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<p>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. <i>c-Myc</i> 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 <i>c-Myc</i>-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.</p>

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Inherent tissue homeostasis of the juvenile metaphysis provides a foundation for osteosarcoma development

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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  • 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

摘要

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.