Database analysis comparing incidence and complication rates between inpatient and outpatient laminotomies for lumbar disc herniation.

Background: Lumbar disc herniation (LDH) is a common condition that can be characterized with disabling pain. While most patients recover without surgery, some still require operative intervention. The epidemiology and trends of laminotomy for LDH have not been recently studied, and current practice patterns might be different from historical norms. This study aimed to investigate the trends of inpatient and outpatient laminotomies for LDH and compare complication rates between these two sites of service. Methods: A large, national database was utilized to identify patients > 8 years old who underwent a laminotomy for LDH between 2009 and 2019. Two cohorts were created based on site of surgery: inpatient versus outpatient. The outpatient cohort was defined as patients who had a length of stay less than 1 day without any associated hospitalization. Epidemiologic analyses for these cohorts were performed by demographics. Patients in both groups were then 1:1 propensity-score matched based on age, sex, insurance type, geographic region, and comorbidities. Ninety-day postoperative complications were compared between cohorts utilizing multivariate logistic regressions. Results: The average incidence of laminotomy for LDH was 13.0 per 10,000 persons-years. Although the national trend in incidence had not changed from 2009 to 2019, the proportion of outpatient laminotomies significantly increased in this time period (p=.02). Outpatient laminotomies were more common among younger and healthier patients. Patients with inpatient laminotomies had significantly higher rates of surgical site infections (odds ratio [OR] 1.61, p<.001), venous thromboembolism (VTE) (OR 1.96, p<.001), hematoma (OR 1.71, p<.001), urinary tract infections (OR 1.41, p<.001), and acute kidney injuries (OR 1.75, p=.001), even when controlling for selected confounders. Conclusions: Our study demonstrated an increasing trend in the performance of laminotomy for LDH toward the outpatient setting. Even when controlling for certain confounders, patients requiring inpatient procedures had higher rates of postoperative complications. This study highlights the importance of carefully evaluating the advantages and disadvantages of performing these procedures in an outpatient versus inpatient setting.

Machine learning approach to predict venous thromboembolism among patients undergoing multi-level spinal posterior instrumented fusion.

Background: The absence of consensus for prophylaxis of venous thromboembolism (VTE) in spine surgery underscores the importance of identifying patients at risk. This study incorporated machine learning (ML) models to assess key risk factors of VTE in patients who underwent posterior spinal instrumented fusion. Methods: Data was collected from the IBM MarketScan Database [2009-2021] for patients ≥18 years old who underwent spinal posterior instrumentation (3-6 levels), excluding traumas, malignancies, and infections. VTE incidence (deep vein thrombosis and pulmonary embolism) was recorded 90-day post-surgery. Risk factors for VTE were investigated and compared through several ML models including logistic regression, linear support vector machine (LSVM), random forest, XGBoost, and neural networks. Results: Among the 141,697 patients who underwent spinal fusion with posterior instrumentation (3-6 levels), the overall 90-day VTE rate was 3.81%. The LSVM model demonstrated the best prediction with an area under the curve (AUC) of 0.68. The most important features for prediction of VTE included remote history of VTE, diagnosis of chronic hypercoagulability, metastatic cancer, hemiplegia, and chronic renal disease. Patients who did not have these five key risk factors had a 90-day VTE rate of 2.95%. Patients who had an increasing number of key risk factors had subsequently higher risks of postoperative VTE. Conclusions: The analysis of the data with different ML models identified 5 key variables that are most closely associated with VTE. Using these variables, we have developed a simple risk model with additive odds ratio ranging from 2.80 (1 risk factor) to 46.92 (4 risk factors) over 90 days after posterior spinal fusion surgery. These findings can help surgeons risk-stratify their patients for VTE risk, and potentially guide subsequent chemoprophylaxis.

Development of an International AO Spine Guideline for the Use of Osteobiologics in Anterior Cervical Fusion and Decompression (AO-GO).

