ABSTRACT
The cartilage endplates (CEPs) on the superior and inferior surfaces of the intervertebral disk (IVD), are the primary nutrient transport pathways between the disk and the vertebral body. Passive diffusion is responsible for transporting small nutrient and metabolite molecules through the avascular CEPs. The baseline solute diffusivities in healthy CEPs have been previously studied, however alterations in CEP diffusion associated with IVD degeneration remain unclear. This study aimed to quantitatively compare the solute diffusion in healthy and degenerated human CEPs using a fluorescence recovery after photobleaching (FRAP) approach. Seven healthy CEPs and 22 degenerated CEPs were collected from five fresh-frozen human cadaveric spines and 17 patients undergoing spine fusion surgery, respectively. The sodium fluorescein diffusivities in CEP radial and vertical directions were measured using the FRAP method. The CEP calcification level was evaluated by measuring the average X-ray attenuation. No difference was found in solute diffusivities between radial and axial directions in healthy and degenerated CEPs. Compared to healthy CEPs, the average solute diffusivity was 44% lower in degenerated CEPs (Healthy: 29.07 µm2/s (CI: 23.96-33.62 µm2/s); degenerated: 16.32 µm2/s (CI: 13.84-18.84 µm2/s), p < 0.001). The average solute diffusivity had an inverse relationship with the degree of CEP calcification as determined by the normalized X-ray attenuation values (ß = -22.19, R2 = 0.633; p < 0.001). This study suggests that solute diffusion through the disk and vertebral body interface is significantly hindered by CEP calcification, providing clues to help further understand the mechanism of IVD degeneration.
Subject(s)
Calcinosis , Intervertebral Disc Degeneration , Intervertebral Disc , Humans , Cartilage/metabolism , Intervertebral Disc/metabolism , Intervertebral Disc Degeneration/metabolism , Biological Transport , DiffusionSubject(s)
Decompression, Surgical , Laminectomy , Constriction, Pathologic , Humans , Microsurgery , PainABSTRACT
STUDY DESIGN: Diagnostic retrospective case series. OBJECTIVE: To evaluate cervical intersegmental motion in rheumatoid arthritis patients using specialized tracking software (QMA) and compare the findings with a previously published cohort of "normal" subjects. SUMMARY OF BACKGROUND DATA: Rheumatoid arthritis follows 3 patterns of cervical involvement, atlantoaxial subluxation, atlantoaxial impaction, and subaxial subluxation. Deformities present are sometimes considered "unstable" to the point where surgery can be recommended based on the interpretation of cervical radiographs. METHODS: Cervical flexion-extension radiographs of 99 subjects with rheumatoid arthritis were evaluated. Angular and translational segmental motions were determined at each level using specialized tracking software. Findings were compared with previously published normative data using the same device. RESULTS: Relative to controls, patients with rheumatoid arthritis demonstrated significantly less overall sagittal motion. Segmental analysis at C1-C2 demonstrated a 10% prevalence of dynamic motion outside the 95% confidence interval for "normal" patients. In contrast, segmental analysis at C2-C7 demonstrated no intersegmental motion outside the 95% confidence interval for "normal" subjects. CONCLUSIONS: In patients with rheumatoid arthritis, abnormal motion at C1-C2 was consistent with truly dynamic deformity and should be closely evaluated. Conversely, subaxial subluxations, although frequently present, were relatively fixed deformities and in most cases, may not represent an unstable condition.
