Advanced glycation end products promote intervertebral disc degeneration by transactivation of matrix metallopeptidase genes.

OBJECTIVE: Examine the mechanism by which advanced glycation end products (AGEs) induce intervertebral disc degeneration (IDD) in C57BL/6J mice. METHODS: Matrix metallopeptidase (MMP) gene mRNA levels were assessed using RT-qPCR. Immunoprecipitation and co-immunoprecipitation were performed to identify the transcriptional complex regulating MMP expression due to AGEs. The preventive effects of inhibitors targeting this complex were tested in mice on high AGE diets. RESULTS: IDD and AGE accumulation were evident in mice on high-AGE diets (HAGEs), persisting across dietary shifts but absent in mice exclusively on low-AGE diets. Molecularly, HAGEs activated p21-activated kinase 1 (PAK1), prompting peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) phosphorylation. Ubiquitin-specific protease 12 (USP12) interacted with the phosphorylated PPRC1 (pPPRC1), safeguarding it from proteasomal degradation. This pPPRC1, in collaboration with two histone acetyltransferases p300/CREB-binding protein (CBP) and a transcription factor activator protein 1(AP1), enhanced the expression of 12 MMP genes (MMP1a/1b/3/7/9/10/12/13/16/19/23/28). In vitro AGE exposure on nucleus pulposus and annulus fibrosus cells replicated this gene activation pattern, driven by the PAK1/pPPRC1-p300/CBP-AP1 pathway. The application of PAK1, p300, and AP1 inhibitors reduced pPPRC1-p300/CBP-AP1 binding to MMP promoters, diminishing their expression. These inhibitors effectively thwarted IDD in HAGE mice. CONCLUSION: Our results revealed that HAGEs instigate IDD via the PAK1/pPPRC1-p300/CBP-AP1 signaling pathway. This insight can guide therapeutic strategies to slow IDD progression in prediabetic/diabetic patients.

The CRL4DCAF6 E3 ligase ubiquitinates CtBP1/2 to induce apoptotic signalling and promote intervertebral disc degeneration.

Inflammation and apoptosis are two important pathological causes of intervertebral disc degeneration (IDD). The crosstalk between these two biological processes during IDD pathogenesis remains elusive. Herein, we discovered that chronic inflammation induced apoptosis through a cullin-RING E3 ligase (CRL)-dependent mechanism. Two cullin proteins, CUL4A and 4B, recruited DNA damage-binding protein 1 (DDB1), RING-box protein 1 (RBX1) and DDB1- and CUL4-associated factor 6 (DCAF6) to assemble a CRL4DCAF6 E3 ligase in intervertebral discs (IVDs) derived from IDD patients. The CRL4DCAF6 E3 ligase ubiquitinated and degraded C-terminal-binding protein 1 and 2 (CtBP1/2), two homologues of transcriptional corepressors. The degradation of CtBP1/2 disassociated from the p300-forkhead box O3a (FOXO3a) complex, inducing the expression of B-cell lymphoma 2 (Bcl2)-binding component 3 (BBC3) and causing BBC3-dependent apoptosis. TSC01131, a small molecule that specifically targets CUL4-DDB1 interaction, could inhibit the ubiquitination of CtBP1/2 in vitro and in vivo, thereby decreasing the BBC3 expression level and preventing apoptosis signalling. Using a mouse chronic inflammation model, we found that chronic inflammation could accelerate the IDD process through a conserved CRL4DCAF6-mediated mechanism. The administration of TSC01131 to mice could significantly improve the outcome of IDD. Collectively, our results revealed that inflammation-dependent CRL4DCAF6 E3 ligase triggered apoptosis through the removal of CtBP-mediated transrepression. The blockage of the CRL4DCAF6 E3 ligase by TSC01131 may represent a new therapeutic strategy for IDD treatment. KEY MESSAGES: CUL4A and CUL4B recruited DDB1, RBX1 and DCAF6 to assemble a CRL4DCAF6 E3 ligase in human IDD biopsies. The CRL4DCAF6 E3 ligase ubiquitinated and degraded CtBP1/2, causing BBC3-dependent apoptosis. A small molecule TSC01131 that specifically targets CUL4-DDB1 interaction could inhibit the ubiquitination of CtBP1/2, improving the outcome of IDD in a mouse model.

