Sumihisa Orita

Low Density Lipoprotein Receptor-Related Protein 1 (LRP1) Dependent Cell Signaling Promotes Axonal Regeneration

Background: LRP1 activation is neuroprotective in vitro. The role of LRP1 in axonal plasticity and regeneration is unknown. Results: LRP1-dependent cell signaling that includes TrkC activation promotes axonal growth in the CNS. Conclusion: LRP1 agonists promote regeneration after spinal cord injury. Significance: A significant role is established for LRP1 in axonal growth and regeneration after CNS injury, identifying a novel class of therapeutic targets for neurological disorders. Low-density lipoprotein receptors (LRPs) are present extensively on cells outside of the nervous system and classically exert roles in lipoprotein metabolism. It has been reported recently that LRP1 activation could phosphorylate the neurotrophin receptor TrkA in PC12 cells and increase neurite outgrowth from developing cerebellar granule cells. These intriguing findings led us to explore the hypothesis that LRP1 activation would activate canonical neurotrophic factor signaling in adult neurons and promote axonal regeneration after spinal cord injury. We now find that treatment of adult rat dorsal root ganglion neurons in vitro with LRP1 agonists (the receptor binding domain of α-2-macroglobulin or the hemopexin domain of matrix metalloproteinase 9) induces TrkC, Akt, and ERK activation; significantly increases neurite outgrowth (p < 0.01); and overcomes myelin inhibition (p < 0.05). These effects require Src family kinase activation, a classic LRP1-mediated Trk transactivator. Moreover, intrathecal infusions of LRP1 agonists significantly enhance sensory axonal sprouting and regeneration after spinal cord injury in rats compared with control-infused animals (p < 0.05). A significant role is established for lipoprotein receptors in sprouting and regeneration after CNS injury, identifying a novel class of therapeutic targets to explore for traumatic neurological disorders.

IκB kinase β inhibitor downregulates pain-related neuropeptide production in the sensory neurons innervating injured lumbar intervertebral discs in the dorsal root ganglia of rats

BACKGROUND CONTEXT Nuclear factor-κB (NF-κB) is an essential gene transcriptional regulator of inflammatory cytokines, and it plays important roles in numerous conditions, including inflammatory and neuropathic pain, especially when discogenic pain is involved. Phosphorylation of IκB protein through IκB kinase (IKK) is the first step in the activation of NF-κB activation and the upregulation of NF-κB-responsive genes. PURPOSE To investigate whether IKK inhibition alters the properties of pain-related neuropeptides in the rat lumbar degenerative intervertebral disc (IVD) model. STUDY DESIGN Retrograde neurotracing and immunofluorescent investigation of pain-related neuropeptide (calcitonin gene-related peptide [CGRP]) in the sensory innervation of injured lumbar IVD in rat dorsal root ganglia (DRGs). METHODS Forty female Sprague-Dawley rats were equally divided into four groups: naive, sham, and two agent-treated groups (vehicle [saline] group and anti-IKKβ [IMD-0560, IKKβ inhibitor] group). The L5-L6 IVDs of the agent-treated rats were exposed and injured by repeated punctures. The retrograde neurotracer Fluoro-Gold (FG) and corresponding treatment agents were intradiscally applied. In the sham group, FG alone was applied onto uninjured IVDs. One week later, L1-L3 DRGs were harvested and immunolabeled for CGRP as a pain marker. The proportions of FG-labeled CGRP-immunoreactive (-ir) DRG neurons were assessed. RESULTS Fluoro-Gold-labeled DRG neurons were almost equally prevalent at each DRG level. The proportions of FG-labeled CGRP-ir DRG neurons in the two agent-treated groups were significantly increased in comparison with those in the naive and the sham groups (p<.05) and were significantly decreased in the anti-IKKβ group in comparison with that in the vehicle group (p<.05). CONCLUSIONS The neuropeptide CGRP as a pain marker was upregulated in DRG neurons innervating the injured IVDs, and intradiscal inhibition of IKKβ significantly suppressed CGRP production in the DRG neurons innervating the rat IVD, suggesting the possible analgesic effect of IKKβ inhibition in discogenic pain.