Subject(s)
Arthritis, Rheumatoid/diagnostic imaging , Cervical Vertebrae/diagnostic imaging , Cervical Vertebrae/physiopathology , Female , Humans , Male , Middle Aged , Radiography , Range of Motion, Articular , Retrospective StudiesABSTRACT
STUDY DESIGN: Observational diagnostic study on consecutive patients. OBJECTIVE: To assess the efficacy of magnetic resonance imaging (MRI) for detecting spinal soft tissue injury after acute trauma using intraoperative findings as a reference standard. SUMMARY OF BACKGROUND DATA: Recognizing injuries to spinal soft tissue structures is critical for proper decision making and management for blunt trauma victims. Although MRI is considered the gold standard for imaging of soft tissues, its ability to identify specific components of soft tissue damage in acute spine trauma patients is poorly documented and controversial. METHODS: Intraoperative findings were recorded for 21 acute spinal trauma patients (study group) and 14 nontraumatic spinal surgery patients (control group). Preoperative MRI's were evaluated randomly and blindly by 2 neuroradiologists. MRI and intraoperative findings were compared. By using the intraoperative findings as the reference standard, sensitivity, specificity, positive and negative predictive values of MRI in detecting spinal soft tissue injury were determined. RESULTS: MRI was 100% sensitive and specific in detecting injury to the anterior longitudinal ligament. MRI was moderately sensitive (80%) but highly specific (100%) for injury to the posterior longitudinal ligament. In contrast, MRI was highly sensitive but less specific in detecting injury to paraspinal muscles (100%, 77%), intervertebral disk (100%, 71%), and interspinous ligament (100%, 64%). MRI was moderately sensitive and specific in detecting ligamentum flavum injury (80% and 86.7%) but poorly sensitive for facet capsule injury (62.5%). CONCLUSIONS: MRI demonstrated high sensitivity for spinal soft tissue injuries. However, MRI showed a definite trend to overestimate interspinous ligament, intervertebral disk, and paraspinal muscle injuries. On the basis of these results, we would consider MRI to be a useful tool for spine clearance after trauma. Conversely, caution should be applied when using MRI for operative decision making due to its less predictable specificity.
Subject(s)
Longitudinal Ligaments/injuries , Magnetic Resonance Imaging/methods , Orthopedic Procedures/methods , Spinal Injuries/diagnosis , Adolescent , Adult , Aged , Female , Humans , Intervertebral Disc/injuries , Ligamentum Flavum/injuries , Male , Middle Aged , Monitoring, Intraoperative , Paraspinal Muscles/injuries , Reproducibility of Results , Spinal Diseases/complications , Spinal Injuries/surgery , Young AdultABSTRACT
Robust reference data, representing a large and diverse population, are needed to objectively classify measurements of spondylolisthesis and disc space narrowing as normal or abnormal. The reference data should be open access to drive standardization across technology developers. The large collection of radiographs from the 2nd National Health and Nutrition Examination Survey was used to establish reference data. A pipeline of neural networks and coded logic was used to place landmarks on the corners of all vertebrae, and these landmarks were used to calculate multiple disc space metrics. Descriptive statistics for nine SPO and disc metrics were tabulated and used to identify normal discs, and data for only the normal discs were used to arrive at reference data. A spondylolisthesis index was developed that accounts for important variables. These reference data facilitate simplified and standardized reporting of multiple intervertebral disc metrics.
ABSTRACT
BACKGROUND CONTEXT: There has been increasing scrutiny on the standardization of surgical training in the US. PURPOSE: This study provides case volume benchmarks for Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopedic spine surgery fellowship training. STUDY DESIGN/SETTING: This was a retrospective cross-sectional study of fellows at ACGME-accredited orthopedic spine surgery fellowships (2017-2022). PATIENT SAMPLE: N/A. OUTCOME MEASURES: Reported case volume during fellowship training. METHODS: Case volume percentiles were calculated across ACGME-defined case categories and temporal changes assessed via linear regression. Variability between the highest and lowest deciles by case volume was calculated as fold-differences (90th percentile/10th percentile). Sensitivity analyses were performed to identify potential targets for case minimum requirements. RESULTS: A total of 163 spine surgery fellows were included in this study. Total mean reported spine surgery case volume increased from 313.2±122 in 2017 to 382.0±164 in 2022 (p=.19). Most cases were classified as adult (range, 97.2%-98.0%) over pediatric cases (range, 2.0%-2.8%). An average of 322.0 cases were reported and most were classified as laminectomy (32%), posterior arthrodesis (29%), and anterior arthrodesis (20%). Overall variability in total case volume was 2.4 and the greatest variability existed for posterior instrumentation (38.1), application of cage (34.6), anterior instrumentation (20.8), and fractures and dislocations (17.3). If case minimum requirements for total reported cases was assumed at 200 cases, then all spine fellows included in this study would achieve this requirement. However, if case minimum requirements were assumed at 250 total cases, then approximately thirty percent of fellows (n=49) would not achieve this requirement for graduation. CONCLUSIONS: Increasingly, national societies and accrediting bodies for surgical education recognize the need for standardized training. This study provides benchmarks to inform potential case minimum requirements and help reduce variability during spine fellowship training. Future studies are needed to establish case minimum requirements for spine surgery fellowship training across comprehensive and granular case categories that cover the full gamut of orthopedic spine surgery.
