile of human osteosarcomas.