Transcriptome of rat subcortical white matter and spinal cord after spinal injury and cortical stimulation.

Spinal cord injury disrupts ascending and descending neural signals causing sensory and motor dysfunction. Neuromodulation with electrical stimulation is used in both clinical and research settings to induce neural plasticity and improve functional recovery following spinal trauma. However, the mechanisms by which electrical stimulation affects recovery remain unclear. In this study we examined the effects of cortical electrical stimulation following injury on transcription at several levels of the central nervous system. We performed a unilateral, incomplete cervical spinal contusion injury in rats and delivered stimulation for one week to the contralesional motor cortex to activate the corticospinal tract and other pathways. RNA was purified from bilateral subcortical white matter and 3 levels of the spinal cord. Here we provide the complete data set in the hope that it will be useful for researchers studying electrical stimulation as a therapy to improve recovery from the deficits associated with spinal cord injury.

Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury.

Axon regeneration failure causes neurological deficits and long-term disability after spinal cord injury (SCI). Here, we found that the α2δ2 subunit of voltage-gated calcium channels negatively regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased α2δ2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI. In contrast, α2δ2 pharmacological blockade through gabapentin administration promoted corticospinal structural plasticity and regeneration in adulthood. Using an optogenetic strategy combined with in vivo electrophysiological recording, we demonstrated that regenerating corticospinal axons functionally integrate into spinal circuits. Mice administered gabapentin recovered upper extremity function after cervical SCI. Importantly, such recovery relies on reorganization of the corticospinal pathway, as chemogenetic silencing of injured corticospinal neurons transiently abrogated recovery. Thus, targeting α2δ2 with a clinically relevant treatment strategy aids repair of motor circuits after SCI.

Extracellular Matrix and Adhesion Molecule Gene Expression in the Normal and Injured Murine Intervertebral Disc.

OBJECTIVE: The aim of the study was to determine the transcription profile of the mouse nucleus pulposus and annulus fibrosus with an unbiased method. Furthermore, pathophysiological relevance of selected genes was demonstrated in the mouse tail intervertebral disc injury model. DESIGN: Paired normal mouse nucleus pulposus and annulus fibrosus tissue from C57BL/6j mice was examined by a polymerase chain reaction array. Key gene expression in the normal and injured intervertebral discs was confirmed by real-time polymerase chain reaction. RESULTS: Among the 84 genes studied, 63 were expressed higher in annulus fibrosus than in nucleus pulposus; only four genes were expressed higher in nucleus pulposus than in annulus fibrosus (n = 4, P ≤ 0.05). Real-time polymerase chain reaction confirmed that cadherin (cdh) 2 gene expression was higher in nucleus pulposus than in annulus fibrosus, and type I collagen (col1) gene expression was higher in the annulus fibrosus than in nucleus pulposus (n = 8, P < 0.01). One week after tail intervertebral disc injury, cdh2 gene expression decreased, while col1 expression increased (n = 8, P < 0.01). CONCLUSIONS: This is the first study to examine the relative expression of 84 genes in normal mouse nucleus pulposus and annulus fibrosus. Key genes in the normal and injured mouse intervertebral discs were confirmed with real-time polymerase chain reaction. This information should be useful for studying the mouse model of intervertebral disc degeneration and guide future cell therapy approaches.

KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons.

The failure of axon regeneration in the CNS limits recovery from damage and disease. Members of the KLF family of transcription factors can exert both positive and negative effects on axon regeneration, but the underlying mechanisms are unclear. Here we show that forced expression of KLF6 promotes axon regeneration by corticospinal tract neurons in the injured spinal cord. RNA sequencing identified 454 genes whose expression changed upon forced KLF6 expression in vitro, including sub-networks that were highly enriched for functions relevant to axon extension including cytoskeleton remodeling, lipid synthesis, and bioenergetics. In addition, promoter analysis predicted a functional interaction between KLF6 and a second transcription factor, STAT3, and genome-wide footprinting using ATAC-Seq data confirmed frequent co-occupancy. Co-expression of the two factors yielded a synergistic elevation of neurite growth in vitro. These data clarify the transcriptional control of axon growth and point the way toward novel interventions to promote CNS regeneration.

Quantitative assessment of the associations between MTHFR C677T and A1298C polymorphisms and risk of fractures: a meta-analysis.