Subject(s)
Benchmarking , Fellowships and Scholarships , Orthopedics , Humans , Orthopedics/education , Orthopedics/standards , Fellowships and Scholarships/statistics & numerical data , Fellowships and Scholarships/standards , Retrospective Studies , Accreditation/standards , Cross-Sectional Studies , Education, Medical, Graduate/standards , Orthopedic Procedures/education , Orthopedic Procedures/standards , Orthopedic Procedures/statistics & numerical data , Adult , Spine/surgery , Internship and Residency/standards , Internship and Residency/statistics & numerical data , Male , FemaleABSTRACT
Cartilage endplates (CEPs) act as protective mechanical barriers for intervertebral discs (IVDs), yet their heterogeneous structure-function relationships are poorly understood. This study addressed this gap by characterizing and correlating the regional biphasic mechanical properties and biochemical composition of human lumbar CEPs. Samples from central, lateral, anterior, and posterior portions of the disc (n = 8/region) were mechanically tested under confined compression to quantify swelling pressure, equilibrium aggregate modulus, and hydraulic permeability. These properties were correlated with CEP porosity and glycosaminoglycan (s-GAG) content, which were obtained by biochemical assays of the same specimens. Both swelling pressure (142.79 ± 85.89 kPa) and aggregate modulus (1864.10 ± 1240.99 kPa) were found to be regionally dependent (p = 0.0001 and p = 0.0067, respectively) in the CEP and trended lowest in the central location. No significant regional dependence was observed for CEP permeability (1.35 ± 0.97 * 10-16 m4/Ns). Porosity measurements correlated significantly with swelling pressure (r = -0.40, p = 0.0227), aggregate modulus (r = -0.49, p = 0.0046), and permeability (r = 0.36, p = 0.0421), and appeared to be the primary indicator of CEP biphasic mechanical properties. Second harmonic generation microscopy also revealed regional patterns of collagen fiber anchoring, with fibers inserting the CEP perpendicularly in the central region and at off-axial directions in peripheral regions. These results suggest that CEP tissue has regionally dependent mechanical properties which are likely due to the regional variation in porosity and matrix structure. This work advances our understanding of healthy baseline endplate biomechanics and lays a groundwork for further understanding the role of CEPs in IVD degeneration.
