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Lumbar spondylolysis is a defect of the pars interarticularis known to occur as a stress fracture. Its incidence varies considerably depending on ethnicity, sex, and sports activity. However, there are few literature reviews describing its incidence in different ethnic groups or in people who engage in different sports. We reviewed the most relevant articles on spondylolysis published in scientifi c journals. First, we focused on its incidence in various ethnic groups distributed by sex, the familial occurrence, and in patients with relevant diseases. Second, we focused on the incidence of spondylolysis in relation to the sports practiced by the patients. Although placing special emphasis on the incidence of lumbar spondylolysis in the general population in Japan, we also reviewed the Japanese and English literature to investigate its incidence among those who engage in different sports. The incidence of lumbar spondylolysis in the general Japanese population was 5.9%. Most studies report that the incidence in higher in male subjects than in female subjects. We found that Japanese rugby and judo players were prone to suffer lumbar spondylolysis, at an incidence of about 20%. However, the incidence for Japanese professional soccer and baseball players was much higher, at 30%, which was more than fi ve times the incidence in the general Japanese population. The incidence of lumbar spondylolysis varies depending on ethnicity, sex, family history, relevant disease, and sports activity.

Purpose Achondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported. Methods After completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day. Results In children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected. Conclusion Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

Chondromodulin (Cnmd) is a glycoprotein known to stimulate chondrocyte growth. We examined in this study the expression and functional role of Cnmd during distraction osteogenesis that is modulated by mechanical forces. The right tibiae of the mice were separated by osteotomy and subjected to slow progressive distraction using an external fixator. In situ hybridization and immunohistochemical analyses of the lengthened segment revealed that Cnmd mRNA and its protein in wild-type mice were localized in the cartilage callus, which was initially generated in the lag phase and was lengthened gradually during the distraction phase. In Cnmd null ( Cnmd −/− ) mice, less cartilage callus was observed, and the distraction gap was filled by fibrous tissues. Additionally, radiological and histological investigations demonstrated delayed bone consolidation and remodeling of the lengthened segment in Cnmd −/− mice. Eventually, Cnmd deficiency caused a one-week delay in the peak expression of VEGF , MMP2 , and MMP9 genes and the subsequent angiogenesis and osteoclastogenesis. We conclude that Cnmd is necessary for cartilage callus distraction.

Hyperparathyroidism, which is increased parathyroid hormone (PTH) levels in the blood, could cause delayed or non-union of bone fractures. But, no study has yet demonstrated the effects of excess continuous PTH exposure, such as that seen in hyperparathyroidism, for fracture healing. Continuous human PTH 1–34 (teriparatide) infusion using an osmotic pump was performed for stabilized tibial fractures in eight-week-old male mice to determine the relative bone healing process compared with saline treatment. Radiographs and micro-computed tomography showed delayed but increased calcified callus formation in the continuous PTH 1–34 infusion group compared with the controls. Histology and quantitative histomorphometry confirmed that continuous PTH 1–34 treatment significantly increased the bone callus area at a later time point after fracture, since delayed endochondral ossification occurred. Gene expression analyses showed that PTH 1–34 resulted in sustained Col2a1 and reduced Col10a1 expression, consistent with delayed maturation of the cartilage tissue during fracture healing. In contrast, continuous PTH 1–34 infusion stimulated the expression of both Bglap and Acp5 through the healing process, in accordance with bone callus formation and remodeling. Mechanical testing showed that continuously administered PTH 1–34 increased the maximum load on Day 21 compared with control mice. We concluded that continuous PTH 1–34 infusion resulted in a delayed fracture healing process due to delayed callus cell maturation but ultimately increased biomechanical properties.

The fate of hypertrophic chondrocytes during endochondral ossification remains controversial. It has long been thought that the calcified cartilage is invaded by blood vessels and that new bone is deposited on the surface of the eroded cartilage by newly arrived cells. The present study was designed to determine whether hypertrophic chondrocytes were destined to die or could survive to participate in new bone formation. In a rabbit experiment, a membrane filter with a pore size of 1 µm was inserted in the middle of the hypertrophic zone of the distal growth plate of ulna. In 33 of 37 animals, vascular invasion was successfully interposed by the membrane filter. During 8 days, the cartilage growth plate was enlarged, making the thickness 3-fold greater than that of the nonoperated control side. Histological examination demonstrated that the hypertrophic zone was exclusively elongated. At the terminal end of the growth plate, hypertrophic chondrocytes extruded from their territorial matrix into the open cavity on the surface of the membrane filter. The progenies of hypertrophic chondrocytes (PHCs) were PCNA positive and caspase-3 negative. In situ hybridization studies demonstrated that PHCs did not express cartilage matrix proteins anymore but expressed bone matrix proteins. Immunohistochemical studies also demonstrated that the new matrix produced by PHCs contained type I collagen, osteonectin, and osteocalcin. Based on these results, we concluded that hypertrophic chondrocytes switched into bone-forming cells after vascular invasion was interposed in the normal growth plate.

Background: Many risk factors for throwing injuries have been proposed. However, little is known about the risk factors for elbow injuries, particularly on physeal injuries in youth baseball players without prior elbow pain. Purpose: To investigate the risk factors for elbow injuries with a focus on physeal injuries that could predispose youth baseball players without elbow pain to elbow injuries. Study Design: A prospective epidemiology study. Methods: In 2006, 449 players without prior elbow pain were observed prospectively for 1 season to study injury incidence in relation to specific risk factors. The average age was 10.1 years (range, 7-11 years). One year later, all players were examined by administering a questionnaire, physical examination, and radiographic examination. Data for the groups with and without elbow pain were analyzed using multivariate logistic regression models. Results: Among the 449 participants, 30.5% reported episodes of elbow pain during the season. Of the players who reported elbow pain, 72.3% presented abnormal findings on physical examination, and of those players, 81.4% had radiographic abnormalities. Multivariate analysis showed that the age of 12 years (at 1-year examination), pitcher and catcher positions, and playing more than 100 games per year were risk factors for elbow pain. Conclusion: It is expected that 30% of youth baseball players have elbow pain each year, and nearly 60% of players with elbow pain exhibit radiographic abnormalities. The age of 12 years, pitcher and catcher positions, and playing more than 100 games per year are risk factors for elbow pain.