Many studies have investigated the associations between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and risk of fractures, but the impact of MTHFR polymorphisms on fractures risk is unclear owing to the obvious inconsistence among those studies. This study aims to quantify the strength of association between MTHFR C677T and A1298C polymorphisms and risk of fractures. We searched the PubMed, Embase and Wanfang databases for articles relating the association between MTHFR C677T and A1298C polymorphisms and risk of fractures in humans. We estimated summary odds ratios (ORs) with their confidence intervals (CIs) to assess the associations. Meta-analyses suggested MTHFR C677T polymorphism was associated with increased risk of any site fractures (for T vs. C, OR = 1.17, 95 % CI 1.03-1.32; for TT vs. CC, OR = 1. 31, 95 % CI 1.11-1.54; for TT vs. CT, OR = 1.22, 95 % CI 1.04-1.43; for TT vs. CT/CC, OR = 1.31, 95 % CI 1.13-1.51). Besides, MTHFR A1298C polymorphism was also associated with increased risk of any site fractures. Subgroup meta-analyses suggested MTHFR C677T polymorphism was associated with increased risk of vertebral fractures under three genetic contrast modes (for TT vs. CC, OR = 1.43, 95 % CI 1.05-1.95; for TT vs. CT, OR = 1.36, 95 % CI 1.01-1.85; for TT vs. CT/CC, OR = 1.50, 95 % CI 1.17-1.91), but there was no association between MTHFR C677T polymorphism and risk of hip fractures and non-vertebral fractures (all P values were more than 0.05). Thus, individuals with homozygote genotype TT of MTHFR C677T have obviously increased risk of vertebral fractures compared those with heterozygote genotype CT or homozygote genotype CC. There is no association between MTHFR C677T polymorphism and risk of hip fractures and non-vertebral fractures.

Cloning and expression of a retinoic acid receptor ß2 subtype from the adult newt: evidence for an early role in tail and caudal spinal cord regeneration.

Retinoic acid receptor beta 2 (RARß2) has been proposed as an important receptor mediating retinoid-induced axonal growth and regeneration in developing mammalian spinal cord and brain. In urodele amphibians, organisms capable of extensive central nervous system (CNS) regeneration as adults, this receptor had not been isolated, nor had its function been characterized. We have cloned a full-length RARß2 cDNA from adult newt CNS. This receptor, NvRARß2, is expressed in various adult organs capable of regeneration, including the spinal cord. Interestingly, both the NvRARß2 mRNA and protein are up-regulated during the first 2 weeks after amputation of the tail, primarily in the ependymoglial and meningeal tissues near the rostral cut surface of the cord. Treatment with LE135, a RARß-selective antagonist, caused a significant inhibition of ependymal outgrowth and a decrease in tail regenerate length. These data support an early role for this receptor in caudal spinal cord and tail regeneration in this amphibian.

MTHFR C677T polymorphism and osteoporotic fractures.

The C677T (rs1801133) polymorphism of MTHFR (methylenetetrahydrofolate reductase) has been associated with the risk of cardiovascular events, and also with osteoporosis in some studies. However, the results are controversial. Our objective was to determine the relationship of the polymorphism with osteoporotic fractures by means of a case-control study. C677T was analyzed in 823 subjects (365 controls, 136 with vertebral fractures and 322 with hip fracture) by using a Taqman assay. The distribution of MTHFR genotypes was similar in patients and controls. In comparison with TC/CC genotypes, the age-adjusted OR for hip fractures of the TT genotype was 1.0 (95% confidence interval 0.6-1.7) in women and 0.7 (0.3-1.8) in men. The OR for vertebral fractures was 0.8 (0.4-1.7) in women and 1.7 (0.4-6.7) in men. A meta-analysis combining these data with previous reports confirmed the lack of association between MTHFR and fractures, with an OR of 1.1 (0.7-1.9, p=0.65) for vertebral fractures and 1.2 (0.7-2.0; p=0.45) for peripheral fractures, but there was significant heterogeneity among the results of individual studies, particularly about peripheral fractures. In conclusion, the C677T polymorphism of the MTHFR gene does not appear to be associated with the overall risk of osteoporotic fractures. However, given the heterogeneity of the results of published studies, further investigations are needed to evaluate its influence in specific population subgroups.

Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites.