Glucose-stimulated PGC-1α couples with CBP and Runx2 to mediate intervertebral disc degeneration through transactivation of ADAMTS4/5 in diet-induced obesity mice.

Emerging evidence suggests that type 2 diabetes mellitus (T2DM) is associated with the pathogenesis of intervertebral disc degeneration (IDD). However, it is still unclear how T2DM contributes to IDD. Herein, we observed the accumulation of blood glucose and degenerative lumbar discs in mice fed a high-fat diet. Detection of differentially expressed genes in degenerative lumbar discs revealed that ADAMTS4 (A Disintegrin and Metalloproteinase with Thrombospondin motifs) and ADAMTS5 genes were significantly increased. In vitro analyses demonstrated that Runt-Related Transcription Factor 2 (Runx2) recruited both PPARgamma Coactivator 1alpha (PGC-1α) and CREB-Binding Protein (CBP) to transactivate the expression of ADAMTS4/5. Glucose stimulation could dose-dependently induce the accumulation of PGC-1α and promoted the binding of the CBP-PGC-1α-Runx2 complex to the promoters of ADAMTS4/5. Depletion of CBP-PGC-1α-Runx2 complex members and treatment with either PGC-1α inhibitor SR-18292 or CBP inhibitor EML425 in vitro could dramatically inhibit the glucose-induced expression of ADAMTS4/5. Administration of SR-18292 and EML425 in diabetic mice could prevent the degeneration of lumbar discs. Collectively, our results revealed a molecular mechanism by which the hyperglycemia-dependent CBP-PGC-1α-Runx2 complex was required for the transactivation of ADAMTS4/5. The blockage of this complex in diabetic mice may help prevent IDD.

Dynamic change of pelvic incidence after long fusion to pelvis with S2-alar-iliac screw: a 2-year follow-up study.

INTRODUCTION: Pelvic incidence (PI) is a key morphological parameter that reflects the relation between the sacrum and iliac wings. It is well accepted that PI remains constant after reaching maturity. However, recent studies indicated that PI might be altered after lumbosacral fusion. Additionally, it remains uncertain on the long-term influence of long fusion to pelvis with S2-alar-iliac screw on PI in patients with adult spinal deformity (ASD). STUDY DESIGN: A retrospective study. OBJECTIVE: To investigate whether and how PI would change during the follow-up in ASD patients who underwent S2AI fixation and to identify factors associated with the change in PI. METHODS: We retrospectively reviewed all ASD patients who underwent spinal surgery using S2AI screws between November 2014 and January 2017 at our institution. Patients with minimum follow-up of two years were included. The following sagittal radiographic parameters were measured: PI, Lumbar lordosis (LL), pelvic tilt (PT), PI-LL, sagittal vertical axis (SVA) at pre-op, post-op and 2-year follow-up. According to the changes in PI at immediate post-operation, patients were classified into two groups; Group A: Changes of PI less than or equal 5° and Group B: Changes of PI greater than 5°. RESULTS: A total of 82 ASD patients (Group A: 32, Group B: 50; mean age of 53.5 ± 12.6 years) with a mean follow-up period of 30.2 ± 9.2 months were included in this study. At immediate post-operation, Group A showed no significant change in PI (45.7° ± 11.4° to 45.3° ± 11.2°, p = 0.749); while Group B had a significant decrease in PI (51.6° ± 14.5° to 40.9° ± 14.0°, p < 0.001). At the last follow-up, 48% patients (24/50) in Group B had a significant increase in PI (32.8° ± 6.4° to 45.8° ± 11.2°, p < 0.001). Intergroup analysis showed that ΔPI, post-op PI, post-op PT and age were significantly different between both groups. In addition, pre-op PI, post-op PI, post-op PT, post-op PI-LL were significantly correlated with ΔPI at last follow-up. Also, logistic regression analysis showed that post-op PI was the associated risk factor (OR = 0.865, p = 0.024) for PI-LL mismatch. CONCLUSION: Our study showed that PI decreased in more than half of ASD patients immediately after spinal surgery using S2AI screws. Approximately 48% of them were able to recover during the 2-year follow-up. Lower pre-op PI, post-op PI and PT were found to be strongly associated with the return of PI. Thus, these current findings indicated that patients with a high PI at pre-operation should not be over-corrected to avoid PI-LL mismatch postoperatively.

Determining the association between the radiographic parameters and the SRS-22 scores in Chinese female patients with adolescent idiopathic scoliosis: does curve pattern matter?

Background: The Scoliosis Research Society (SRS)-22 outcomes have been shown to be correlated with radiographic parameter of adolescent idiopathic scoliosis (AIS). A recent study suggested that curve patterns might play a role in assessing the influence of deformity on patient's reported outcomes. The aim of this study was to examine the relationship between radiographic parameters and SRS-22 questionnaire outcomes in female patients with adolescent AIS among the Chinese population based on five curve patterns.Patients and Methods: The radiographic data and SRS-22 questionnaires of 259 female AIS patients were reviewed. Radiographic measurements included: Cobb angle of the major curve, T1 tilt angle, apical vertebral rotation, apical vertebral translation (AVT), thoracic kyphosis, and lumbar lordosis. Curve patterns included single thoracic (T), single thoracolumbar/lumbar (TL), double thoracic (DT), double major (DM), and triple major (TM). The correlation between radiographic measurements and each domain in SRS-22 was determined by Pearson's correlation coefficient.Results: The curve magnitude and AVT of the major curve were found to be significantly correlated with the self-image domain in all cases (Cobb angle: r = -0.426, p = 0.002; AVT: r = -0.281, p=0.006) and in all curve patterns except for TM. Compared to other groups, the TM group had a significantly larger major curve than the DT group and TL group (p ≤ 0.004). In TM group, the self-image scores were lower than TL group (p =0.018), and the function scores were lower than that in T, TL (p < 0.001) and DM groups (p =0.013). In the DT group, the T1 tilt was significantly correlated with the self-image domain (r = -0.376, p =0.004). In the T group, coronal curve magnitude was significantly correlated with function domain (r = -0.397, p < 0.001).Conclusion: Our findings suggested curve patterns should be considered in evaluating the correlations between radiographic parameters and SRS-22 outcomes in patients with AIS.

Correction of Scoliosis with Large Thoracic Curves in Marfan Syndrome: Does the High-Density Pedicle Screw Construct Contribute to Better Surgical Outcomes.

BACKGROUND The aim of this study was to determine whether higher density screw constructs resulted in better surgical outcomes in patients with scoliosis secondary to Marfan syndrome (MF-S) with large thoracic curves (≥70°). MATERIAL AND METHODS There were 34 MF-S patients who met the inclusion criteria and were evaluated radiographically before surgery, 2 weeks after operation, and at the final follow-up. The mean screw density was taken as the boundary, and patients were categorized as either in the high density (HD) group or the low density (LD) group. Parameters measured included coronal Cobb angle, T5-T12 kyphosis (TK), and T12-S1 lordosis (LL). Additionally, the operation duration, estimated blood loss, screw accuracy, complication rate, and clinical outcomes were compared between the 2 groups. RESULTS The mean screw density of all patients was 1.40±0.15 (range 1.13 to 1.67). Correction rate of the thoracic curve was closely related to the screw density at the concave side (r=0.783, P=0.007). Intergroup comparison showed a significantly higher correction rate of the thoracic coronal curve in HD group (56.59±4.80% versus 44.54±9.61%, P=0.036). At last follow-up, coronal correction loss of >5° occurred in 8 cases (47.1%) in the LD group and 3 cases (17.6%) in the HD group. Both groups demonstrated improvement in each domain of the SRS-22 questionnaire after surgery and no significant intergroup difference was found. CONCLUSIONS The high-density pedicle screw construct contributed to the significantly improved correction rate of thoracic curves in MF-S patients with large thoracic curves (≥70°). Additionally, increasing of pedicle screw number could help to enhance the structural stability and reduce the correction loss during the follow-up period.

Long fusion to the pelvis with S2-alar-iliac screws can induce changes in pelvic incidence in adult spinal deformity patients: analysis of predictive factors in a retrospective cohort.

