Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a(-/-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.

Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed ”the Superoxide Theory,” which postulates that superoxide (O2•−) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q10) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich’s seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.

Impairment of retinal vascular homeostasis is associated with the development and progression of diabetic retinopathy involving gap junction intercellular communication (GJIC) activity. The principal gap junction protein of intercellular communication, connexin, was investigated to determine the effects of high glucose concentrations on the expression of endothelial-specific connexins (Cx37, Cx40, and Cx43), connexin phosphorylation pattern, and GJIC activity. Rat microvascular endothelial (RME) cells grown in high (30 mmol/l)-glucose medium for 9 days had reduced Cx43 expression: Cx43 mRNA (68 ؎ 13% of control; P ‫؍‬ 0.019, n ‫؍‬ 5) and protein (55.6 ؎ 16% of control; P ‫؍‬ 0.003, n ‫؍‬ 5) levels were reduced; however, Cx37 and Cx40 expression was not affected. Using alkaline phosphatase and Western blot analyses, we identified three forms of Cx43: a nonphosphorylated form (P0) and two phosphorylated forms (P1 and P2). Expression of all three forms was decreased in cells grown in high-glucose medium: PO, 73 ؎ 15% of control (P ‫؍‬ 0.04); P1, 57 ؎ 16% of control (P ‫؍‬ 0.01); and P2, 42 ؎ 22% of control (P ‫؍‬ 0.006). Using immunofluorescence microscopy, we observed Cx43 localization at specific sites of contact (plaques) between adjacent cells. In cells grown in highglucose medium, we observed reduced plaque counts (63 ؎ 6% of control; P ‫؍‬ 0.009) and decreased intensity of Cx43 immunofluorescence compared with cells grown in normal medium. Furthermore, using scrape load dye transfer (SLDT) technique, we found that these cells exhibited reduced GJIC activity (60% of control; P ‫؍‬ 0.01, n ‫؍‬ 5). The reduction in GJIC activity correlated with the decreased Cx43 protein levels (r ‫؍‬ 0.9). These results indicate that high glucose concentrations inhibited GJIC activity by reducing Cx43 synthesis in RME cells. Impaired intercellular communication may contribute to breakdown of homeostatic balance in diabetic microangiopathy. Diabetes 51:1565-1571, 2002

No abstract

A cross-sectional study that targeted a total of 43,630 pupils in Niigata City, Japan was performed. The objective of the study was to evaluate the association between sports activities and low back pain (LBP) in childhood and adolescence in Japan. Regarding risk factors of LBP, a large number of studies have been conducted that have examined gender differences, height and weight, body mass index, sports time, differences in lifestyle, family history, and mental factors; however, no definitive conclusion has yet been made. A questionnaire survey was conducted using 43,630 pupils, including all elementary school pupils from the fourth to sixth grade (21,893 pupils) and all junior high pupils from the first to third year (21,737 pupils) in Niigata City (population of 785,067). 26,766 pupils who were determined to have valid responses (valid response rate 61.3%) were analyzed. Among the 26,766 pupils with valid responses, 2,591 (9.7%) had LBP at the time of the survey, and 8,588 (32.1%) had a history of LBP. The pupils were divided between those who did not participate in sports activities except the physical education in school (No sports group: 5,486, 20.5%) and those who participated in sports activities (Sports group: 21,280, 79.5%), and the difference in lifetime prevalence between No sports group and Sports group was examined. The odds ratio for LBP according to sports activity was calculated by multiple logistic regression analysis adjusted for gender, age, and body mass index. In addition, the severity of LBP was divided into three levels (Level 1: no limitation in any activity, Level 2: necessary to refrain from participating in sports and physical activities, and Level 3: necessary to be absent from school), and Levels 2 and 3 were defined as severe LBP; the severity was compared between No sports group and Sports group and in each sport's items. Moreover, in Sports group, the amount of time spent participating in sports activities were divided into three groups (Group 1: less than 6 h per week, Group 2: 6-12 h per week, and Group 3: 12.1 h per week or more), and the dose-response between the amount of time spent participating in sports activities and the occurrence of LBP were compared. In No sports group, 21.3% experienced a history of LBP; in Sports group, 34.9% experienced LBP (P < 0.001). In comparison to No sports group, the odds ratio was significantly higher for Sports group (1.57), and also significantly higher for most of the sports items. The severity of LBP was significantly higher in Sports group (20.1 vs. 3.2%, P < 0.001). The amount of time spent participating in sports activities averaged 9.8 h per week, and a history of LBP significantly increased in the group which spent a longer time participating in sports activities (odds ratio 1.43 in Group 3). These findings suggest that sports activity is possible risk factors for the occurrence of LBP, and it might increase the risk for LBP in childhood and adolescence.