Osteoporosis has a strong genetic component, but the genes involved are poorly defined. We studied whether the sclerosteosis/van Buchem disease gene (SOST) is an osteoporosis-risk gene by examining its association with bone-mineral density (BMD). Mutations in SOST result in sclerosteosis, and alterations in the SOST gene expression may be causal in the closely related van Buchem disease. We used a set of eight polymorphisms from the SOST gene region to genotype 1,939 elderly men and women from a large population-based prospective-cohort study of Dutch whites. A 3-bp insertion (f=0.38) in the presumed SOST promoter region (SRP3) was associated with decreased BMD in women at the femoral neck (FN) (P=.05) and lumbar spine (LS) (P=.01), with evidence of an allele-dose effect in the oldest age group (P=.006). Similarly, a G variant (f=0.40) in the van Buchem deletion region (SRP9) was associated with increased BMD in men at the FN (P=.007) and LS (P=.02). In both cases, differences between extreme genotypes reached 0.2 SD. We observed no genotype effects on fracture risk, for the 234 osteoporotic fractures validated during 8.2 years of follow-up and for the 146 vertebral prevalent fractures analyzed. We did not find association between any of several frequent haplotypes across the SOST gene region and BMD. We did find evidence of additive effects of SRP3 with the COLIA1 Sp1 polymorphism but not with haplotypes of 3' polymorphisms in the vitamin-D receptor gene. The SOST-COLIA1 additive effect increased with age and reached 0.5 SD difference in BMD at LS in the oldest age group (P=.02). The molecular mechanism whereby these moderate SOST genotype effects are mediated remains to be elucidated, but it is likely to involve differences in regulation of SOST gene expression.

Association of polymorphisms of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis.

Osteoporosis exhibits a substantial genetic component. Although polymorphisms of a variety of genes have been associated with bone mineral density and genetic susceptibility to osteoporosis, the genes responsible for these traits have not been definitively identified. We have shown that a T869-->C polymorphism of the transforming growth factor-beta1 gene, which results in a Leu-->Pro substitution at amino acid 10, is associated with bone mineral density in Japanese adolescents and postmenopausal women, with genetic susceptibility to both osteoporosis and vertebral fracture, and with the outcome of treatment for osteoporosis with active vitamin D. We have also shown that a C-509-->T polymorphism in the promoter region of this gene is associated with both bone mineral density and the prevalence of osteoporosis in postmenopausal women. In addition, analysis of combined genotypes for both the C-509-->T and T869-->C polymorphisms revealed that bone mineral density decreases and the susceptibility to osteoporosis increases with the number of T alleles. Thus, combined genotyping of the C-509-->T and T869-->C polymorphisms may prove beneficial in the prevention of osteoporosis in postmenopausal Japanese women. I review here the association of transforming growth factor-beta1 gene polymorphisms with genetic susceptibility to osteoporosis, which has provided insight into the function of transforming growth factor-beta1 as well as into the role of genetic factors in the development of osteoporosis.

A familial predisposition toward lumbar disc injury.

STUDY DESIGN: A retrospective case-control study was performed. OBJECTIVES: To test the hypothesis that there is a familial predisposition to lumbar disc pain and injury. SUMMARY OF BACKGROUND DATA: The few studies that have addressed this question have suggested that a familial predisposition is present, but the techniques used for identifying discogenic pain and accounting for potentially confounding extrinsic factors make it difficult to formulate a clear conclusion. METHODS: Immediate relatives of index patients who had surgically proven lumbar disc herniations (disc/case subjects) or repetitive upper extremity overuse syndromes (upper extremity/control subjects) were given a questionnaire that had been tested previously and found to reliably identify discogenic lower back pain. The prevalence of lumbar disc pain and injury was determined in the two groups of patients; logistic regression was used to control for demographic factors and activities known to increase risk for lumbar disc injury. RESULTS: The questionnaire was returned by 60 (59%) of 102 disc subjects and 41 (50%) of 81 upper extremity subjects. Sixteen (28%) disc subjects and one (2%) of the upper extremity subjects met questionnaire criteria for discogenic lumbar pain; seven (12%) disc subjects and no upper extremity subjects had received surgical therapy for lumbar disc pain. Logistic regression analysis identified familial grouping and a history of lifting as the only variables associated with a positive response on the questionnaire. Information obtained from index patients about their nonresponding relatives' history of significant back pain suggested similar findings. CONCLUSIONS: There is a familial predisposition toward lumbar disc pain and injury. This information may be helpful in occupational counseling or for targeting specific populations with preventative, interventional strategies.

Osteoporosis and heredity.

A retrospective epidemiological study was performed to determine whether postmenopausal osteoporosis is a hereditary condition. Frequency of fractures was calculated in women whose mothers had suffered vertebral fractures after a low-energy trauma three decades earlier. The frequency of fractures was compared to the frequency in an age-matched control group. The daughters of the osteoporotic women were not more prone to sustain fractures than the controls.