2. Academic Validation
  3. Innate immune training of osteoclastogenesis promotes inflammatory bone loss in mice

Innate immune training of osteoclastogenesis promotes inflammatory bone loss in mice

  • Dev Cell. 2025 Jul 7;60(13):1854-1870.e6. doi: 10.1016/j.devcel.2025.02.001.
Nora Haacke 1,  Hui Wang 2,  Shu Yan 3,  Marko Barovic 1,  Xiaofei Li 4,  Kosuke Nagai 1,  Adelina Botezatu 1,  Aikaterini Hatzioannou 1,  Bettina Gercken 1,  Giulia Trimaglio 3,  Anisha U Shah 5,  Jun Wang 6,  Ling Ye 7,  Mangesh T Jaykar 1,  Martina Rauner 8,  Ben Wielockx 1,  Kyoung-Jin Chung 1,  Mihai G Netea 9,  Lydia Kalafati 10,  George Hajishengallis 11,  Triantafyllos Chavakis 12
Affiliations

Affiliations

  • 1 Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, TU Dresden, 01307 Dresden, Germany.
  • 2 Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
  • 3 Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, TU Dresden, 01307 Dresden, Germany; National Center for Tumor Diseases, Partner Site Dresden, 01307 Dresden, Germany.
  • 4 Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 5 Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 6 State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
  • 7 State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
  • 8 Department of Medicine III & Center for Healthy Aging, Faculty of Medicine, TU Dresden, 01307 Dresden, Germany.
  • 9 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 XZ Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.
  • 10 Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, TU Dresden, 01307 Dresden, Germany; Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany. Electronic address: lydia.kalafati@ukdd.de.
  • 11 Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: geoh@upenn.edu.
  • 12 Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, TU Dresden, 01307 Dresden, Germany; National Center for Tumor Diseases, Partner Site Dresden, 01307 Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, 01307 Dresden, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address: triantafyllos.chavakis@ukdd.de.
PMID: 40020679 DOI: 10.1016/j.devcel.2025.02.001
Abstract

We previously demonstrated that long-term trained immunity (TRIM) involves adaptations that imprint innate immune memory in long-lived myelopoiesis precursors and their progeny, monocytes/macrophages and neutrophils, which thereby acquire enhanced responsiveness to future challenges. Here, we show that a distinct component of myeloid biology, osteoclastogenesis, can also undergo innate immune training. Indeed, β-glucan-induced TRIM was associated with an increased osteoclastogenesis bias in the bone marrow and an expansion of monocytes/osteoclast progenitors in the periphery, resulting in aggravated severity of experimental periodontitis and arthritis. In the setting of trained inflammatory osteoclastogenesis, we observed transcriptomic rewiring in synovial myeloid cells of arthritic mice, featuring prominent upregulation of the transcription factor melanogenesis-associated transcription factor (MITF). Adoptive transfer of splenic monocytes from β-glucan-trained mice to naive recipients exacerbated arthritis in the latter in a strictly MITF-dependent manner. Our findings establish trained osteoclastogenesis as a maladaptive component of TRIM and potentially provide therapeutic targets in inflammatory bone loss disorders.

Keywords

inflammatory bone loss; innate immune memory; monocytes; osteoclastogenesis; trained immunity.

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