STUDY DESIGN: Methodological study for guideline development. OBJECTIVE: AO Spine Guideline for Using Osteobiologics (AO-GO) project for spine degenerative pathologies was an international, multidisciplinary collaborative initiative to identify and evaluate evidence on existing use of osteobiologics in Anterior Cervical Fusion and Decompression (ACDF). The aim was to formulate precisely defined, clinically relevant and internationally applicable guidelines ensuring evidence-based, safe and effective use of osteobiologics, considering regional preferences and cost-effectiveness. METHODS: Guideline was completed in two phases: Phase 1- evidence synthesis; Phase 2- recommendation development based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. In Phase 1, key questions identified by a panel of experts were addressed in a series of systematic reviews of randomized and non-randomized studies. In Phase 2, the GRADE approach was used to formulate a series of recommendations, including expert panel discussions via web calls and face-to-face meetings. DISCUSSION: AO-GO aims to bridge an important gap between evidence and use of osteobiologics in spine fusion surgeries. Owing to differences in osteobiologics preparation and functional characteristics, regulatory requirements for approval may vary, therefore it is highly likely that these products enter market without quality clinical trials. With a holistic approach the guideline aims to facilitate evidence-based, patient-oriented decision-making processes in clinical practice, thus stimulating further evidence-based studies regarding osteobiologics usage in spine surgeries. In Phase 3, the guideline will be disseminated and validated using prospectively collected clinical data in a separate effort of the AO Spine Knowledge Forum Degenerative in a global multicenter clinical study.

Comparative Complications Associated With BMP Use In Patients Undergoing ACDF for Degenerative Spinal Conditions: Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic Review and Meta-Analysis. OBJECTIVES: To compare complication incidence in patients with or without the use of recombinant human Bone Morphogenic Protein-2 (BMP2) undergoing anterior cervical discectomy and fusion (ACDF) for degenerative conditions. METHODS: A systematic search of eight online databases was conducted using PRISMA guidelines. Inclusion criteria included English language studies with a minimum of 10 adult patients undergoing instrumented ACDF surgery for a degenerative spinal condition in which BMP2 was used in all patients or one of the treatment arms. Studies with patients undergoing circumferential fusions, with non-degenerative indications, or which did not report post-operative complication data were excluded. Patients with and without BMP2 were compared in terms of the incidence of dysphagia/dysphonia, anterior soft tissue complications (hematoma, seroma, infection, dysphagia/dysphonia), nonunion, medical complications, and new neurologic deficits. RESULTS: Of 1832 preliminary search results, 27 manuscripts were included. Meta-analysis revealed the relative risk of dysphagia or dysphonia (RR = 1.39, CI 95% 1.18 - 1.64, P = <.001), anterior soft tissue complications (RR = 1.43, CI 95% 1.25-1.64, P = <.001), and medical complications (RR = 1.32, CI 95% 1.06-1.66, P = .013) were statistically significant in the BMP2 group while the relative risk of non-union (RR = .5, CI 95% .23 - 1.13, P = .09) trended lower in the BMP2 group. Neurological deficit (RR = 1.06, CI 95% .82-1.37, P = .66), and additional medical complications (RR = 1.53, CI 95% .98-2.38, P = .06) were not found to be statistically different between the groups. CONCLUSIONS: This meta-analysis identified a high rate of arthrodesis when BMP2 was used in ACDF, but confirmed increased rates of dysphagia and anterior soft tissue complications. Surgeons may consider reserving BMP2 implementation for cases with a high risk of non-union, and should be aware of the risk of airway compromise.

Trends and Costs of External Electrical Bone Stimulators and Grafting Materials in Anterior Lumbar Interbody Fusion.