Subject(s)
Intervertebral Disc , Lumbar Vertebrae , Humans , Lumbar Vertebrae/physiology , Intervertebral Disc/physiology , Middle Aged , Male , Female , Porosity , Adult , Aged , Glycosaminoglycans/metabolism , Biomechanical Phenomena , Cartilage/physiology , Stress, MechanicalABSTRACT
BACKGROUND CONTEXT: Sex diversity in the spine surgery workforce remains limited. Accelerated efforts to recruit more female trainees into spine surgery fellowship training may help promote diversity and inclusion in the emerging spine surgery workforce. PURPOSE: This study assessed the representation of female trainees in spine surgery fellowship training and program factors associated with greater sex diversity among fellows. STUDY DESIGN/SETTING: This was a cross-sectional analysis of spine surgery fellows in the United States during the 2016-2017 to 2022-2023 academic years. PATIENT SAMPLE: N/A. OUTCOME MEASURES: Representation (%) and participation-to-prevalence ratios (PPRs) defined as the participation of female trainees in spine surgery fellowship training divided by the prevalence of female trainees in previous training cohorts. PPR values <0.8 indicated underrepresentation. METHODS: Sex diversity was assessed among spine surgery faculty, spine surgery fellows, orthopaedic surgery residents, neurosurgery residents, and allopathic medical students. Fellowship program characteristics associated with increased sex diversity were calculated with chi square tests. RESULTS: There were 693 spine surgery fellows and 41 were female (5.9%). Sex diversity in spine surgery fellowship training decreased over the study period (6.4% vs. 4.1%, p=.025). Female trainee representation in spine surgery fellowship training was less than that in orthopaedic surgery residency (14.2%, PPR=0.42), neurosurgery residency (17.1%, PPR=0.35), and allopathic medical school (47.6%, PPR=0.12) training (p<.001). There were 508 faculty at 78 spine surgery fellowships and 25 were female (4.9%). There were 3 female fellowship program directors (3.8%). Fellowship program characteristics associated with increased sex diversity included the presence of female faculty (p=.020). Additional program characteristics including geographic region, accreditation status, number of faculty and fellows were not associated with sex diversity (p>.05). CONCLUSIONS: Female representation in spine surgery fellowship training decreased over the study period and remains underrepresented relative to earlier stages of medical and surgical training. There was a positive association between female faculty and increased sex diversity among fellows. Greater efforts are needed to create training environments that promote diversity, equity, and inclusion in spine surgery fellowship training.
ABSTRACT
BACKGROUND: Accurate identification of pain generators in the context of low back and spine-related pain is crucial for effective treatment. This review aims to evaluate the potential usefulness of single photon emission computed tomography with computed tomography (SPECT/CT) as an imaging modality in guiding clinical decision-making. METHODS: A broad scoping literature review was conducted to identify relevant studies evaluating the use of SPECT/CT in patients with spine-related pain. Studies were reviewed for their methodology and results. RESULTS: SPECT/CT appears to have advantages over traditional modalities, such as magnetic resonance imaging and CT, in certain clinical scenarios. It may offer additional information to clinicians and improve the specificity of diagnosis. However, further studies are needed to fully assess its diagnostic accuracy and clinical utility. CONCLUSIONS: SPECT/CT is a promising imaging modality in the evaluation of low back pain, particularly in cases where magnetic resonance imaging and CT are inconclusive or equivocal. However, the current level of evidence is limited, and additional research is needed to determine its overall clinical relevance. CLINICAL RELEVANCE: SPECT/CT may have a significant impact on clinical decision-making, particularly in cases in which traditional imaging modalities fail to provide a clear diagnosis. Its ability to improve specificity could lead to more targeted and effective treatment for patients with spinal pathology.
