ACVR1 sensory neuron-specific signaling in neuropathic pain and injury-induced heterotopic ossification

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PROJECT SUMMARY Debilitating pain, a hallmark of tissue injury and neuropathy, is an unmet clinical challenge particularly in musculoskeletal diseases, such as heterotopic ossification (HO). HO can occur following orthopedic surgery and traumatic injuries, manifests with pathological bone formation in muscle and connective tissues. However, little progress has been made in developing effective treatments for either HO or its associated pain. Persistent neuropathic pain can arise from hyperexcitability of sensory neuron nociceptors in dorsal root ganglia (DRG), which release neuropeptides, interact with immune cells, and modulate the host response after injury to innervated tissues including bone and muscle. A critical link between bone homeostasis and neuropathic pain has been suggested by the impaired ossification and bone loss in mice lacking Trpv1+ nociceptors. Although the mechanisms that underlie HO formation or HO related pain are poorly understood, important insights derive from studies of an hereditary HO subset, namely Fibrodysplasia Ossificans Progressiva (FOP). FOP is commonly caused by an arginine206 to histidine gain-of-function point mutation in the BMP type I receptor (ACVR1, also known as ALK2) in 97% of patients. We recently found that adult patients with FOP have baseline heat and mechanical hypersensitivity, in the absence of an inflammatory flareup. Utilizing FOP patient induced pluripotent stem cell (iPSC)-derived nociceptive sensory neurons (iSNs), we demonstrated that ACVR1R206H is both necessary and sufficient for the hyperexcitability of nociceptors, a hallmark of neuropathic pain. To determine whether neuronal ACVR1 hyperactivity is also relevant to more common neuropathic pain conditions, we conditionally expressed activating Acvr1R206H in sensory neurons of non-FOP transgenic mice. This led to a remarkable recapitulation of the mechanical and heat hypersensitivity in patients with FOP. As Acvr1 expression is profoundly increased in axotomized DRG neurons in a traditional preclinical model of neuropathic pain produced by spared nerve injury (SNI), we found that inhibiting injury-induced active neuronal ACVR1 signaling in the DRG by intrathecal (IT) injections of a small-molecule ACVR1/ALK2 kinase inhibitor prevented injury-induced mechanical hypersensitivity and, most importantly, reversed persistent pain in the mouse SNI model. Based on our observation that trauma-induced HO triggered massive nociceptor sprouting at the injury site in a preclinical mouse model of FOP, we further hypothesize that active ACVR1 signaling in sensory neurons is a critical link between neuropathic pain and HO. Together, aiming to elucidate the mechanisms downstream of active ACVR1 signaling, mechanisms that may be shared by other chronic pain and musculoskeletal injury conditions; while developing new treatment strategies, we will define molecular targets of sensory neuron-specific ACVR1 that contribute to neuropathic pain (Aim 1); validate if inhibiting peripheral neuronal ACVR1 reduces hypersensitivity (Aim 2); and determine if sensory neuron-specific ACVR1 contributes to injury-induced HO (Aim 3).