STUDY DESIGN: Retrospective review. PURPOSE: To identify the trends in stimulator use, pair those trends with various grafting materials, and determine the influence of stimulators on the risk of revision surgery. OVERVIEW OF LITERATURE: A large number of studies has reported beneficial effects of electromagnetic energy in healing long bone fractures. However, there are few clinical studies regarding the use of electrical stimulators in spinal fusion. METHODS: We used insurance billing codes to identify patients with lumbar disc degeneration who underwent anterior lumbar interbody fusion (ALIF). Comparisons between patients who did and did not receive electrical stimulators following surgery were performed using logistic regression analysis, chi-square test, and odds ratio (OR) analysis. RESULTS: Approximately 19% of the patients (495/2,613) received external stimulators following ALIF surgery. There was a slight increase in stimulator use from 2008 to 2014 (multi-level R2=0.08, single-level R2=0.05). Patients who underwent multi-level procedures were more likely to receive stimulators than patients who underwent single-level procedures (p<0.05; OR, 3.72; 95% confidence interval, 3.02-4.57). Grafting options associated with most frequent stimulator use were bone marrow aspirates (BMA) plus autograft or allograft for single-level and allograft alone for multi-level procedures. In both cohorts, patients treated with bone morphogenetic proteins were least likely to receive electrical stimulators (p<0.05). Patients who received stimulation generally had higher reimbursements. Concurrent posterior lumbar fusion (PLF) (ALIF+PLF) increased the likelihood of receiving stimulators (p<0.05). Patients who received electrical stimulators had similar revision rates as those who did not receive stimulation (p>0.05), except those in the multilevel ALIF+PLF cohort, wherein the patients who underwent stimulation had higher rates of revision surgery. CONCLUSIONS: Concurrent PLF or multi-level procedures increased patients' likelihood of receiving stimulators, however, the presence of comorbidities did not. Patients who received BMA plus autograft or allograft were more likely to receive stimulation. Patients with and without bone stimulators had similar rates of revision surgery.

Sagittal Plane Correction Using the Lateral Transpsoas Approach: A Biomechanical Study on the Effect of Cage Angle and Surgical Technique on Segmental Lordosis.

STUDY DESIGN: Cadaveric biomechanical study. OBJECTIVE: To determine the degree of segmental correction that can be achieved through lateral transpsoas approach by varying cage angle and adding anterior longitudinal ligament (ALL) release and posterior element resection. SUMMARY OF BACKGROUND DATA: Lordotic cage insertion through the lateral transpsoas approach is being used increasingly for restoration of sagittal alignment. However, the degree of correction achieved by varying cage angle and ALL release and posterior element resection is not well defined. METHODS: Thirteen lumbar motion segments between L1 and L5 were dissected into single motion segments. Segmental angles and disk heights were measured under both 50 N and 500 N compressive loads under the following conditions: intact specimen, discectomy (collapsed disk simulation), insertion of parallel cage, 10° cage, 30° cage with ALL release, 30° cage with ALL release and spinous process (SP) resection, 30° cage with ALL release, SP resection, facetectomy, and compression with pedicle screws. RESULTS: Segmental lordosis was not increased by either parallel or 10° cages as compared with intact disks, and contributed small amounts of lordosis when compared with the collapsed disk condition. Placement of 30° cages with ALL release increased segmental lordosis by 10.5°. Adding SP resection increased lordosis to 12.4°. Facetectomy and compression with pedicle screws further increased lordosis to approximately 26°. No interventions resulted in a decrease in either anterior or posterior disk height. CONCLUSION: Insertion of a parallel or 10° cage has little effect on lordosis. A 30° cage insertion with ALL release resulted in a modest increase in lordosis (10.5°). The addition of SP resection and facetectomy was needed to obtain a larger amount of correction (26°). None of the cages, including the 30° lordotic cage, caused a decrease in posterior disk height suggesting hyperlordotic cages do not cause foraminal stenosis. LEVEL OF EVIDENCE: N/A.

Mild diabetes is not a contraindication for surgical decompression in cervical spondylotic myelopathy: results of the AOSpine North America multicenter prospective study (CSM).

