TrkA+ Neurons Induce Pathologic Regeneration After Soft Tissue Trauma

Abstract

Heterotopic ossification (HO) is a dynamic, complex pathologic process that often occurs after severe polytrauma trauma, resulting in an abnormal mesenchymal stem cell differentiation leading to ectopic bone growth in soft-tissues including tendons, ligaments, and muscles. The abnormal bone structure and location induce pain and loss of mobility. Recently, we observed that NGF (Nerve growth factor)-responsive TrkA (Tropomyosin receptor kinase A)-expressing nerves invade sites of soft-tissue trauma, and this is a necessary feature for heterotopic bone formation at sites of injury. Here, we assayed the effects of the partial TrkA agonist Gambogic amide (GA) in peritendinous heterotopic bone after extremity trauma. Mice underwent HO induction using the burn/tenotomy model with or without systemic treatment with GA, followed by an examination of the injury site via radiographic imaging, histology, and immunohistochemistry. Single-cell RNA Sequencing confirmed an increase in neurotrophin signaling activity after HO-inducing extremity trauma. Next, TrkA agonism led to injury site hyper-innervation, more brisk expression of cartilage antigens within the injured tendon, and a shift from FGF to TGFβ signaling activity among injury site cells. Nine weeks after injury, this culminated in higher overall levels of heterotopic bone among GA-treated animals. In summary, these studies further link injury site hyper-innervation with increased vascular ingrowth and ultimately heterotopic bone after trauma. In the future, modulation of TrkA signaling may represent a potent means to prevent the trauma-induced heterotopic bone formation and improve tissue regeneration.

TrkA-mediated sensory innervation of injured mouse tendon supports tendon sheath progenitor cell expansion and tendon repair

“…NGF itself has been shown to induce TGFβ expression, although, to our knowledge, this was not directly examined in tendon injury ( 56 , 57 ). Similar to the above neural regulation of tendon repair by TGFβ signaling, in our past report of the tendon-associated heterotopic bone, we observed that loss of innervation led to reduced TGFβ signaling among heterotopic ossification (HO)–associated progenitor cells ( 25 , 46 ). Mechanistically, it is unclear why tendon-associated nerves induce tendon repair in some contexts versus abnormal cartilage and bone formation in other contexts.…”

“…Since then, evidence that TrkA + sensory neurons regulate key aspects of skeletal morphogenesis and tissue repair continues to grow ( 43 , 44 ). TrkA + neurons are required for proper bone anabolic response to mechanical load ( 45 ), long bone stress fracture repair ( 12 ), cranial bone development and repair ( 13 , 30 ), and even abnormal bone formation in traumatic injury–associated heterotopic bone ( 25 , 46 ). These findings are consistent with a large body of literature regarding the role of peripheral neurons in regenerative processes across species ( 47 , 48 ).…”

TrkA+sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

“…More recently, the FDA approval for antibodies against the CGRP (erenumab and fremanezumab) to treat chronic migraines [55][56][57][58] , brings up an exciting possibility of drug repurposing to ameliorate sarcoma progression and bone Sensory neurons modulate the tumor microenvironment via secondary mechanisms such as promoting vascularization 60 . In our xenograft orthotopic model of OS, we observed that blocking of sensory (TrkA + /CGRP + ) nerve fibers resulted in marked reduction in tumor-associated blood vessels (EMCN + /CD31 + ) and reduced pro-vasculogenic ligand VEGFA, as described in other contexts 18,25,61,62 . These aggregate findings suggest a likelihood that NGF secreting endothelial cells may secondarily contribute to the changes in tumor vasculature as both VEGF-A and NGF sensitize peripheral sensory nerve fibers to several sensory stimuli 63,64 .…”

Designing Nerve Growth Factor Analogues to Suppress Pain Signal Transduction Mediated by the p75NTR-NGF-TrkA Complex: A Structural and Biophysical Perspective

“…While the implication of NGF and its receptors, TrkA and p75NTR (referred to as the NGF system) in CNS autoimmune neuroinflammation is not fully elucidated, the necessity of designing nerve growth factor (NGF) analogues to suppress pain signal transduction mediated by the p75NTR-NGF-TrkA complex arises from the intricate and multifaceted nature of the neurotrophic signaling pathways involved in CNS autoimmune neuroinflammation [29][30][31][32][33][34]. Since native NGF plays a pivotal role in both promoting neuronal survival and contributing to pain sensitization through its interactions with the p75NTR and TrkA receptors, the delicate balance between these contrasting effects underscores the need for targeted interventions that selectively modulate the signaling cascade to alleviate pain without compromising essential neurotrophic functions [35][36][37][38]. Therefore, in this article, designing NGF analogues provides a strategic approach to fine-tune the molecular interactions within the p75NTR-NGF-TrkA complex, aiming to attenuate the nociceptive signals while preserving the beneficial aspects of NGF-mediated neurotrophic support [39][40][41][42][43][44][45][46].…”