Role of Schwann cells in neuroregeneration and skeletal pain during femoral fracture repair
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Citation
Abstract
Intense bone pain is the primary marker for progression of healing and is associated with many skeletal pathologies including long bone fractures. New mechanism-based analgesics to relieve bone pain and augment bone recovery post-fracture is required but, further understandings of the pathophysiology of bone pain are necessary before we can develop novel mechanism-based alternative treatments. The four stages of bone healing have been established to be in the following order: hematoma formation, granulation tissue formation, bony callus formation, then bone remodeling. Studies have shown that bone fracture repair processes and the neuronal regrowth that occurs following a peripheral nerve injury share many genes and proteins that interplay with one another to aide in fracture healing and repair. However, little to no research has been done on such set of genes and proteins and their role in the sensation of pain associated with normal bone healing. Expressions of messenger RNA for marker genes for cartilage and bone formation, along with neuronal factors involved with peripheral nerve repair, were assessed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis over a specific time course of healing, ranging from pre-fracture (day 0) to day 35 post-fracture. Structural identification and quantifications of specific fracture callus contents were assessed using staining and immunohistochemistry techniques, using day 10, day 14, and day 21 tissue samples. Potential pain-associated mechanisms and related genes to neuronal regrowth including SCPs markers were analyzed in a temporal manner.
The biological assessments of fracture healing demonstrated temporal differences in their relative peak expressions and quantity throughout the 35 day period studied. Genes associated with initial hematoma formation and neuroinflammation, including IL-6, NGF, and SC markers including PLP1, SOX2, and SOX10, reached a peak in expression early in the time course. However, SC-related genes including MAG and MOG did not reach their highest peaks in expression until mid-course around day 14, and day 20, when the bony callus and bone remodeling processes are occurring, respectively. Neuronally, such processes are occurring simultaneously as axonal reinnervation and remyelination is occurring with new vessel formation. Osteogenesis genes like BGLAP and NCAM, showed a later burst of maximal expression at day 14 and 20, associated with the later occurrence of bony callus formation and bone remodeling (secondary bone formation). Anti-Collagen type I, CNTF and SOX10 antibody staining demonstrated its presence are restricted to the lining of blood vessels and the bone marrow.
These results suggest that further research in the pain mechanisms involved with peripheral nerve damage occurring during bone fractures are necessary in understanding and developing further treatments related to bone pain. With each stage of the bone repair model, pain associated with specific genes and proteins are expected to be peak and wane off with completion of each stage. Future studies need to be carried out to determine the length of pain and localization of pain-related factors are associated with a healing fracture callus.
Description
2024