BACKGROUND CONTEXT: Cervical spondylotic myelopathy (CSM) is a chronic spinal cord disease and can lead to progressive or stepwise neurologic decline. Several factors may influence this process, including extent of spinal cord compression, duration of symptoms, and medical comorbidities. Diabetes is a systemic disease that can impact multiple organ systems, including the central and peripheral nervous systems. There has been little information regarding the effect of diabetes on patients with coexistent CSM. PURPOSE: To provide empirical data regarding the effect of diabetes on treatment outcomes in patients who underwent surgical decompression for coexistent CSM. STUDY DESIGN/SETTING: Large prospective multicenter cohort study of patients with and without diabetes who underwent decompressive surgery for CSM. PATIENT SAMPLE: Two hundred thirty-six patients without and 42 patients with diabetes were enrolled. Of these, 37 were mild cases and five were moderate cases. Four required insulin. There were no severe cases associated with end-organ damage. OUTCOME MEASURES: Self-report measures include Neck Disability Index and version 2 of 36-Item Short Form Health Survey (SF-36v2), and functional measures include modified Japanese Orthopedic Association (mJOA) score and Nurick grade. METHODS: We compared presurgery symptoms and treatment outcomes between patients with and without diabetes using univariate and multivariate models, adjusting for demographics and comorbidities. RESULTS: Diabetic patients were older, less likely to smoke, and more likely to be on social security disability insurance. Patients with diabetes presented with a worse Nurick grade, but there were no differences in mJOA and SF-36v2 at presentation. Overall, there was a significant improvement in all outcome parameters at 12 and 24 months. There was no difference in the level of improvement between the patients with and without diabetes, except in the SF-36v2 Physical Functioning, in which diabetic patients experienced significantly less improvement. There were no differences in surgical complication rates between diabetic patients and nondiabetic patients. CONCLUSIONS: Except for a worse Nurick grade, diabetes does not seem to affect severity of symptoms at presentation for surgery. More importantly, with the exception of the SF-36v2 Physical Functioning scores, outcomes of surgical treatment are similar in patients with diabetes and without diabetes. Surgical decompression is effective and should be offered to patients with diabetes who have symptomatic CSM and are appropriate surgical candidates.

Anterior versus posterior surgical approaches to treat cervical spondylotic myelopathy: outcomes of the prospective multicenter AOSpine North America CSM study in 264 patients.

STUDY DESIGN: A prospective observational multicenter study. OBJECTIVE: To help solve the debate regarding whether the anterior or posterior surgical approach is optimal for patients with cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: The optimal surgical approach to treat CSM remains debated with varying opinions favoring anterior versus posterior surgical approaches. We present an analysis of a prospective observational multicenter study examining outcomes of surgical treatment for CSM. METHODS: A total of 278 subjects from 12 sites in North America received anterior/posterior or combined surgery at the discretion of the surgeon. This study focused on subjects who had either anterior or posterior surgery (n = 264, follow-up rate, 87%). Outcome measures included the modified Japanese Orthopedic Assessment scale, the Nurick scale, the Neck Disability Index, and the Short-Form 36 (SF-36) Health Survey version 2 Physical and Mental Component Scores. RESULTS: One hundred and sixty-nine patients were treated anteriorly and 95 underwent posterior surgery. Anterior surgical cases were younger and had less severe myelopathy as assessed by mJOA and Nurick scores. There were no baseline differences in Neck Disability Index or SF-36 between the anterior and posterior cases. Improvement in the mJOA was significantly lower in the anterior group than posterior group (2.47 vs. 3.62, respectively, P < 0.01), although the groups started at different levels of baseline impairment. The extent of improvement in the Nurick Scale, Neck Disability Index, SF-36 version 2 Physical Component Score, and SF-36 version 2 Mental Component Score did not differ between the groups. CONCLUSION: Patients with CSM show significant improvements in several health-related outcome measures with either anterior or posterior surgery. Importantly, patients treated with anterior techniques were younger, with less severe impairment and more focal pathology. We demonstrate for the first time that, when patient and disease factors are controlled for, anterior and posterior surgical techniques have equivalent efficacy in the treatment of CSM. LEVEL OF EVIDENCE: 3.

Efficacy and safety of surgical decompression in patients with cervical spondylotic myelopathy: results of the AOSpine North America prospective multi-center study.