A cross-sectional study targeted a total of 43,630 pupils in Niigata City, Japan was performed. The objective was to clarify the present incidence of low back pain (LBP) in childhood and adolescence in Japan. It has recently been recognized that LBP in childhood and adolescence is also as common a problem as that for adults and most of these studies have been conducted in Europe, however, none have so far been made in Japan. A questionnaire survey was conducted using 43,630 pupils, including all elementary school students from the fourth to sixth grade (21,893 pupils) and all junior high students from the first to third year (21,737 pupils) in Niigata City (population of 785,067) to examine the point prevalence of LBP, the lifetime prevalence, the gender differences, the age of first onset of LBP in third year of junior high school students, the duration, the presence of recurrent LBP or not, the trigger of LBP, and the influences of sports and physical activities. In addition, the severity of LBP was divided into three levels (level 1: no limitation in any activity; level 2: necessary to refrain from participating in sports and physical activities, and level 3: necessary to be absent from school) in order to examine the factors that contribute to severe LBP. The validity rate was 79.8% and the valid response rate was 98.8%. The point prevalence was 10.2% (52.3% male and 47.7% female) and the lifetime prevalence was 28.8% (48.5% male and 51.5% female). Both increased as the grade level increased and in third year of junior high school students, a point prevalence was seen in 15.2% while a lifetime prevalence was observed in 42.5%. About 90% of these students experienced first-time LBP during the first and third year of junior high school. Regarding the duration of LBP, 66.7% experienced it for less than 1 week, while 86.1% suffered from it for less than 1 month. The recurrence rate was 60.5%. Regarding the triggers of LBP, 23.7% of them reported the influence of sports and exercise such as club activities and physical education, 13.5% reported trauma, while 55.6% reported no specific triggers associated with their LBP. The severity of LBP included 81.9% at level 1, 13.9% at level 2 and 4.2% at level 3. It was revealed that LBP in childhood and adolescence is also a common complaint in Japan, and these findings are similar to previous studies conducted in Europe. LBP increased as the grade level increased and it appeared that the point and lifetime prevalence in adolescence are close to the same levels as those seen in the adulthood and there was a tendency to have more severe LBP in both cases who experienced pain for more than 1 month and those with recurrent LBP.

High-glucose-induced downregulation of Cx43 expression and inhibition of GJIC in retinal pericytes may play a role in the disruption of vascular homeostasis in diabetic retinopathy.

a b s t r a c tRecent studies have indicated that acetylcholine (ACh) plays a vital role in various tissues, while the role of ACh in bone metabolism remains unclear. Here we demonstrated that ACh induced cell proliferation and reduced alkaline phosphatase (ALP) activity via nicotinic (nAChRs) and muscarinic acetylcholine receptors (mAChRs) in osteoblasts. We detected mRNA expression of several nAChRs and mAChRs. Furthermore, we showed that cholinergic components were up-regulated and subunits/subtypes of acetylcholine receptors altered during osteoblast differentiation. To our knowledge, this is the first report demonstrating that osteoblasts express specific acetylcholine receptors and cholinergic components and that ACh plays a possible role in regulating the proliferation and differentiation of osteoblasts. Crown