ABSTRACT
BACKGROUND CONTEXT: Failure to fuse following anterior cervical discectomy and fusion (ACDF) may result in symptomatic pseudoarthrosis. Traditional diagnosis involves computerized tomography to detect bridging bone and/or flexion-extension radiographs to assess whether segmental motion is above specific thresholds; however, there are currently no well-validated diagnostic tests. We propose a biomechanically rational approach to achieve a reliable diagnostic test for pseudoarthrosis. PURPOSE: Develop and test a biomechanically based approach to the diagnosis of pseudoarthrosis. STUDY DESIGN: Literature review, development of theory, re-analysis of a previously published study with surgical exploration as the gold-standard, and retrospective analysis of pooled studies to understand time to fusion. METHODS: Fully automated methods were used to measure disc space strains (change in disc space height divided by initial height). Measurement error combined with the reported failure strain of trabecular bone led to a proposed strain threshold for diagnosis of pseudoarthrosis following ACDF. We reanalyzed previously reported flexion-extension radiographs for asymptomatic volunteers to assess whether flexion-extension radiographs, in the absence of fusion surgery, can be expected to provide sufficient stress on motion segments to allow for reliable strain-based fusion assessment. The sensitivity and specificity of strain- and rotation-based pseudoarthrosis diagnosis were assessed by reanalysis of previously reported post-ACDF flexion-extension radiographs, where intraoperative fusion assessments were also available. Finally, we assessed changes in strain over time using 9,869 flexion-extension radiographs obtained 6 weeks to 84 months post-ACDF surgery from 1,369 patients. RESULTS: The estimated error in automated measurement of disc space strain from radiographs was approximately 3%, and the reported failure strain of bridging bone was less than 2.5%. On that basis, we propose a 5% strain threshold for pseudoarthrosis diagnosis. Reanalysis of a study in which intraoperative fusion assessments were available revealed 67% sensitivity and 82% specificity for strain-based diagnosis of pseudoarthrosis, which was comparable to rotation-based diagnosis. Analysis of post-ACDF flexion-extension radiographs revealed rapid strain reduction for up to 24 months, followed by a slower decrease for up to 84 months. When rotation is less than 2 degrees, the strain-based diagnosis differed from the rotation-based diagnosis in approximately 14% of the cases. CONCLUSIONS: We propose steps for standardizing diagnosis of pseudoarthrosis based on the failure strain of bone, measurement error, and retrospective data. These steps include obtaining high-quality flexion-extension studies, the application of proposed diagnostic thresholds, and the use of image stabilization for conclusive diagnosis, when motion is near thresholds. The necessity for an accurate diagnosis with minimal radiation exposure underscores the need for further optimization and standardization in diagnosing pseudoarthrosis following ACDF surgery. CLINICAL SIGNIFICANCE: In a symptomatic postspine fusion patient, it is important to diagnose or rule-out pseudoarthrosis. There are currently no well-validated diagnostic tests for this condition. Incorporating strain-based intervertebral motion analysis into the diagnosis could lead to a standardized and validated test for detecting spine pseudoarthrosis.
ABSTRACT
STUDY DESIGN: Comparison of extravasations in fractured cadaver vertebrae augmented with commercial low-viscosity versus high-viscosity cements. OBJECTIVE: Use of high-resolution, 3-dimensional (3D) imaging to test the hypothesis that high-viscosity cements can reduce the type and severity of extravasations after vertebral augmentation procedures. SUMMARY OF BACKGROUND DATA: Cement extravasations are one of the primary complications of vertebral augmentation procedures. There is some evidence that high-viscosity cements might reduce extravasations, but additional data are needed to confirm the early findings. METHODS: A range of vertebral fractures were created in fresh human cadavers. One group was then augmented with a low-viscosity polymethylmethacrylate (PMMA)-based cement and the other group injected with high-viscosity PMMA-based cement. High-resolution computerized tomography exams were obtained, and extravasations were assessed using 3D volume renderings. The type and severity of extravasations were recorded and analyzed. RESULTS: The proportion of vertebrae with any type of extravasation through the posterior wall to the spinal canal, into small vessels laterally or anteriorly, through the endplates, or anywhere around the body was not significantly different between the high-viscosity and low-viscosity groups. There was significantly less severe extravasation through the endplates (P=0.02), and a trend toward less severe extravasation through vessels (P=0.06) with the high versus low-viscosity cements. CONCLUSIONS: In agreement with previous research, high-viscosity PMMA-based cement may help to reduce the more severe forms of extravasations after vertebral augmentation procedures in newly fractured vertebrae.
