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Parathyroid hormone (PTH) can reduce vertebral endplate sclerosis and improve pain behavior in three models of spinal degeneration in mice. The mechanism is related to the upregulation of the neuronal exclusion factor Slit3 in osteoblasts. PTH promotes Slit3 expression through the transcription factor FoxA2, thereby reducing abnormal sensory nerve innervation of the vertebral body and endplate. The loss of PTH1 receptor or Slit3 in osteoblasts weakens this effect.
01 Research Background
As the body ages, the spine undergoes degenerative changes, including the bone expansion and sclerosis of the vertebral endplates, which are associated with the occurrence of nonspecific low back pain. This pathological process urgently needs to be further explored.
02 Main Content
This study focuses on the analgesic effect of PTH on spinal degeneration-related low back pain and deeply analyzes the molecular mechanism by which it regulates abnormal sensory nerve innervation of the vertebral endplate. It particularly clarifies the core role of the Slit3 derived from osteoblasts in this process and the upstream regulatory pathways.
03 Research Design
Three models of spinal degeneration were used in the study: aged mice, SM/J mice, and young lumbar instability mice. After PTH intervention in the mice, the degree of vertebral endplate sclerosis and pain-related behaviors were detected; the distribution of PGP9.5+ and CGRP+ nerve fibers in the vertebral body and endplate, as well as the expression level of CGRP in the dorsal root ganglion, were analyzed; the influence of PTH on Slit3 expression and the regulatory role of transcription factor FoxA2 were investigated; by constructing osteoblast PTH1 receptor knockout or Slit3 knockout models, the functional necessity of these molecules was verified.
04 Results
PTH treatment can effectively improve the sclerosis of vertebral endplates in the three models of spinal degeneration, and at the same time alleviate their pain behaviors; this treatment can reduce abnormal sensory nerve innervation of the vertebral body and endplate during spinal degeneration; PTH can significantly upregulate Slit3 expression in osteoblasts through the transcription factor FoxA2; when the PTH1 receptor or Slit3 is lost in osteoblasts, PTH cannot improve the porosity of the endplate or relieve the pain-related behaviors of the mice.
05 Extension of Thoughts
Further exploration of downstream molecular targets regulated by Slit3 in the abnormal sensory nerve innervation; discussion of the differences in the role of the PTH-Slit3 pathway in different spinal degeneration processes; in-depth analysis of the specific molecular mechanism by which FoxA2 mediates PTH regulation of Slit3 transcription; expansion of research on the synergistic or antagonistic effects of other neural exclusion factors and Slit3 in this pathological process.