BACKGROUND: Cervical spondylotic myelopathy is the leading cause of spinal cord dysfunction worldwide. The objective of this study was to evaluate the impact of surgical decompression on functional, quality-of-life, and disability outcomes at one year after surgery in a large cohort of patients with this condition. METHODS: Adult patients with symptomatic cervical spondylotic myelopathy and magnetic resonance imaging evidence of spinal cord compression were enrolled at twelve North American centers from 2005 to 2007. At enrollment, the myelopathy was categorized as mild (modified Japanese Orthopaedic Association [mJOA] score ≥ 15), moderate (mJOA = 12 to 14), or severe (mJOA < 12). Patients were followed prospectively for one year, at which point the outcomes of interest included the mJOA score, Nurick grade, Neck Disability Index (NDI), and Short Form-36 version 2 (SF-36v2). All outcomes at one year were compared with the preoperative values with use of univariate paired statistics. Outcomes were also compared among the severity classes with use of one-way analysis of variance. Finally, a multivariate analysis that adjusted for baseline differences among the severity groups was performed. Treatment-related complication data were collected and the overall complication rate was calculated. RESULTS: Eighty-five (30.6%) of the 278 enrolled patients had mild cervical spondylotic myelopathy, 110 (39.6%) had moderate disease, and 83 (29.9%) had severe disease preoperatively. One-year follow-up data were available for 222 (85.4%) of 260 patients. There was a significant improvement from baseline to one year postoperatively (p < 0.05) in the mJOA score, Nurick grade, NDI score, and all SF-36v2 health dimensions (including the mental and physical health composite scores) except general health. With the exception of the change in the mJOA, the degree of improvement did not depend on the severity of the preoperative symptoms. These results remained unchanged after adjusting for relevant confounders in the multivariate analysis. Fifty-two patients experienced complications (prevalence, 18.7%), with no significant differences among the severity groups. CONCLUSIONS: Surgical decompression for the treatment of cervical spondylotic myelopathy was associated with improvement in functional, disability-related, and quality-of-life outcomes at one year of follow-up for all disease severity categories. Furthermore, complication rates observed in the study were commensurate with those in previously reported cervical spondylotic myelopathy series.

A clinical prediction model to determine outcomes in patients with cervical spondylotic myelopathy undergoing surgical treatment: data from the prospective, multi-center AOSpine North America study.

BACKGROUND: Cervical spondylotic myelopathy is a progressive spine disease and the most common cause of spinal cord dysfunction worldwide. The objective of this study was to develop a prediction model, based on data from a prospective multi-center study, relating a combination of clinical and imaging variables to surgical outcome in patients with cervical spondylotic myelopathy. METHODS: Two hundred and seventy-eight patients diagnosed with cervical spondylotic myelopathy treated surgically were enrolled at twelve different sites in the multi-center AOSpine North America study. Univariate analyses were performed to evaluate the relationship between outcome, assessed with the modified Japanese Orthopaedic Association (mJOA) score, and various clinical and imaging predictors. A set of important candidate variables for the final model was selected on the basis of author consensus, literature support, and statistical findings. Logistic regression was used to formulate the final model. RESULTS: Univariate analyses demonstrated that the odds of a successful outcome decreased with a longer duration of symptoms (odds ratio [OR] = 0.80, 95% confidence interval [CI] = 0.65 to 0.98, p = 0.030); a lower baseline mJOA score (OR = 0.74, 95% CI = 0.65 to 0.84, p < 0.0001); the presence of psychological comorbidities (OR = 0.51, 95% CI = 0.29 to 0.92, p = 0.024); the presence of broad-based, unstable gait (OR = 2.72, 95% CI = 1.47 to 5.06, p = 0.0018) or other gait impairment (OR = 3.56, 95% CI = 1.75 to 7.22, p = 0.0005); and older age (OR = 0.96, 95% CI = 0.93 to 0.98, p = 0.0004). The dependent variable, the mJOA score at one year, was dichotomized for logistic regression: a "successful" outcome was defined as a final score of ≥16 and a "failed" outcome was a score of <16. The final model included age (OR = 0.97, 95% CI = 0.94 to 0.99, p = 0.0017), duration of symptoms (OR = 0.78, 95% CI = 0.61 to 0.997, p = 0.048), smoking status (OR = 0.46, 95% CI = 0.21 to 0.98, p = 0.043), impairment of gait (OR = 2.66, 95% CI = 1.17 to 6.06, p = 0.020), psychological comorbidities (OR = 0.33, 95% CI = 0.15 to 0.69, p = 0.0035), baseline mJOA score (OR = 1.22, 95% CI = 1.05 to 1.41, p = 0.0084), and baseline transverse area of the cord on magnetic resonance imaging (OR = 1.02, 95% CI = 0.99 to 1.05, p = 0.19). The area under the receiver operator characteristic curve was 0.79, indicating good model prediction. CONCLUSIONS: On the basis of the results of the AOSpine North America study, we identified a list of the most important predictors of surgical outcome for cervical spondylotic myelopathy.

