OR23-06 Sensory neuronal ACVR1-mediated neuroimmune contribution to neuropathic pain and heterotopic ossification in fibrodysplasia ossificans progressiva

Abstract Disclosure: X. Yu: None. J. Braz: None. L. Lam: None. K. Bhardwaji: None. K. Jin: None. H. Yuan: None. D. Mohsenin: None. E. Yu: None. J. Weinrich: None. B. Ahanonu: None. A. Basbaum: None. E.C. Hsiao: None. Heterotopic ossification (HO), a pathological bone formation within muscle and connective tissues, is acquired following orthopedic surgery, severe burns, combat wounds, and traumatic injury of the central nervous system. Neither HO nor its associated pain has effective treatments, and the underlying mechanisms remain unclear. However, insight has come from studies of an hereditary HO subset, namely Fibrodysplasia Ossificans Progressiva (FOP), in which 97% of patients carry an arginine206 to histidine gain-of-function point mutation (R206H) in the BMP type I receptor (ACVR1). We previously reported that adult FOP patients have baseline nociceptive hypersensitivity to both heat and mechanical stimuli in the absence of an inflammatory flareup or entrapment neuropathy. Most importantly, R206H is both necessary and sufficient for the hyperexcitability of nociceptive sensory neurons differentiated from FOP patient-derived iPSCs, a hallmark of some forms of injury-induced neuropathic pain. However, to what extent debilitating HO contributes to these pain phenotypes in FOP patients remains unclear. We now demonstrated that conditional expression of activating R206H in sensory neurons of non-FOP transgenic mice, was sufficient for a recapitulation of the mechanical and heat hypersensitivity observed in patients with FOP. To gain mechanistic insight, we revealed that sensory neuronal R206H induced CGRP-dependent neuroimmune interaction by recruiting circulating macrophages to the dorsal root ganglia (DRG). Notably, the contribution of reciprocal interaction between sensory neurons and macrophages to persistent neuropathic pain has been well elucidated in both sexes. Given the considerable evidence that activated nociceptors contribute to the host immune response after injury of the innervated tissues including skin, bone and muscle, we further examined the contribution of ACVR1+ nociceptors to trauma-induced HO in a FOP preclinical animal model (PdgfrαCre-Acvr1R206H). Systemic Resiniferatoxin (RTX) mediated TRPV1 afferent ablation effectively prevented the development of injury-induced HO, while intramuscular administration of Onabotulinumtoxin A (Botox) to block CGRP release at the injury site, alleviated the injury outcome in both sexes. Next, we showed that nociceptor-macrophage interaction, critical for HO development in FOP mice, was induced by the muscle trauma but can be suppressed by either RTX or Botox injection. Together, we demonstrated that ACVR1+ nociceptive neuronal contribution is necessary but not sufficient for HO development in FOP. Moreover, we revealed a novel link between neuropathic pain and HO in FOP, and targeting sensory neuronal ACVR1-induced CGRP-dependent neuroimmune interaction may ultimately improve the quality of care in managing these two unmet clinical challenges. Presentation: Sunday, July 13, 2025