title: Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity.
abstract: This investigation used capsaicin to selectively lesion unmyelinated sensory neurons in rats. Neuronal lesioning induced a loss of trabecular integrity, reduced bone mass and strength, and depleted neuropeptides in nerve and bone. These data suggest that capsaicin-sensitive sensory nerves contribute to trabecular bone integrity.
  
  
  BACKGROUND
  Familial dysautomia is an autosomal recessive disease in which patients suffer from unmyelinated sensory neuron loss, reduced BMD, and frequent fractures. It has been proposed that the loss of neurotransmitters synthesized by unmyelinated neurons adversely affects bone integrity in this hereditary syndrome. The purpose of this study was to determine whether small sensory neurons are required for the maintenance of bone integrity in rats.
  
  
  METHODS
  Ten-month-old male Sprague-Dawley rats were treated with either capsaicin or vehicle. In vivo DXA scanning and micro CT scanning, and histomorphometry were used to evaluate BMD, structure, and cellular activity. Bone strength was measured in distal femoral sections. Body weight and gastrocnemius/soleus weights were measured and spontaneous locomotor activity was monitored. Peroneal nerve morphometry was evaluated using light and electron microscopy. Substance P and calcitonin gene-related peptide (CGRP) content in the sciatic nerve and proximal tibia were determined by enzyme immunoassay (EIA). Substance P signaling was measured using a sciatic nerve stimulation extravasation assay.
  
  
  RESULTS
  Four weeks after capsaicin treatment, there was a loss of BMD in the metaphyses of the tibia and femur. In the proximal tibia, the osteoclast number and surface increased, osteoblast activity and bone formation were impaired, and trabecular bone volume and connectivity were diminished. There was also a loss of bone strength in the distal femur. No changes occurred in body weight, 24-h grid-crossing activity, weight bearing, or muscle mass after capsaicin treatment, indicating that skeletal unloading did not contribute to the loss of bone integrity. Capsaicin treatment destroyed 57% of the unmyelinated sensory axons, reduced the substance P and CGRP content in the sciatic nerve and proximal tibia, and inhibited neurogenic extravasation.
  
  
  CONCLUSIONS
  These results support the hypothesis that capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. Capsaicin-sensitive neurons have efferent functions in the tissues they innervate, effects mediated by transmitters released from the peripheral nerve terminals. We postulate that the deleterious effects of capsaicin treatment on trabecular bone are mediated by reductions in local neurotransmitter content and release.
authors.affiliation: Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Offley
authors.forename: Tian-Zhi
authors.initials: TZ
authors.lastname: Guo
authors.forename: Tzuping
authors.initials: T
authors.lastname: Wei
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Derek P
authors.initials: DP
authors.lastname: Lindsey
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jacobs
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
authors.forename: Wade S
authors.initials: WS
authors.lastname: Kingery
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001369:Axons / Q000378:metabolism; D001835:Body Weight; D015519:Bone Density; D001842:Bone and Bones / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008297:Male; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009929:Organ Size; D010010:Osteoclasts / Q000378:metabolism; D010024:Osteoporosis / Q000628:therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013373:Substance P / Q000378:metabolism; D013977:Tibia / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014057:Tomography, X-Ray Computed
chemical_list: D018377:Neurotransmitter Agents; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin