Investigating the association between serum ADAM/ADAMTS levels and bone mineral density by mendelian randomization study.

PURPOSE: A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) have been reported potentially involved in bone metabolism and related to bone mineral density. This Mendelian Randomization (MR) analysis was performed to determine whether there are causal associations of serum ADAM/ADAMTS with BMD in rid of confounders. METHODS: The genome-wide summary statistics of four site-specific BMD measurements were obtained from studies in individuals of European ancestry, including forearm (n = 8,143), femoral neck (n = 32,735), lumbar spine (n = 28,498) and heel (n = 426,824). The genetic instrumental variables for circulating levels of ADAM12, ADAM19, ADAM23, ADAMTS5 and ADAMTS6 were retrieved from the latest genome-wide association study of European ancestry (n = 5336 ~ 5367). The estimated causal effect was given by the Wald ratio for each variant, the inverse-variance weighted model was used as the primary approach to combine estimates from multiple instruments, and sensitivity analyses were conducted to assess the robustness of MR results. The Bonferroni-corrected significance was set at P < 0.0025 to account for multiple testing, and a lenient threshold P < 0.05 was considered to suggest a causal relationship. RESULTS: The causal effects of genetically predicted serum ADAM/ADAMTS levels on BMD measurements at forearm, femoral neck and lumbar spine were not statistically supported by MR analyses. Although causal effect of ADAMTS5 on heel BMD given by the primary MR analysis (ß = -0.006, -0.010 to 0.002, P = 0.004) failed to reach Bonferroni-corrected significance, additional MR approaches and sensitivity analyses indicated a robust causal relationship. CONCLUSION: Our study provided suggestive evidence for the causal effect of higher serum levels of ADAMTS5 on decreased heel BMD, while there was no supportive evidence for the associations of ADAM12, ADAM19, ADAM23, and ADAMTS6 with BMD at forearm, femoral neck and lumbar spine in Europeans.

Postoperative quality of life in patients with ankylosing spondylitis and thoracolumbar kyphosis: risk factors and personalized sagittal reconstruction strategy.

OBJECTIVE: The aim of this study was to investigate the factors affecting postoperative quality of life in patients with ankylosing spondylitis (AS) and thoracolumbar kyphosis (TLK), and establish a personalized sagittal reconstruction strategy. METHODS: Patients with AS and TLK who underwent pedicle subtraction osteotomy (PSO) from February 2009 to May 2019 were retrospectively included. Quality of life and spinal sagittal radiographic parameters were collected before surgery and at the last follow-up. Patients were divided into two groups based on the attainment of minimal clinically important difference (MCID) on the Bath Ankylosing Spondylitis Functional Index and Oswestry Disability Index. Comparisons of radiographic parameters and clinical outcomes were conducted between and within groups. Regression analysis was used to identify the risk factors within the missing MCID cohort. Sagittal reconstruction equations were established using the pelvic incidence (PI) and thoracic inlet angle (TIA) in the reached MCID cohort. RESULTS: The study comprised 82 participants. Significant improvements were observed in most radiographic parameters and all quality-of-life indicators during the final follow-up compared with the preoperative measures (p < 0.05). Factors including cervical lordosis (CL) ≥ 18° (OR 9.75, 95% CI 2.26-58.01, p = 0.005), chin-brow vertical angle (CBVA) ≥ 25° (OR 14.7, 95% CI 3.29-91.21, p = 0.001), and pelvic tilt (PT) ≥ 33° (OR 21.77, 95% CI 5.92-103.44, p < 0.001) independently correlated with a failure to attain MCID (p < 0.05). Sagittal realignment targets were constructed as follows: sacral slope (SS) = 0.84 PI - 17.4° (R2 = 0.81, p < 0.001), thoracic kyphosis (TK) = 0.51 PI + 10.8° (R2 = 0.46, p = 0.002), neck tilt (NT) = 0.52 TIA - 5.8° (R2 = 0.49, p < 0.001), and T1 slope (T1S) = 0.48 TIA + 5.8° (R2 = 0.45, p = 0.002). CONCLUSIONS: PSO proved efficacious in treating AS complicated by TLK, yielding favorable outcomes. CBVA ≥ 25°, CL ≥ 18°, and PT ≥ 33° were the primary factors affecting postoperative quality of life in patients with AS. The personalized sagittal reconstruction strategy in this study focused on the subjective sensations and daily needs of patients with AS, which were delineated by the equations SS = 0.84 PI - 17.4°, TK = 0.51 PI + 10.8°, NT = 0.52 TIA - 5.8°, and T1S = 0.48 TIA + 5.8°.

Application of vertebral body compression osteotomy in pedicle subtraction osteotomy on ankylosing spondylitis kyphosis: Finite element analysis and retrospective study.

Background: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease, with pathological characteristics of bone erosion, inflammation of attachment point, and bone ankylosis. Due to the ossified intervertebral disc and ligament, pedicle subtraction osteotomy (PSO) is one of the mainstream surgeries of AS-related thoracolumbar kyphosis, but the large amount of blood loss and high risk of instrumental instability limit its clinical application. The purpose of our study is to propose a new transpedicular vertebral body compression osteotomy (VBCO) in PSO to reduce blood loss and improve stability. Methods: A retrospective analysis was performed on patients with AS-related thoracolumbar kyphosis who underwent one-level PSO in our hospital from February 2009 to May 2019. A total of 31 patients were included in this study; 6 received VBCO and 25 received eggshell vertebral body osteotomy. We collected demographic data containing gender and age at diagnosis. Surgical data contained operation time, estimated blood loss (EBL), and complications. Radiographic data contained pre-operative and follow-up sagittal parameters including chin brow-vertical angle (CBVA), global kyphosis (GK), thoracic kyphosis (TK), and lumbar lordosis (LL). A typical case with L2-PSO was used to establish a finite element model. The mechanical characteristics of the internal fixation device, vertebral body, and osteotomy plane of the two osteotomy models were analyzed under different working conditions. Results: The VBCO could provide comparable restoring of CBVA, GK, TK, and LL in the eggshell osteotomy procedure (all p > 0.05). The VBCO significantly reduced EBL compared to those with eggshell osteotomy [800.0 ml (500.0-1,439.5 ml) vs. 1,455.5 ml (1,410.5-1,497.8 ml), p = 0.033]. Compared with the eggshell osteotomy, VBCO showed better mechanical property. For the intra-pedicular screw fixation, the VBCO group had a more average distributed and lower stress condition on both nails and connecting rod. VBCO had a flattened osteotomy plane than the pitted osteotomy plane of the eggshell group, showing a lower and more average distributed maximum stress and displacement of osteotomy plane. Conclusion: In our study, we introduced VBCO as an improved method in PSO, with advantages in reducing blood loss and providing greater stability. Further investigation should focus on clinical research and biomechanical analysis for the application of VBCO.

Study on the clinical efficacy of bone-filled mesh vertebroplasty combined with posterior screw and rod internal fixation in the treatment of thoracolumbar metastases: a retrospective cohort study.

BACKGROUND: Thoracolumbar metastases is a difficult disease to deal with in spinal surgery. The aim of this study is to investigate the clinical efficacy of bone-filled mesh vertebroplasty combined with posterior spinal internal fixation in the treatment of thoracolumbar metastases. METHODS: The clinical data of 68 patients with thoracolumbar vertebral metastases from January 2018 to April 2020 were retrospectively analyzed. A total of 37 cases underwent bone filling mesh pocket vertebroplasty combined with posterior spinal internal fixation as the observation group, and 31 cases underwent routine vertebroplasty combined with posterior spinal internal fixation as the control group. The visual analogue scale (VAS) scores, Oswestry disability index (ODI) scores, Karnofsky performance status (KPS) scores, and the heights of the anterior margin and middle of the diseased vertebra were compared between the 2 groups before and 1 week, 3 months, 6 months, and 1 year after surgery. RESULTS: All cases successfully completed the operation, and there was no pulmonary embolism, paraplegia, or perioperative death in follow-up reported. Intraoperative bone cement leakage occurred in 4 cases with a total of 6 vertebrae in the observation group (leakage rate: 14.29%), and in 8 cases with a total of 11 vertebrae in control group (leakage rate: 31.43%). The differences in VAS scores, ODI scores, KPS scores, and the heights of the anterior margin and middle of the diseased vertebra between preoperative and postoperative periods at 1 week, 3 months, 6 months, and 1 year in both groups were statistically significant (P<0.05), while the differences between the 2 groups were not statistically significant (P<0.05). CONCLUSIONS: The application of bone-filled mesh vertebroplasty combined with posterior internal pedicle screws fixation for the treatment of thoracolumbar metastases can not only reduce the injury of the operation, but also achieve the purpose of relieving pain, controlling local tumor growth to a certain extent, restoring neural function, and rebuilding the stability of the spine, which has important clinical value.

Prognostic Nomogram of Osteocarcinoma after Surgical Treatment.

Purpose: This study aimed to establish a valid prognostic nomogram for osteocarcinoma after surgical management. Methods: Based on the SEER database, we retrieved the clinical variables of patients confirmed to have osteocarcinoma between 1975 and 2016. Then, we performed univariate and multivariate analyses and constructed a nomogram of overall survival. Results: Multivariate analysis of the primary cohort revealed that the independent factors for survival were age, grade, pathologic stage, T stage, and surgery performed. All these factors were showed by the nomogram. The correction curve of survival probability showed that the prediction results of nomogram well agreed with the actual observation results. The C index of the nomogram used to predict survival was 0.82; the AUC of 1-year, 3-year, and 5-year survival rates in the training cohort were 0.9, 0.819, and 0.80631, respectively, indicating that the model was accurate and reliable; whether the operation was performed or not; T stage; grade; and age were the main factors affecting the survival of patients. The AUC of the validation cohort for 1 year, 3 years, and 5 years were 0.8, 0.831, and 0.80023, respectively. Conclusion: The proposed nomogram can more accurately predict the prognosis of patients with osteocarcinoma after surgical management. This could be a potential method that services clinical work.

Development of a Chemoresistant Risk Scoring Model for Prechemotherapy Osteosarcoma Using Single-Cell Sequencing.

Background: Chemoresistance is one of the leading causes that severely limits the success of osteosarcoma treatment. Evaluating chemoresistance before chemotherapy poses a new challenge for researchers. We established an effective chemoresistance risk scoring model for prechemotherapy osteosarcoma using single-cell sequencing. Methods: We comprehensively analyzed osteosarcoma data from the bulk mRNA sequencing dataset TARGET-OS and the single-cell RNA sequencing (scRNA-seq) dataset GSE162454. Chemoresistant tumor clusters were identified using enrichment analysis and AUCell scoring. Its differentiated trajectory was achieved with inferCNV and pseudotime analysis. Ligand-receptor interactions were annotated with iTALK. Furthermore, we established a chemoresistance risk scoring model using LASSO regression based on scRNA-seq-based markers of chemoresistant tumor clusters. The TARGET-OS dataset was used as the training group, and the bulk mRNA array dataset GSE33382 was used as the validation group. Finally, the performance was verified for its discriminatory ability and calibration. Results: Using bulk RNA data, we found that osteogenic expression was upregulated in chemoresistant osteosarcoma as compared to chemosensitive osteosarcoma. Then, we transferred the bulk RNA findings to scRNA-seq and noticed osteosarcoma tumor clusters C14 and C25 showing osteogenic cancer stem cell expression patterns, which fit chemoresistant characteristics. C14 and C25 possessed bridge roles in interactions with other clusters. On the one hand, they received various growth factor stimulators and could potentially transform into a proliferative state. On the other hand, they promote local tumor angiogenesis, bone remodeling and immunosuppression. Next, we identified a ten-gene signature from the C14 and C25 markers and constructed a chemoresistant risk scoring model using LASSO regression model. Finally, we found that chemoresistant osteosarcoma had higher chemoresistance risk score and that the model showed good discriminatory ability and calibration in both the training and validation groups (AUCtrain = 0.82; AUCvalid = 0.84). Compared with that of the classic bulk RNA-based model, it showed more robust performance in validation environment (AUCvalid-scRNA = 0.84; AUCvalid-bulk DEGs = 0.54). Conclusions: Our work provides insights into understanding chemoresistant osteosarcoma tumor cells and using single-cell sequencing to establish a chemoresistance risk scoring model. The model showed good discriminatory ability and calibration and provided us with a feasible way to evaluate chemoresistance in prechemotherapy osteosarcoma.

Circulating Monocytes Act as a Common Trigger for the Calcification Paradox of Osteoporosis and Carotid Atherosclerosis via TGFB1-SP1 and TNFSF10-NFKB1 Axis.

Background: Osteoporosis often occurs with carotid atherosclerosis and causes contradictory calcification across tissue in the same patient, which is called the "calcification paradox". Circulating monocytes may be responsible for this unbalanced ectopic calcification. Here, we aimed to show how CD14+ monocytes contribute to the pathophysiology of coexisting postmenopausal osteoporosis and carotid atherosclerosis. Methods: We comprehensively analyzed osteoporosis data from the mRNA array dataset GSE56814 and the scRNA-seq dataset GSM4423510. Carotid atherosclerosis data were obtained from the GSE23746 mRNA dataset and GSM4705591 scRNA-seq dataset. First, osteoblast and vascular SMC lineages were annotated based on their functional expression using gene set enrichment analysis and AUCell scoring. Next, pseudotime analysis was applied to draw their differentiated trajectory and identify the key gene expression changes in crossroads. Then, ligand-receptor interactions between CD14+ monocytes and osteoblast and vascular smooth muscle cell (SMC) lineages were annotated with iTALK. Finally, we selected calcification paradox-related expression in circulating monocytes with LASSO analysis. Results: First, we found a large proportion of delayed premature osteoblasts in osteoporosis and osteogenic SMCs in atherosclerosis. Second, CD14+ monocytes interacted with the intermediate cells of the premature osteoblast and osteogenic SMC lineage by delivering TGFB1 and TNFSF10. This interaction served as a trigger activating the transcription factors (TF) SP1 and NFKB1 to upregulate the inflammatory response and cell senescence and led to a retarded premature state in the osteoblast lineage and osteogenic transition in the SMC lineage. Then, 76.49% of common monocyte markers were upregulated in the circulating monocytes between the two diseases, which were related to chemotaxis and inflammatory responses. Finally, we identified 7 calcification paradox-related genes on circulating monocytes, which were upregulated in aging cells and downregulated in DNA repair cells, indicating that the aging monocytes contributed to the development of the two diseases. Conclusions: Our work provides a perspective for understanding the triggering roles of CD14+ monocytes in the development of the calcification paradox in osteoporosis- and atherosclerosis-related cells based on combined scRNA and mRNA data. This study provided us with an elucidation of the mechanisms underlying the calcification paradox and could help in developing preventive and therapeutic strategies.

The Difference of Sagittal Correction of Adult Subaxial Cervical Spine Surgery According to Age: A Retrospective Study.

OBJECTIVE: At present, the true sagittal alignment of the cervical spine is uncertain, resulting in no standard reference for subaxial cervical surgery. So, we aimed to explore the age difference of normal cervical sagittal alignment and to further investigate the mid-and long-term changes of sagittal alignment after subaxial cervical spine surgery. MATERIALS AND METHODS: This was a retrospective study and 1223 asymptomatic volunteers and 79 patients undergoing subaxial cervical spine surgery were retrospectively reviewed in total. Asymptomatic volunteers and patients were divided into six subgroups: 20-29, 30-39, 40-49, 50-59, 60-69 and ≥70 groups. The age difference and trend with age of cervical sagittal parameters of asymptomatic volunteers were assessed by cervical lateral radiography and analyzed by ANOVA test, and the regression equation of C2-7 Cobb was established via multiple linear regression. Based on the C2-7 Cobb regression equations of different ages, the theoretical value, deviation value, loss value of the C2-7 Cobb, and JOA recovery rate of patients were calculated, and the correlation among the loss value, deviation value of the C2-7 Cobb, and JOA recovery rate of the 79 patients was evaluated by Pearson correlation analysis. RESULTS: For the asymptomatic volunteers, the C0-2 Cobb decreased gradually with increasing age. The C2-7 Cobb, C2-7 SVA, T1S, NT, and TIA increased gradually with increasing age. The CBVA fluctuated with increasing age. T1S demonstrated a moderate correlation with C2-7 Cobb (r = 0.60, p < 0.01); C0-2 Cobb, C2-7 SVA, CBVA, and TIA demonstrated a fair correlation with C2-7 Cobb (r = -0.30, -0.33, 0.41, 0.40, p < 0.01); age demonstrated a poor correlation with C2-7 Cobb (r = 0.19, p < 0.01). The regression equations of C2-7 Cobb were established using C0-2 Cobb, C2-7 SVA, CBVA, and T1S. For the patients with subaxial cervical spine surgery, the loss of C2-7 Cobb was moderately correlated with the deviation of C2-7 Cobb (r = 0.33, p < 0.01). CONCLUSION: The age difference of cervical sagittal alignment was obvious, and the C2-7 Cobb increased with age especially. The closer the postoperative C2-7 Cobb was to the theoretical value of corresponding age, the smaller the loss of correction angle was, and the better the mid- and long-term outcomes. The personalized sagittal reconstruction should be performed according to age difference for subaxial cervical spine surgery.

Special type of distal junctional failure exhibits pelvic incidence changes: sacroiliac joint-related pain following lumbar spine surgery.

Background: Currently, change in pelvic incidence (PI) in patients after spinal surgery have not been associated with clear clinical symptoms. This study sought to compare changes in the sagittal parameters of different patients before and after thoracolumbar spine surgery, the relationship between PI change and sacroiliac joint pain (SIJP) after surgery was clarified, and the correlation between PI change and sacroiliac joint (SIJ) activity was verified. Methods: This study retrospectively analyzed the data of patients who underwent thoracolumbar fusion at Sun Yat-sen Memorial Hospital from January 2019 to June 2021. The spinal and pelvic parameters [including pelvic tilt (PT), sacral slope (SS), PI, lumbar lordosis (LL) angle, etc.] of 409 patients with standard standing lateral radiographs before and after surgery were compared and analyzed. Postoperative follow-up of all patients with standardized SIJP assessment. The incidence of postoperative SIJP, and its correlation with sagittal parameters of the spine and pelvis, surgical methods, and the basic characteristics of patients were analyzed. The Chi-square test was used for categorical variables, the independent-sample t-test was used for generally conformed normally distributed continuous variables. Risk factors associated with the development of SIJP were analyzed using logistics regression. Correlations among SS, PI, and the 4 other sagittal parameters were analyzed using the Pearson correlation coefficient (r). Results: Postoperative PI changes tended to be larger in the lowest instrumented vertebra (LIV) (L4 and above: 1.63°; L5: 2.43°; S1: 3.83°; P<0.05) and longer fixed segment. The risk factors for SIJP included a PI >4° [odds ratio (OR) =13.051; P<0.001], LIV S1 (OR =3.378; P=0.023), and fixed total segment ≥3 (OR =2.632; P=0.038). ∆PI was significantly correlated with ∆SS in patients with non-S1 distal fixation vertebrae (R2=0.388; P<0.01), but no such correlation was found in patients with S1 distal fixation vertebrate. Conclusions: Changes in PI values after thoracolumbar spine surgery can correctly reflect the motion state of the SIJ. Excessive changes in PI (>4°) are similar to the mechanism of distal junctional kyphosis (DJK), while such changes make patients prone to SIJP following lumbar spine surgery.

Posterior wedge osteotomy assisted by O-arm navigation for treating ankylosing spondylitis with thoracolumbar fractures: an early clinical evaluation.

BACKGROUND: To explore the feasibility and efficiency of posterior wedge osteotomy assisted by O-arm navigation treatment of ankylosing spondylitis (AS) patients with thoracolumbar fracture. METHODS: This is a case series study. A total of 16 cases of AS accompanied by thoracolumbar fractures from January 2012 to July 2015 were retrospectively analyzed. All patients underwent "posterior wedge osteotomy assisted by O-arm navigation". The operation time, blood loss volume, preoperative and postoperative visual analogue scale (VAS), American Spinal Injury Association (ASIA) classification, and spinal imaging parameters [Cobb angle, C7 plumb line (C7PL), and jaw-brow angle] were collected and analyzed. RESULTS: The operative time consumption was 120-350 mins and the intra-operative blood loss volume was 200-800 mL. No obvious postoperative complications occurred in any participants. The back pain of all participants was relieved, and the neurological functions of eight participants with spinal cord injury (SCI) were recovered in varying degrees except for one patient with severe SCI. The spinal deformities of the participants were corrected to varying degrees. The fracture sites of 16 participants were all healed, and there was no loosening or detachment of internal fixation during the 6-month follow-up period. CONCLUSIONS: Posterior wedge osteotomy assisted by O-arm navigation was shown to be a safe and effective method to treat AS accompanied by thoracolumbar fractures. This treatment strategy can accurately decompress and reduce the fracture and significantly correct the kyphosis, with good surgical effect.

RAB5C, SYNJ1, and RNF19B promote male ankylosing spondylitis by regulating immune cell infiltration.

BACKGROUND: This study aimed to identify the key genes related to male ankylosing spondylitis (AS) and to analyze the role of immune cell infiltration in the pathological process of this disease. METHODS: The AS dataset was downloaded from the Gene Expression Omnibus (GEO) public database, and the data of male healthy controls (M_HC) and male AS patients (M_AS) were extracted. R software was used to identify differentially expressed genes (DEGs). Functional and pathway enrichment analysis of the DEGs was performed. A protein-protein interaction (PPI) network was constructed, and the hub genes were screened out. All expression profile data were analyzed by weighted correlation network analysis (WGCNA) to screen out the hub genes, which were then intersected with the hub genes from the PPI network to obtain the key genes. Finally, the difference in immune cell infiltration in the two sets of samples was evaluated with CIBERSORT, and the correlation between the key genes and infiltrating immune cells was analyzed. RESULTS: A total of 689 DEGs were obtained, of which 395 genes were up-regulated and 294 genes were down-regulated. Functional and pathway enrichment analysis showed that DEGs were mainly enriched in pathways related to immune response. Based on the PPI analysis, five clusters with high scores were selected. Through WGCNA, 14 gene modules were obtained. The green module with the highest correlation was selected and intersected with the cluster previously obtained to obtain three key genes, RAB5C, SYNJ1, and RNF19B. Immune infiltration analysis found that monocytes and gamma delta T cells may be involved in the process of AS. Also, RAB5C, SYNJ1, and RNF19B are all related to increased levels of monocytes and macrophages. CONCLUSIONS: RAB5C, SYNJ1, and RNF19B are key DEGs expressed in M_AS and may play a role in the disease's occurrence and development through regulating immune cell functions.