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.Introduction: 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. Materials and Methods: Ten-month-old male Sprague-Dawley rats were treated with either capsaicin or vehicle. In vivo DXA scanning and 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 generelated 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. Conclusion: 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.

Osseointegration of Hydroxyapatite Implants in Rat Tibial Defects with Sciatic Nerve Injury

“…The results of macroscopic analysis showed no difference in body weight between animals with and without sciatic nerve injury, suggesting that skeletal unloading due to muscle inactivity of the hind limbs did not contribute to the loss of bone integrity demonstrated by histologic analysis. Similar results have been reported by Offley et al (2005) who evaluated the contribution of capsaicinsensitive sensory neurons to the maintenance of trabecular bone integrity. These authors also observed a loss of bone mineral density in the tibial and femoral metaphyses of rats 4 weeks after capsaicin treatment.…”

“…These results support the hypothesis that sensory neurons contribute to the maintenance of trabecular bone integrity, which can be explained by the fact that neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) are synthesized by sensory neurons and released from peripheral nerve terminals. A reduction in the levels of these local neuropeptides in bone affects bone integrity (Maayan et al 2001;Offley et al).…”

“…Immunocytochemical studies have shown the presence of the substance P receptor (NK1) on the plasma membrane and in the cytoplasm of osteoclasts, osteoblasts and osteocytes, and NK1 mRNA expression has been demonstrated in osteoclasts. Furthermore, substance P can increase osteoblastogenesis, inducing bone formation and protein accumulation in bone cell cultures (Bjurholm et al, 1992;Shih & Bernard, 1997;Goto et al, 1998;Adamus & Dabrowski, 2001;Offley et al;Togari, 2002). In contrast, CGRP inhibits bone resorption in vitro (Imai & Matsusue, 2002), and increases cyclic AMP (Bjurholm et al) and intracellular calcium in osteoblasts (Kawase et al, 1995).…”

Effect of anti-NGF antibodies in a rat tibia fracture model of complex regional pain syndrome type I

“…NGF, CGRP and SP contents in the sciatic nerve were measured as we have previously described (Offley et al 2005). Briefly, nerve samples were minced in 1 ml of 3:1 ethanol/0.7M HCl and homogenized for 20 s. The homogenates were shaken for 2 h at 4°C and centrifuged at 3000g for 20 min at 4°C.…”

Fat and Bone: Where are We Now?

“…Starting with leptin at the turn of the century [13], the number of central mediators of bone metabolism has grown significantly and their roles now extended to controlling bone homeostasis rather than simply exerting a positive or negative effect on bone. Our understanding of neuronal control has extended from the sympathetic nervous system [14] to the parasympathetic and sensory nervous systems [15,16]. Abnormalities in the central nervous system such as vestibular dysfunction may also indirectly affect bone mass [17].…”