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

Bone pain is a major symptom of many skeletal disorders. Fibrous dysplasia (FD) is a genetic disease with mono or polyostotic skeletal phenotype due to the post-zygotic occurrence of the causative Gs mutation. Bone pain in FD often associates with skeletal deformities and fractures or nerve impingement by the pathological tissue. However, even in the absence of complications, FD patients often complain of a chronic pain that does not correlate with their disease burden. Multiple hypotheses have been made to explain this pain. However, its pathogenetic mechanisms remain, as yet, largely unexplored. In this study, we first demonstrate that the FD mouse model EF1-GsR201C develops a painful-like behavior and an altered response to nociceptive stimuli that, as in FD patients, do not correlate with the severity of their phenotype, thus providing a reliable model to study bone pain in FD. Then, we show that in EF1-GsR201C mice, the overall pattern of skeletal innervation is preserved and that within FD lesions, sensory fibers are variably and focally distributed, mainly at perivascular sites. Finally, we provide the first analysis of a series of human FD bone biopsies showing that sensory nerve fibers are rarely detected within the pathological tissue. These data confirm that bone pain is an intrinsic and reproducible feature of FD. They also show that, albeit sensory nerve fibers are found within FD lesions and may contribute to the unpleasant sensation that accompanies the disease, pathological sensory nerve sprouting or formation of neuromas are not detected in the Gs-mutated skeleton.