Sensory nerves protect against preclinical tendinopathic changes through FGF1 signaling

Chronic tendinopathy is typified by persistent tendon-associated pain, transmitted by local nociceptive neurons. However, the regulatory function of somatosensory neurons in the development of tendinopathy is unknown. Here, we show that sensory neurons grow into the tendon proper across preclinical models of chronic tendinopathy to serve a protective function against tendinopathic changes through interactions with resident tenocytes and infiltrating macrophages. Retrograde neuronal tracing combined with single-cell RNA sequencing (scRNA-seq) of dorsal root ganglion neurons revealed a tendon-specific innervation profile, including calcitonin gene-related peptide (CGRP)-positive nociceptors among other sensory neuron types. We further evaluated these findings in three complementary surgical and transgenic mouse models of disrupted sensory nerve growth. Conditional deletion of nerve growth factor (Ngf) in macrophages (Ngf^Csfr1) or inactivation of its high-affinity receptor, tropomyosin receptor kinase A (TrkA), on sensory neurons exacerbated tendinopathic changes. Subsequently, a "sensory-only" sural nerve denervation model phenocopied these results, including heightened macrophage infiltration and tenocyte apoptosis. scRNA-seq of tendinous tissue identified defective tenocyte differentiation and altered macrophage migration and polarization with tendon denervation. Last, neuron-tendon interaction analyses implicated neuron-derived fibroblast growth factor 1 (FGF1) as a preventative factor for tendon degeneration, a finding supported by tendon organ culture and in vivo assessment. Consistent with a conserved mechanism, human tendinopathy specimens showed FGF1 immunoreactivity associated with tendon-innervating nerve fibers. Collectively, our findings demonstrate that peripheral afferent neural networks exert a protective effect in preclinical tendinopathy models by secreting FGF1 and that targeting this pathway may offer therapeutic strategies to prevent tendinopathic changes.