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

Abstract

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 alpha 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 alpha-Gs alpha R201C develops behavioral impairments and altered response to nociceptive stimuli that, as in FD patients, do not correlate with their skeletal disease burden, thus providing a reliable model to study bone pain in FD. Then, we show that in EF1 alpha-Gs alpha R201C 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, within the lesional tissue, sensory nerve fibers are few despite the rich vascular network and appear to be well-organized. These data show that, albeit sensory nerve fibers are found within FD lesions, bone pain in humans and functional impairment in mice are not associated to pathological sensory nerve sprouting or formation of neuromas in the Gs alpha-mutated skeleton.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 alpha-Gs alpha 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.