Upregulation of intervertebral disc-cell matrix synthesis by pulsed electromagnetic field is mediated by bone morphogenetic proteins.

STUDY DESIGN: An in vitro study on the effects of pulsed electromagnetic field (PEMF) on intervertebral disc-cell matrix synthesis. OBJECTIVES: The objective of the study was to determine whether (1) PEMF can upregulate intervertebral disc-cell matrix synthesis and (2) any upregulation obtained is through transforming growth factor (TGF)-ß or bone morphogenetic proteins (BMPs). SUMMARY OF BACKGROUND DATA: PEMF has been reported to produce cell proliferation, enhance cell function, and upregulate matrix synthesis in cell types such as osteoblasts, chondroblasts, endothelial cells, and fibroblasts through the upregulation of several growth factors. PEMF has been used clinically in the treatment of delayed bone union. However, PEMF has never been tested on human intervertebral disc cells. METHODS: The PEMF signal used was similar to that used in the clinical treatment of delayed fracture healing. Human disc cells were treated with PEMF for 8 hours per day for 3 days. Quantitative real-time polymerase chain reaction was performed to determine mRNA expression levels of aggrecan, collagen-2, TGF-ß, BMP-2, and BMP-7. Sulfated glycosaminoglycan synthesis was analyzed using the dimethylmethylene blue (DMMB) method. Western blot analysis was performed to determine the protein levels of TGF-ß, BMP-2, and BMP-7. To determine whether any action of PEMF was through BMP, recombinant human Noggin was used at a dose of 100 ng/mL to block BMP. RESULTS: PEMF could upregulate intervertebral disc-cell matrix synthesis. BMP-7 was markedly upregulated by PEMF and was upregulated much more than BMP-2. TGF-ß was not upregulated by PEMF. The effect of PEMF on disc-cell matrix was entirely inhibited in the presence of Noggin. CONCLUSIONS: PEMF acts through BMPs to upregulate intervertebral disc-cell matrix synthesis.

Pulsed Electromagnetic Field (PEMF) plus BMP-2 upregulates intervertebral disc-cell matrix synthesis more than either BMP-2 alone or PEMF alone.

STUDY DESIGN: An in vitro study using human intervertebral disc (IVD) cells. OBJECTIVES: To determine if pulsed electromagnetic field (PEMF) plus bone morphogenetic protein (BMP)-2 could upregulate IVD-cell matrix synthesis more than either BMP-2 alone or PEMF alone. SUMMARY OF BACKGROUND DATA: BMP-7 and BMP-2 can both upregulate IVD-cell matrix synthesis. There are problems associated with using either BMP-2 or BMP-7. They can diffuse away rather quickly after injection into the IVD space, they cost a lot, and they have side effects such as soft-tissue inflammation and swelling. PEMF has been reported to stimulate various types of cells. PEMF is safe, inexpensive, and noninvasive, thus multiple use is possible. However, PEMF alone has a rather weak effect on disc cells. We decided to carry out an experiment whereby we combined PEMF with BMP-2. Our thoughts were that BMP-2 plus PEMF could be better than either alone. METHODS: The PEMF signal used was similar to that used in the clinical treatment of fracture nonunions or delayed fracture healing. Human disc cells were treated with BMP-2 alone or PEMF alone or PEMF plus BMP-2. Quantitative real-time PCR was performed to determine mRNA expression levels of aggrecan, collagen-2, transforming growth factor (TGF)-ß, BMP-2, and BMP-7. Sulfated glycosaminoglycansynthesis was analyzed using the dimethylmethylene blue method. Western blot analysis was performed to determine the protein levels of TGF-ß, BMP-2, and BMP-7. RESULTS: PEMF plus BMP-2 upregulates IVD-cell matrix synthesis more than BMP-2 alone or PEMF alone, and the effect seems to be synergistic. Also, PEMF plus BMP-2 induces more endogenous BMP-7 and BMP-2 mRNA levels as well as protein levels, as compared with either PEMF alone or BMP-2 alone. CONCLUSIONS: PEMF plus BMP-2 acts in synergy to upregulate intervertebral disc-cell matrix synthesis more than either BMP-2 alone or PEMF alone.

