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Principal Investigator: Xiaobing Yu
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $106,611
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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).
Terms: <21+ years old><ACTRI><ACVR1><ACVR1 gene><ACVRLK2><ALK2><Activin A Receptor, Type II-Like Kinase 2 Gene><Activin Receptor-Like Kinase 2 Gene><Adult><Adult Human><Afferent Neurons><Allergy><Assay><Autoregulation><Axotomy><BMP type I receptor><BMPR-I><Bioassay><Biological Assay><Body Tissues><Bone Formation><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical><Connective Tissue><Dorsal Root Ganglia><Ectopic Ossification><Fibrodysplasia Ossificans Progressiva><Genes><Hereditary><Heterotopic Ossification><Histidine><Homeostasis><Hyperactivity><Hypersensitivity><Immune><Immune response><Immunes><Immunological response><Impairment><In Vitro><Inflammatory><Inherited><Injury><Intracellular Communication and Signaling><Intrathecal Injections><Link><Macrophage><Mechanics><Mice><Mice Mammals><Modeling><Molecular><Molecular Target><Murine><Mus><Muscle><Muscle Tissue><Musculoskeletal Diseases><Mφ><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuroimmune><Neurons><Neuropathy><Neuropeptides><Nociception><Nociceptors><Orthopedic Surgery><Osteogenesis><Pain><Painful><Pathologic><Pathologic Ossification><Pathological Ossification><Patients><Peripheral><Persistent pain><Physiologic Ossification><Physiological Homeostasis><Physiological Ossification><Point Mutation><Pre-Clinical Model><Preclinical Models><SKR1><Sensory Neurons><Signal Transduction><Signal Transduction Systems><Signaling><Site><Spinal Ganglia><Surgical Injuries><Testing><Therapeutic><Tissues><Transgenic Mice><Trauma><Traumatic injury><Type I Gene Activin A Receptor><adulthood><biological signal transduction><bone><bone loss><bone morphogenetic protein receptor type I><bone tissue formation><chronic pain><constant pain><debilitating pain><dorsal root ganglion><effective therapy><effective treatment><gain of function><host response><iPS><iPSC><iPSCs><immune system response><immunoresponse><in vivo Model><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><inhibitor><injuries><injury of musculoskeletal system (disorder)><injury of musculoskeleted system><injury to tissue><insight><kinase inhibitor><lasting pain><mechanic><mechanical><mouse model><murine model><muscular><musculoskeletal disorder><musculoskeletal injury><musculoskeletal trauma><myositis ossificans progressiva><nerve injury><neural injury><neuronal><neuropathic><neuropathic pain><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><nociceptive><nociceptive neurons><normal ossification><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><on-going pain><ongoing pain><ossification><pain model><pain-sensing neurons><pain-sensing sensory neurons><pain-sensing somatosensory neurons><painful neuropathy><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><phase 2 trial><phase II trial><pre-clinical><preclinical><prevent><preventing><progressive myositis ossificans><progressive ossifying myositis><release factor><response><small molecule><spared nerve><tissue injury><transcriptome profiling><transcriptomic profiling><transcriptomics>