Spinal fusion on adolescent idiopathic scoliosis patients with the level of L4 or lower can increase lumbar disc degeneration with sagittal imbalance 35 years after surgery

Introduction The purpose of this study was to investigate the long-term incidence of lumbar disc degeneration and Modic changes in the non-fused segments of patients with adolescent idiopathic scoliosis (AIS) who previously underwent spinal fusion. Methods Study subjects consisted of 252 patients with AIS who underwent spinal fusion between 1968 and 1988. Of 252 patients, 35 subjects underwent lumbar spine MRI and whole spine X-ray examination. The mean patient age at the time of follow-up was 49.8 years, with an average follow-up period of 35.1 years. We classified the subjects into two groups based on the lowest fused vertebra: H group whose lowest fused vertebra was L3 or higher levels and L group whose lowest fused vertebra was L4 or lower levels. Results The L group had significantly advanced disc degeneration on MRI. There was no significant difference between two groups in Modic changes. The L group showed less lumbar lordosis than the H group (H group: 48.1 degrees; and L group: 32.1 degrees) and greater SVA (H group: 1.2 cm; and L group: 5.5 cm). Conclusions In AIS patients, 35 years after spinal fusion surgery on average, we evaluated lumbar disc degeneration and Modic changes of the non-fused segments. In patients with the lowest fusion level at L4 or lower, there were reduced lumbar lordosis, considerable SVA imbalance, and severe disc degeneration compared with those with the lowest fusion level at L3 or higher. The lowest fusion level at L3 or higher is recommended to reduce disc degeneration in midlife.

Pathomechanisms and management of osteoporotic pain with no traumatic evidence

Introduction Osteoporosis is a pathological state with an unbalanced bone metabolism mainly caused by accelerated osteoporotic osteoclast activity due to a postmenopausal estrogen deficiency, and it causes some kinds of pain, which can be divided into two types: traumatic pain due to a fragility fracture from impaired rigidity, and pain derived from an osteoporotic pathology without evidence of fracture. We aimed to review the concepts of osteoporosis-related pain and its management. Methods We reviewed clinical and basic articles on osteoporosis-related pain, especially with a focus on the mechanism of pain derived from an osteoporotic pathology (i.e., osteoporotic pain) and its pharmacological treatment. Results Osteoporosis-related pain tends to be robust and acute if it is due to fracture or collapse, whereas pathology-related osteoporotic pain is vague and dull. Non-traumatic osteoporotic pain can originate from an undetectable microfracture or structural change such as muscle fatigue in kyphotic patients. Furthermore, basic studies have shown that the osteoporotic state itself is related to pain or hyperalgesia with increased pain-related neuropeptide expression or acid-sensing channels in the local tissue and nervous system. Traditional treatment for osteoporotic pain potentially prevents possible fracture-induced pain by increasing bone mineral density and affecting related mediators such as osteoclasts and osteoblasts. The most common agent for osteoporotic pain management is a bisphosphonate. Other non-osteoporotic analgesic agents such as celecoxib have also been reported to have a suppressive effect on osteoporotic pain. Conclusions Osteoporotic pain has traumatic and non-traumatic factors. Anti-osteoporotic treatments are effective for osteoporotic pain, as they improve bone structure and the condition of the pain-related sensory nervous system. Physicians should always consider these matters when choosing a treatment strategy that would best benefit patients with osteoporotic pain.

Evaluation of the location of intervertebral cages during oblique lateral interbody fusion surgery to achieve sagittal correction

Introduction Oblique lateral interbody fusion (OLIF) can achieve recovery of lumbar lordosis (LL) in minimally invasive manner. The current study aimed to evaluate the location of lateral intervertebral cages during OLIF in terms of LL correction. Methods The subjects were patients who underwent OLIF for lumbar degenerative diseases, including lumbar spinal stenosis, spondylolisthesis, and discogenic low back pain. Their clinical outcome was evaluated using visual analogue scale on lower back pain (LBP), leg pain and numbness. The following parameters were retrospectively evaluated on plain radiographic images and computed tomography scans before and at 1 year after OLIF: the intervertebral height, vertebral translation, and sagittal angle. The cage position was defined by equally dividing the caudal endplate into five zones (I to V), and its association with segmental lordosis restoration was analyzed. Subjects were also evaluated for a postoperative endplate injury. Results Eighty patients (121 fused levels) with lumbar degeneration who underwent OLIF were included. There were no significant specific distribution in preoperative disc pathology such as disc angle, height, and translation. After OLIF, sagittal alignment was improved with an average correction angle of 3.8º at the instrumented segments in a level-independent fashion. All cases showed significant improvement in clinical outcomes, and had improvement in the radiological parameters (P<0.05). A detailed analysis of the cage position showed that the most significant sagittal correction and the most postoperative endplate injuries occurred in the farthest anterior zone (I). Cages with a 12-mm height were associated with more endplate injuries compared with shorter cages (8 or 10 mm). Conclusions OLIF improves sagittal alignment with an average correction angle of 3.8º at the instrumented segments. We suggest that the optimal cage position for better lordosis correction and the fewest endplate injuries is zone II with a cage height of up to 10 mm.