PURPOSE: To verify whether pelvic incidence (PI) would change in adult spinal deformity (ASD) patients who underwent long instrumentation using S2-alar-iliac (S2AI) screws and to identify factors associated with the change in PI. METHODS: We retrospectively reviewed all patients who underwent spinal surgery using S2AI screws between November 2014 and January 2017 at our institution. Patients aged 20 years or above with available radiographs were included. According to the change in PI, patients were divided into two groups, group C: PI variance reached 5 or more degrees postoperatively and group NC: PI changed less than 5°. RESULTS: A total of 47 patients (3 males, 44 females; mean age, 52.47 ± 15.80 years) were included in this study. PI significantly decreased from 51.25° ± 14.80° to 40.43° ± 14.23° in group C (n = 26), with a mean change in 11.52° ± 6.17° (P < 0.05), but changed from 47.00° ± 13.18° to 46.57° ± 13.71° in group NC without statistical significance. Intergroup analysis showed that change in PI, preoperative PI-LL, preoperative LL, preoperative SVA, and postoperative PT were significantly different between both groups. Correlation analysis showed that the change in PI and preoperative LL and PI were significantly associated. The formula provided by the regression analysis was ΔPI = - 3.108 - 0.11PreLL + 0.211PrePI. CONCLUSIONS: Our study showed that PI decreased in 55% of ASD patients after spinal surgery using S2AI screws. Greater preoperative PI-LL mismatch and PI, as well as lumbar kyphosis, were associated with postoperative change in PI. These slides can be retrieved under Electronic Supplementary Material.

Does Symmetric Thoracic Fusion Make a Difference in Lenke 1 A/B AIS Patients?

STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to compare the long-term outcomes of correction surgery for Lenke 1 A/B scoliosis among those with symmetric fusion (SF), upper-dominant fusion (UF), and lower-dominant fusion (LF) in adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Symmetric fusion, defined as equal number of vertebral levels included in instrumented fusion above and below the apical vertebra or disc of the primary curve, was a new concept raised in AIS selective fusion. Previous study showed that similar correction the effect on clinical outcomes of this fusion style. METHODS: Preoperative, postoperative, and last follow-up radiographs of 117 consecutive patients with Lenke type 1A/B curves who underwent posterior selective thoracic instrumentation surgery were analyzed. Patients were divided into two groups (SF and nonsymmetric fusion [NSF]). Patients in NSF was further divided into two groups UF (more vertebrate was fused above the apex) and LF (more vertebrate was fused below the apex). Clinical outcomes and coronal decompensation including adding-on and trunk shift were analyzed and compared among three groups. RESULTS: There was no significant difference between SF and NSF in magnitude of preoperative main thoracic curve (P = 0.69) and correction rate (P = 0.50). Distal adding-on was observed in 21 patients (17.9%), and coronal decompensation was observed in eight patients (6.8%) in all at final follow up. No significant differences were found between the two groups regarding adding-on phenomenon (P = 0.64) and coronal imbalance (P = 0.72). Significantly higher rates of adding-on were found in UF compared with SF and LF (P < 0.001). In a subgroup analysis between UF and LF in NSF patients, significant differences were found between two subgroups in the rate of trunk shift (P = 0.038). No significant differences in SRS-22 scores were observed among the three groups. CONCLUSION: In Lenke 1A/B AIS with posterior selective fusion, SF provides no significant differences from NSF. However, in NSF, UF was found to be high risky of adding-on phenomenon. LEVEL OF EVIDENCE: 3.

Radiographic and Clinical Outcomes of Surgical Correction of Poliomyelitis-Related Spinal Deformities: A Comparison Among Three Types of Pelvic Instrumentations.