E-cadherin upregulates expression of matrix macromolecules aggrecan and collagen II in the intervertebral disc cells through activation of the intracellular BMP-Smad1/5 pathway.

E-cadherin is a transmembrane protein that mediates cell-cell adhesion and cell-matrix interaction. Although the E-cadherin has been shown to mediate a broad-ranging cellular signals and functions, its effects on matrix metabolism of intervertebral discs (IVDs) are unknown. In this study, we investigated the effects of E-cadherin on IVD matrix synthesis using pharmacological and molecular biology methods. We showed that high levels of the E-cadherin are expressed in rabbits IVD cells. Our study indicates that the ectopic expression of E-cadherin can stimulate matrix anabolism of the IVD cells, which was evidenced by increased expression of the matrix macromolecules aggrecan and collagen II. We found that E-cadherin induces the expression of BMP-4 and BMP-7 genes and enhances Smad1/5 phosphorylation. Blocking BMP activity uses noggin suppressed E-cadherin-mediated upregulation of aggrecan and collagen II. Moreover, inhibition of Smad1/5 phosphorylation by dorsomorphin significantly repressed the E-cadherin induced expression of aggrecan and collagen II at the both mRNA and protein levels. Together this study demonstrates that the E-cadherin stimulates the synthesis of IVD matrix macromolecules aggrecan and collagen II through the induction of BMP genes and enhancement of the Smad1/5 phosphorylation. Thus E-cadherin may have value in the treatment of degenerated discs.

ISSLS prize winner: LMP-1 upregulates intervertebral disc cell production of proteoglycans and BMPs in vitro and in vivo.

STUDY DESIGN: Experiments using both in vitro tissue culture and in vivo rabbit methods were used to study the effect of Lim Mineralization Protein-1 (LMP-1) on intervertebral disc (IVD) cell production of proteoglycans and bone morphogenetic proteins (BMPs). OBJECTIVES: To determine the effect of LMP-1 overexpression in IVD cells on the production of proteoglycans and BMPs both in vitro and in vivo and to show that LMP-1 mediates the control of proteoglycan production through its action on BMPs. SUMMARY OF BACKGROUND DATA: Because BMPs are known to increase proteoglycan synthesis and LMP-1 is known to upregulate BMPs in certain cells, it was hypothesized that LMP-1 may increase proteoglycan production in IVD cells. METHODS: DMMB, real-time polymerase chain reaction, and ELISA methods were used to quantitate proteoglycan, mRNA, and protein levels, respectively. Noggin was used to block the effect of the adenovirus carrying LMP-1 (AdLMP-1) on proteoglycan synthesis. In vivo experiments using intradiscal AdLMP-1 injection were performed with New Zealand White rabbits. Three weeks later, the mRNA levels of LMP-1, aggrecan, BMP-2, and BMP-7 were measured. RESULTS: In vitro experiments revealed that the sulfated glycosaminoglycan (sGAG) and aggrecan mRNA levels were significantly increased with AdLMP-1 treatment. Similarly, BMP-2 and BMP-7 mRNA and protein levels increased significantly, but BMP-4 and BMP-6 levels were unchanged. Noggin blocked the upregulation of proteoglycan by AdLMP-1. In vivo discs injected with AdLMP-1 had significantly elevated levels of LMP-1, BMP-2, and BMP-7 mRNA. CONCLUSIONS: LMP-1 overexpression increases disc cell production of proteoglycan, BMP-2, and BMP-7. LMP-1 mediates the control of proteoglycan production through its action on BMP.