Amazing stuff!
"... Breaking a bone hurts because sensory neurons are triggered by the trauma, and they signal pain to the brain. But that’s not these neurons’ only job, researchers discovered: They also step in to lead bone repair.
To discover this, researchers zoomed in on the nerves that penetrate into bone in mice, tracing them all the way back to the central nervous system, as well as sequencing individual neurons before and after fractures. “We created the first comprehensive single-cell atlas of bone-innervating sensory neurons,” ... This revealed that the same nerves that transmit the feeling of pain later enter what the team calls a “pro-regenerative state … they produce and release proteins that promote the generation of new neurons, blood vessels, and of course, bone and cartilage.” Of particular importance is a protein called fibroblast growth factor 9 (FGF9), which is a key coordinator of bone repair, guiding stem cells to transform into bone-building cells. When the researchers removed the nerves that produce FGF9 from mice, their bones struggled to heal. ..."
From the abstract of the Perspective:
"The skeleton has a remarkable ability to grow: It greatly expands in size from birth to adulthood and continues to remodel throughout adult life, completely replacing itself every 10 years.
But it is also able to regenerate after injury, efficiently regrowing lost bone. Bone injuries are common, with an estimated 6 million to 10 million fractures occurring each year in the United States.
A lack of efficient healing can result in long-term disability, and in the geriatric population, complications from fractures are associated with increased morbidity and mortality.
Because bone repair reflects the successful integration of multiple cellular and molecular processes, it is challenging to precisely define the signaling hierarchy that produces optimal healing. ... report an unexpected role for sensory nerves in bone healing, providing insights into communication between the nervous system and the cells responsible for bone repair."
From the editor's summary and abstract:
"Editor’s summary
Sensory neurons innervating bones can modulate the healing process (bone regeneration) after a fracture. Xu et al. used single-cell transcriptomics to characterize the bone-innervating dorsal root ganglia (DRG) neurons before and after an ulnar stress fracture in mice ... The experiments revealed temporally dynamic responses of the DRG neurons after the fracture. Moreover, the authors identified fibroblast growth factor 9, released by sensory neurons, as a major neural regulator in bone regeneration after injury. These findings show that pathways activated by bone-innervating neurons after an injury might be exploited for accelerating bone fracture repair. ...
Structured Abstract
INTRODUCTION
The profound pain accompanying bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration. Primary somatosensory neurons comprise a diverse subset of neurons, which communicate information about the external environment and internal state to the central nervous system, enabling perception and reaction to a wide range of stimuli including pain.
RATIONALE
Most work in skeletal neurobiology has focused on understanding bone nociceptive pathways, but recent studies provide evidence that sensory nerves also function to initiate bone formation during skeletal morphogenesis. To what extent such bone morphogenic and nociceptive actions are mediated by distinct neuronal pathways has been difficult to study in part due to lack of tractable model systems for studying nerve-bone interactions and the extensive heterogeneity of peripheral sensory neurons.
RESULTS
To characterize neuroanatomical circuitry mediating skeletal nociception and regeneration, dorsal root ganglia (DRG) neurons innervating murine long bones were profiled by retrograde nerve labeling and single-cell transcriptomics before and after experimental fracture.
Highest labeling across CGRP+ and Aβ-Field LTMR neurons was identified, which have nociceptive or mechanoreceptive functions.
Dynamic changes associated with sensory neuron response to injury reflected the phasic nature of bone repair.
At early time points, DRG neurons showed signatures of pain perception and inflammatory responses.
At later time points, DRG neurons demonstrated transcriptomic changes more characteristic of a regenerative response, including mitogenic, angiogenic and osteogenic signals.
This includes expression of morphogens in the fracture reparative phase such as Tgfb1, Fgf9, and Shh.
Two methods to surgically or genetically denervate fractured bones were used to implicate defective mesenchymal cell proliferation and osteo differentiation as underlying poor bone repair with loss of innervation.
Finally, multitissue single-cell RNA-sequencing and interactome analyses implicated neuron-derived fibroblast growth factor 9 (FGF9) as a potent regulator of fracture repair, confirmed by in vivo sensory nerve–specific ablation studies.
CONCLUSION
In sum, somatosensory neurons innervating bone are a group of neurons with nociceptive and mechanoreceptive functions, which are transcriptionally responsive to bone injury in a temporal dynamic fashion and positively regulate fracture healing through FGF9-FGFR signaling."
Not just a pain in the bone (Perspective, no public access) "Growth factors secreted by sensory nerves promote fracture healing"
Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing (preprint, open access, published in June 2024)
Fig. 2 Temporal responses of sensory neurons to fracture injury
When a bone is broken, sensory nerves alert the brain about the painful trauma. But after they’ve reported the break, they go into repair mode, producing FGF9 (red dots)—which, among other important messages, tells special stem cells to start the process of becoming bone cells (osteoblasts).
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