BACKGROUND: We compared the clinical and radiographic outcomes of corrective surgery in patients with poliomyelitis-related spinal deformity (PSD) using 3 types of pelvic fixation and investigated the incidence and risk factors for complications. METHODS: We reviewed the data from 42 patients with PSD who had undergone spinopelvic reconstruction at a single institution from 2000 to 2016. Of the 42 patients, 15 had been treated with the Galveston technique, 13 with iliac screw fixation, and 14 with S2-alar-iliac (S2AI) screw fixation. Demographic data, radiographic parameters, and complications were analyzed. Health-related quality of life was determined using Scoliosis Research Society (SRS) 22-item questionnaires and the Oswestry Disability Index scores. RESULTS: After surgery, the correction rate of the main curve was 51.7%, 57.8%, and 52.1% in the 3 groups, with significant improvement in regional kyphosis, coronal balance, and pelvic obliquity (PO) (P < 0.05). The correction of PO was similar among the 3 types of pelvic fixation; however, the patients treated with S2AI fixation required significantly less operative time (P < 0.05) and blood loss (P < 0.006). The overall complication rate was 40.5%, with a major complication rate of 23.8%. Age at surgery (P = 0.006) and grade >2 SRS-Schwab osteotomy (P = 0.036) were significant risk factors for complications. Significant improvement was found in the SRS-22 and Oswestry Disability Index scores at the final follow-up examination in the 3 groups. CONCLUSIONS: The present study showed satisfactory correction of spinopelvic deformity for 42 patients with PSD. Compared with the Galveston technique and iliac screw fixation, the use of S2AI significantly decrease the operative time and estimated blood loss and obtained similar correction of PO. Patient age at surgery and grade >2 SRS-Schwab osteotomy were significant risk factors for complications.

Selective Fusion in Lenke 5 Adolescent Idiopathic Scoliosis.

OBJECTIVE: To compare the clinical and radiographic outcomes on the sagittal plane between anterior and posterior selective fusion (ASF and PSF) in patients with Lenke 5 adolescent idiopathic scoliosis (AIS) for a minimum of 5 years of follow-up. METHODS: We included 77 patients with Lenke 5 AIS who underwent ASF (n = 40) with a single rod with structural cages or PSF (n = 37) with pedicle screw instrumentation. Radiographic parameters were compared preoperatively, 3 months and 2 years postoperatively, and at final follow-up. RESULTS: The mean follow-up duration was 93.9 ± 21.4 months in the ASF group and 80.4 ± 15.2 in the PSF group (P = 0.002). The correction rate of the coronal curve was comparable between the 2 groups at final follow-up. There was a significant time trend for lumbar lordosis (LL), thoracic kyphosis, thoracolumbar junctional kyphosis, instrumented segmental angle (ISA), proximal junctional angle, and sagittal vertical axis (P < 0.001) and significant group effects for LL (P = 0.0065) and ISA (P = 0.0325). At 3 months postoperatively, LL decreased in the ASF group and increased in the PSF group (-3.1° ± 6.6° vs. 1.3° ± 5.5° change, P = 0.002) and increased in both groups at final follow-up (2° ± 2.9° vs. 4.3° ± 4.9° change, P = 0.070). ISA increased in both groups 3 months postoperatively but decreased significantly in the ASF group compared with the PSF group at 2-year follow-up (4.0° ± 3.9° vs. 0.7° ± 1.9° change, P < 0.001) and final follow-up (8.1° ± 5.8° vs. 0.8° ± 3.4° change, P < 0.001). LL, ISA, and proximal junctional angle were significantly larger at final follow-up in the PSF group (P < 0.05). The incidence of proximal junctional kyphosis was higher in the PSF group (5/37) than in the ASF group (1/40). CONCLUSIONS: A significant and continuous loss of lordosis in ISA was observed after ASF in patients with Lenke 5 AIS. A larger LL was obtained with a higher incidence of proximal junctional kyphosis at long-term follow-up after PSF.

Prediction of respiratory function in patients with severe scoliosis on the basis of the novel individualized spino-pelvic index.

