Bone pain in fibrous dysplasia does not rely on aberrant sensory nerve sprouting or neuroma formation

Palmisano, Biagio Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Visualization; Writing - original draft; Writing - review & editing
Tavanti, Chiara Data curation; Methodology
Farinacci, Giorgia Data curation; Methodology
Gosti, Giorgio Data curation; Methodology
Leonetti, Marco Methodology
Donsante, Samantha Methodology
Giannicola, Giuseppe Methodology
Appelman-Dijkstra, Natasha Investigation; Writing - review & editing
Corsi, Alessandro Investigation; Writing - review & editing
Ippolito, Ernesto Investigation; Writing - review & editing
Riminucci, Mara Conceptualization; Supervision; Writing - original draft; Writing - review & editing

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Soft and Living Matter Laboratory, Institute of Nanotechnology, Consiglio Nazionale delle Ricerche, 00185 Rome, Italy
Center for Life Nano- and Neuro-Science, Italian Institute of Technology, 00161 Rome, Italy
Soft and Living Matter Laboratory, Institute of Nanotechnology, Consiglio Nazionale delle Ricerche, 00185 Rome, Italy
Center for Life Nano- and Neuro-Science, Italian Institute of Technology, 00161 Rome, Italy
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
Department of Anatomical, Histological, Medico Legal and Orthopaedic Sciences, Sapienza University of Rome, 00161 Rome, Italy
Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Centre, 2333 Leiden, The Netherlands
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
Department of Orthopaedic Surgery, University of Rome Tor Vergata, 00133 Rome, Italy
Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy

Corresponding author: Mara Riminucci, Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena, 324, 00161 Rome, Italy ([email protected]).

Received September 16, 2024

Received in revised form April 11, 2025

Accepted April 26, 2025

Revised June 14, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Journal of Bone & Mineral Research 40(8):p 999-1014, August 2025. | DOI: 10.1093/jbmr/zjaf066

Lay Summary

Little is known about the mechanisms causing the chronic and untreatable bone pain that associate with fibrous dysplasia (FD) of bone. We demonstrate that FD-related pain can be reproduced in EF1-Gs^R201C mice and provide a fine tracing of innervation of mouse FD lesions. We also characterize for the first time the sensory innervation in human FD biopsies. Our study reveals that, contrarily to long-standing beliefs, FD bone pain does not associate with haphazard growth of sensory nerve fibers or neuroma formation in skeletal lesions. Our discoveries challenge existing hypotheses and open new avenues for understanding and treating pain in FD patients.