During total hip arthroplasty (THA), the external iliac, femoral, and obturator vessels are at risk of vascular injury when penetrating the inner cortex of the pelvis. The purpose of this study was to clarify the location of these vessels using three-dimensional computed tomographic angiography (3DCT-A). We enrolled 100 subjects (200 hips) without hip disease and performed examinations on the following. (1) External iliac–femoral vessels: we measured the shortest distance from these vessels to the pelvis on axial CT images and investigated the factors affecting distance. The anatomical course of the iliac artery was classified as straight, curved, or tortuous, and the correlation between course and age was established. (2) Obturator vessels: we measured the shortest distance from the obturator vessels to the quadrilateral surface on axial CT images. (3) Visualization of pelvic vessels was through the pelvis by dual-phase 3DCT-A. (1) The external iliac vein was located significantly closer to the pelvis than the artery, especially on the left side and in aged and female subjects. The single-curved and tortuous double-curved vessel types were found in aged subjects, and external iliac vessels of these types were closer to the pelvis than vessels of the straight type. In 36 subjects, the external iliac veins lay directly on the osseous surface of the pelvis (right 16, left 36). Of these 36 subjects, only one had straight-type vessels. (2) Obturator vessels were located just behind the acetabulum near the obturator foramen. (3) Reconstructed 3DCT images enabled us to visualize the pelvic vessels and demonstrated the danger area for penetrating the inner cortex of the pelvis. Understanding the anatomical orientation of the pelvic vessels around the acetabulum using 3DCT-A could be helpful for preventing vascular injury during THA.

Many genetic association studies support a contribution of genetic variants in the KCNJ11 - ABCC8 gene locus to type 2 diabetes (T2D) susceptibility in Caucasians. In non-Caucasian populations, however, there have been only a few association studies, and discordant results were obtained. Herein, we selected a total of 31 SNPs covering a 211.3-kb region of the KCNJ11 - ABCC8 locus, characterized the patterns of linkage disequilibrium (LD) and haplotype structure, and performed a case-control association study in a Japanese population consisting of 909 T2D patients and 893 control subjects. We found significant associations between eight SNPs, including the KCNJ11 E23K and ABCC8 S1369A variants, and T2D. These disease-associated SNPs were genetically indistinguishable because of the presence of strong LD, as found previously in Caucasians. For the KCNJ11 E23K variant, the most significant association was obtained under a dominant genetic model (OR 1.32, 95% CI 1.09–1.60, P =  0.004). A meta-analysis of East Asian studies, comprising a total of 3,357 T2D patients (77.4% Japanese) and 2,836 control subjects (77.8% Japanese), confirmed the significant role of the KCNJ11 E23K variant in T2D susceptibility. Furthermore, we found evidence suggesting that the KCNJ11 E23K genotype is independently associated with higher blood-pressure levels.

We conducted population-based association tests for the four selected SNPs (rs2240340/ padi4_94 , rs7528684/ fcrl3_3 , rs3792876/ slc2F2 and rs2268277/ runx1 ) previously reported to be associated with rheumatoid arthritis (RA). The study population consisted of 950 unrelated Japanese subjects with RA and 507 controls, none of whom had previously been tested for these variants. Only the SNP rs2240340/ padi4_94 was modestly associated with RA [allele odds ratio (OR) 1.22, 95% confidence interval (CI) 1.04–1.43, P  = 0.012]. The most significant association effect was found for genotype contrast between minor and major allele homozygotes (OR 1.53, 95% CI 1.10–2.12, P  = 0.010). No other SNPs showed a statistically significant association with RA in our population. Meta-analysis of published studies and our new data confirmed a highly significant association between PADI4 gene SNPs and increased risk of RA in East Asian populations (allele fixed-effects summary OR 1.31, 95% CI 1.22–1.41, P  < 0.0001). We found some evidence for an association of either rs7528684/ fcrl3_3 or rs3792876/ slc2F2 with RA; however, because the magnitudes of effects were apparently much weaker than those reported in the initial positive reports, and there were substantial levels of inter-study OR heterogeneity, we concluded that additional studies are needed to fully understand the present results.

Cleidocranial dysplasia (CCD), an autosomal-dominant human bone disease, is thought to be caused by heterozygous mutations in runt-related gene 2 (RUNX2)/polyomavirus enhancer binding protein 2α A (PEBP2α A)/core-binding factor A1 (CBFA1). To understand the mechanism underlying the pathogenesis of CCD, we studied a novel mutant of RUNX2, CCDα A376, originally identified in a CCD patient. The nonsense mutation, which resulted in a truncated RUNX2 protein, severely impaired RUNX2 transactivation activity. We show that signal transducers of transforming growth factor β superfamily receptors, Smads, interact with RUNX2 in vivo and in vitro and enhance the transactivation ability of this factor. The truncated RUNX2 protein failed to interact with and respond to Smads and was unable to induce the osteoblast-like phenotype in C2C12 myoblasts on stimulation by bone morphogenetic protein. Therefore, the pathogenesis of CCD may be related to the impaired Smad signaling of transforming growth factor β /bone morphogenetic protein pathways that target the activity of RUNX2 during bone formation.