Background: Although segmental wire fixation has been successful in the treatment of nonathletes with spondylolysis, no information exists on the results of this type of surgery in athletes. Purpose: To evaluate the outcome of surgical repair of pars interarticularis defect by segmental wire fixation in young athletes with lumbar spondylolysis. Methods: Between 1993 and 2000, 20 athletes (6 women and 14 men; average age, 23.7) with lumbar spondylolysis were treated surgically with this technique. They were actively engaged in sports such as baseball, tennis, and golf. Nineteen athletes had one level of spondylolysis and one athlete had two levels. The level of spondylolysis was L4 in 2 athletes and L5 in 19. The average follow-up period was 3.5 years (range, 1.3 to 8.6). Surgical outcome was evaluated by radiographic examination, the Japanese Orthopaedic Association score, preoperative and postoperative sports activity levels and intensities, and the presence of complications. Results: Bony fusion at the site of spondylolysis was obtained in all cases, and the Japanese Orthopaedic Association score was increased significantly after surgery (preoperatively, 21.2 ± 3.9; postoperatively, maximum 27.7 ± 1.0; recovery rate, 80.4%). All of the patients returned to their sports activities, although at varying degrees. No severe complications were noted. Conclusion: We recommend this technique in cases of lumbar spondylolysis in athletes who hope to resume their sports activities.

EWS-Fli1, a fusion gene resulting from the chromosomal translocation t(11;22, q24;q12), encodes a transcriptional activator, promotes cellular transformation, and is often found in Ewing sarcoma and primitive neuroectodermal tumor. The Aurora A and Aurora B kinases belong to a highly conserved family of serine/threonine protein kinases, are tightly regulated during the cell cycle, and are overexpressed in many carcinomas. Because the relationship between the Aurora A and/or Aurora B genes and the EWS-Fli1 fusion gene is unknown, we investigated the regulatory mechanism(s) by which Aurora kinases are controlled. Knockdown of EWS-Fli1 by small interfering RNA reduced mRNA levels not only of EWS-Fli1 but also of Aurora A and Aurora B. Luciferase assay using Aurora A and Aurora B promoters showed up-regulated activities compared with those of an empty vector. Experiments with deletion and point mutants showed positive regulatory Ets-binding sites located −84 and −71 bp upstream of the transcription initiation sites in Aurora A and Aurora B, respectively. Moreover, chromatin immunoprecipitation assay revealed that EWS-Fli1 gene products interact with both the Aurora A and Aurora B promoters. These results strongly suggest that the mitotic kinases Aurora A and Aurora B are regulated by EWS-Fli1 fusion protein in Ewing sarcoma cells. (Mol Cancer Res 2008;6(12):1937–45)

Multiple hereditary exostoses (MHE) is characterized by the development of numerous benign bony tumors (osteochondromas). Although it has been well established that MHE is caused by mutations in EXT1 and EXT2 , which encode glycosyltransferase essential for heparan sulfate (HS) biosynthesis, the cellular origin and molecular mechanisms of MHE remain elusive. Here, we show that in Ext1 mutant mice, osteochondromas develop from mesenchymal stem cell–like progenitor cells residing in the perichondrium, and we show that enhanced BMP signaling in these cells is the primary signaling defect that leads to osteochondromagenesis. We demonstrate that progenitor cells in the perichondrium, including those in the groove of Ranvier, highly express HS and that Ext1 ablation targeted to the perichondrium results in the development of osteochondromas. Ext1 -deficient perichondrial progenitor cells show enhanced BMP signaling and increased chondrogenic differentiation both in vitro and in vivo. Consistent with the functional role for enhanced BMP signaling in osteochondromagenesis, administration of the small molecule BMP inhibitor LDN-193189 suppresses osteochondroma formation in two MHE mouse models. Together, our results demonstrate a role for enhanced perichondrial BMP signaling in osteochondromagenesis in mice, and they suggest the possibility of pharmacological treatment of MHE with BMP inhibitors.

EWS-Fli1, a fusion gene resulting from a chromosomal translocation t(11;22, q24;q12) and found in Ewing sarcoma and primitive neuroectodermal tumors, encodes a transcriptional activator and promotes cellular transformation. However, the precise biological functions of its products remain unknown. To investigate the role of EWS-Fli1 in cell growth signaling, we transfected Ewing sarcoma TC-135 cells with short interfering RNAs for EWS-Fli1. EWS-Fli1 knockdown reduced cell growth and platelet-derived growth factor (PDGF)-BB-induced activation of the growth signaling enzymes. Interestingly, phospholipase D2 (but not the PDGF-BB receptor) showed marked down-regulation in the EWS-Fli1-knocked down TC-135 cells compared with the control cells. In Ewing sarcoma TC-135 cells, the PDGF-BB-induced phosphorylation of growth signaling involving extracellular signal-regulated kinase, Akt, p70S6K, and the expression of cyclin D3 were markedly inhibited by transfection with short interfering RNA phospholipase (PL)-D2. The PDGF-BB-induced activation of growth signaling was also suppressed by 1-butanol, which prevents the production of phosphatidic acid by phospholipase D (but not by t-butyl alcohol), thereby implicating PLD2 in PDGF-BB-mediated signaling in TC-135 cells. These results suggest that EWS-Fli1 may play a role in the regulation of tumor proliferation-signaling enzymes via PLD2 expression in Ewing sarcoma cells.

A delay in establishing the diagnosis of an occult fracture of the hip that remains unrecognised after plain radiography can result in more complex treatment such as an arthroplasty being required. This might be avoided by earlier diagnosis using MRI. The aim of this study was to investigate the best MR imaging sequence for diagnosing such fractures. From a consecutive cohort of 771 patients admitted between 2003 and 2011 with a clinically suspected fracture of the hip, we retrospectively reviewed the MRI scans of the 35 patients who had no evidence of a fracture on their plain radiographs. In eight of these patients MR scanning excluded a fracture but the remaining 27 patients had an abnormal scan: one with a fracture of the pubic ramus, and in the other 26 a T₁-weighted coronal MRI showed a hip fracture with 100% sensitivity. T₂-weighted imaging was undertaken in 25 patients, in whom the diagnosis could not be established with this scanning sequence alone, giving a sensitivity of 84.0% for T₂-weighted imaging. If there is a clinical suspicion of a hip fracture with normal radiographs, T₁-weighted coronal MRI is the best sequence of images for identifying a fracture.

Bone remodeling is a highly coordinated process involving bone formation and resorption, and imbalance of this process results in osteoporosis. It has long been recognized that long-term heparin therapy often causes osteoporosis, suggesting that heparan sulfate (HS), the physiological counterpart of heparin, is somehow involved in bone mass regulation. The role of endogenous HS in adult bone, however, remains unclear. To determine the role of HS in bone homeostasis, we conditionally ablated Ext1 , which encodes an essential glycosyltransferase for HS biosynthesis, in osteoblasts. Resultant conditional mutant mice developed severe osteopenia. Surprisingly, this phenotype is not due to impairment in bone formation but to enhancement of bone resorption. We show that osteoprotegerin (OPG), which is known as a soluble decoy receptor for RANKL, needs to be associated with the osteoblast surface in order to efficiently inhibit RANKL/RANK signaling and that HS serves as a cell surface binding partner for OPG in this context. We also show that bone mineral density is reduced in patients with multiple hereditary exostoses, a genetic bone disorder caused by heterozygous mutations of Ext1 , suggesting that the mechanism revealed in this study may be relevant to low bone mass conditions in humans.