Stress fractures in athletes.

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Abstract

[Indexed for MEDLINE] 4. Nature. 2024 Oct;634(8033):474-481. doi: 10.1038/s41586-024-07822-1. Epub 2024 Aug 21. The periosteum provides a stromal defence against cancer invasion into the bone. Nakamura K(1)(2), Tsukasaki M(3), Tsunematsu T(4), Yan M(1)(5), Ando Y(1), Huynh NC(6), Hashimoto K(1), Gou Q(1), Muro R(1)(7), Itabashi A(1), Iguchi T(1), Okamoto K(8)(9), Nakamura T(10), Nakano K(11), Okamura T(11), Ueno T(12), Ito K(12), Ishimaru N(13), Hoshi K(2), Takayanagi H(14). Author information: (1)Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (2)Oral and Maxillofacial Surgery, Department of Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. (3)Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. tsuka-im@m.u-tokyo.ac.jp. (4)Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan. (5)Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. (6)Laboratory of Oral-Maxillofacial Biology, Faculty of Odonto-Stomatology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam. (7)Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (8)Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (9)Division of Immune Environment Dynamics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. (10)Department of Biochemistry, Tokyo Dental College, Tokyo, Japan. (11)Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. (12)Department of Molecular Tumor Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. (13)Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. (14)Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. takayana@m.u-tokyo.ac.jp. The periosteum is the layer of cells that covers nearly the entire surface of every bone. Upon infection, injury or malignancy the bone surface undergoes new growth-the periosteal reaction-but the mechanism and physiological role of this process remain unknown1,2. Here we show that the periosteal reaction protects against cancer invasion into the bone. Histological analyses of human lesions of head and neck squamous cell carcinomas (HNSCCs) show that periosteal thickening occurs in proximity to the tumour. We developed a genetically dissectible mouse model of HNSCC and demonstrate that inducible depletion of periosteal cells accelerates cancerous invasion of the bone. Single-cell RNA sequencing reveals that expression of the gene encoding the protease inhibitor TIMP1 is markedly increased in the periosteum at the pre-invasive stage. This increase is due to upregulation of HIF1α expression in the tumour microenvironment, and increased TIMP1 inactivates matrix-degrading proteases, promoting periosteal thickening to inhibit cancer invasion. Genetic deletion of Timp1 impairs periosteal expansion, exacerbating bone invasion and decreasing survival in tumour-bearing mice. Together, these data show that the periosteal reaction may act as a functional stromal barrier against tumour progression, representing a unique example of tissue immunity mediated by stromal cells. © 2024. The Author(s), under exclusive licence to Springer Nature Limited. DOI: 10.1038/s41586-024-07822-1