OBJECTIVE: Our study aimed to evaluate the pulmonary function of patients with severe scoliosis after correcting standing height with spino-pelvic index (SPI). METHODS: Inclusion criteria: (1) with a coronal Cobb angle of more than 90°; (2) diagnosed as congenital (CS) or idiopathic scoliosis (IS); (3) aged between ten and 20 years; (4) with pulmonary function test (PFT) at the primary consultation. Patients with previous surgical intervention, with angular kyphosis, and with neuromuscular disease were excluded. Length of spine (LOS), height of spine (HOS), and height of pelvis (HOP) were measured on coronal films. SPI was defined as the ratio between LOS and HOP. The corrected body height was calculated: corrected body height = body height + (SPI × HOP - HOS). The PFTs included the following parameters: VCmax, FVC, FVC% predicted, FEV1, FEV1% predicted, PEF, and MVV. PFT results were recalculated using the corrected body height. RESULTS: Thirty patients were diagnosed as IS and 27 as CS with average Cobb angles of 99.88° ± 11.83 and 98.06° ± 14.27, respectively. Significant differences were observed in VCmax and FVC between IS and CS patients (P < 0.05). All the corrected PFT parameters were significantly lower than the original PFT parameters (P < 0.05). CONCLUSION: For the first time, this study proposed a method to predict pulmonary function of patients with severe scoliosis using SPI, as an age-independent parameter in normal adolescents. After body height correction, pulmonary function of patients with severe scoliosis was found to be significantly decreased, indicating that pulmonary function impairment was underestimated in patients with severe scoliosis when evaluating pulmonary function with arm span.

Comparison of Clinical and Radiologic Outcome of Three-Dimensional Correction in Lenke 5C Curve: Uniplanar Versus Polyaxial Pedicle Screws.

OBJECTIVE: To evaluate radiologic and clinical outcome of three-dimensional correction using the uniplanar pedicle screw (UPS) combined with vertebral body derotation technique for treatment of Lenke 5C adolescent idiopathic scoliosis. METHODS: Fifty patients treated with posterior selective fusion by UPS or polyaxial pedicle screw (PPS) were enrolled. Radiologic parameters, including degree of main curve, thoracic kyphosis, lumbar lordosis, and apical vertebral rotation, were evaluated preoperatively, postoperatively, and at a minimum 2-year follow-up. Scoliosis Research Society Version 22 questionnaire was assessed preoperatively and at 2-year follow-up. RESULTS: Preoperative lumbar Cobb angle was 48.9° in the UPS group and 49.1° in the PPS group (P = 0.59). Postoperatively, no difference in the correction of the main curve magnitude between the 2 groups was observed (74.4% vs. 73.9%, P = 0.74). Correction rate of apical vertebral rotation in the UPS group was significantly higher compared with the PPS group. No difference in average thoracic kyphosis and lumbar lordosis was observed between the 2 groups. At last follow-up, Scoliosis Research Society Version 22 scores were improved in both groups, of which the self-image score in the UPS group was significantly higher compared with the PPS group. CONCLUSIONS: The application of UPS combined with vertebral body derotation technique can reduce vertebral rotation and obtain better patient self-image score when favorable coronal and sagittal realignment is achieved. This improvement remains superior during 2-year follow-up. This combined application is a promising option to achieve spinal three-dimensional correction in treating Lenke 5C curve.

Improved accuracy of screw implantation could decrease the incidence of post-operative hydrothorax? O-arm navigation vs. free-hand in thoracic spinal deformity correction surgery.

PURPOSE: The purpose of this study was to analyze the occurrence of PE after intra-operative O-arm navigation-assisted surgery and determine whether the post-operative PE incidence could be decreased by using O-arm navigation as compared to conventional free-hand technique. METHODS: A cohort of 27 patients with spinal deformity who were operated upon with an O-arm navigated system (group A) between 2013 and 2016 were enrolled in the study. A total of 27 curve-matched patients treated by conventional free-hand technique were included as the control group (group B). Whole spine posterior-anterior and lateral radiographs, and CT scans were taken pre and post-operation. Radiologic parameters and volume of PE were measured and compared between the two groups. RESULTS: There were no significant differences in age, Cobb angle, and sagittal contour between the two groups pre-operatively. The mean total volume of post-operative PE was significantly larger in the free-hand group (p < 0.001). In the O-arm group, 59 malpositioned screws were identified in 22 patients. In the free-hand group, 88 malpositioned screws were found among 26 patients. The screw perforation rate was higher in the free-hand group than in the O-arm group (p = 0.007). In the O-arm group, the mean volume of PE was significantly larger among patients with malpositioned screws than those without malpositioned screws (p < 0.001), as well as in the free-hand group. CONCLUSION: The volume of PE after correction surgery can be significantly decreased by application of O-arm navigation system as compared to conventional free-hand technique. We ascribed the improvement to the accuracy of screw implantation navigated by O-arm.