Subject(s)
Bone Cements/chemistry , Bone Cements/standards , Spinal Fractures/surgery , Aged , Aged, 80 and over , Cadaver , Female , Humans , Male , Polymethyl Methacrylate/chemistry , Polymethyl Methacrylate/standards , Radiography , Spinal Fractures/diagnostic imaging , Vertebroplasty/methods , Vertebroplasty/standards , ViscosityABSTRACT
BACKGROUND: Terrible triad complex elbow fracture-dislocations are represented by elbow dislocations associated with fractures of the coronoid and radial head. Published literature has focused on classifying coronoid fractures by their radiographic morphology on plain x-ray images and computed tomography imaging. No study has specifically related native coronoid osteology to in situ fracture morphology. We identified 3 distinct bony regions of the coronoid, (medial, intermediate, and lateral ridges) with correlation to common fracture patterns associated with terrible triad injuries. METHODS: Coronoid osteology in 8 fresh frozen cadaveric elbows was examined, and three distinct ridges were identified and dimensions measured. RESULTS: The measurements were compared with retrospective intraoperative measurements taken of coronoid fracture fragments being stabilized during terrible triad injury repair. CONCLUSION: Classification of native coronoid process anatomy into functional ridges (medial, intermediate, lateral) may improve our understanding of coronoid fracture patterns in unstable terrible triad injuries. LEVEL OF EVIDENCE: Basic Science, Anatomic Study, Cadaver and In Vivo.
Subject(s)
Elbow Injuries , Joint Dislocations , Radius Fractures , Ulna Fractures/classification , Ulna/anatomy & histology , Cadaver , Humans , Joint Dislocations/diagnostic imaging , Joint Dislocations/surgery , Radiography , Radius Fractures/diagnostic imaging , Radius Fractures/surgery , Ulna Fractures/diagnostic imaging , Ulna Fractures/surgeryABSTRACT
STUDY DESIGN: Retrospective administrative database review. OBJECTIVE: Analyze patterns of opioid use in patients undergoing lumbar surgery and determine associated risk factors in a Medicaid population. SUMMARY OF BACKGROUND DATA: Opioid use in patients undergoing surgery for degenerative lumbar spine conditions is prevalent and impacts outcomes. There is limited information defining the scope of this problem in Medicaid patients. MATERIALS AND METHODS: Longitudinal cohort study of adult South Carolina (SC) Medicaid patients undergoing lumbar surgery from 2014 to 2017. All patients had continuous SC Medicaid coverage for 15 consecutive months, including six months before and nine months following surgery. The primary outcome was a longitudinal assessment of postoperative opioid use to determine trajectories and group-based membership using latent modeling. Univariate and multivariable modeling was conducted to assess risk factors for group-based trajectory modeling and chronic opioid use (COU). RESULTS: A total of 1455 surgeries met inclusion criteria. Group-based trajectory model demonstrated patients fit into five groups; very low use (23.4%), rapid wean following surgery (18.8%), increasing use following surgery (12.9%), slow wean following surgery (12.6%) and sustained high use (32.2%). Variables predicting membership in high opioid use included preoperative opioid use, younger age, longer length of stay, concomitant medications, and readmissions. More than three quarter of patients were deemed COUs (76.4%). On bivariate analysis, patients with degenerative disk disease were more likely to be COUs (24.8% vs. 18.6%; P =0.0168), more likely to take opioids before surgery (88.5% vs. 61.9%; P <0.001) and received higher amounts of opioids during the 30 days following surgery (mean morphine milligram equivalents 59.6 vs. 25.1; P <0.001). CONCLUSIONS: Most SC Medicaid patients undergoing lumbar elective lumbar spine surgery were using opioids preoperatively and continued long-term use postoperatively at a higher rate than previously reported databases. Preoperative and perioperative intake, degenerative disk disease, multiple prescribers, depression, and concomitant medications were significant risk factors.
Subject(s)
Analgesics, Opioid , Opioid-Related Disorders , Humans , Adult , Analgesics, Opioid/therapeutic use , Retrospective Studies , Longitudinal Studies , Medicaid , Pain, Postoperative/drug therapy , Opioid-Related Disorders/epidemiologyABSTRACT
OBJECTIVE: The objective of this study was to evaluate opioid use trajectories among a sample of 10,138 Medicaid patients receiving one of six index surgeries: lumbar spine, total knee arthroplasty, cholecystectomy, appendectomy, colon resection, and tonsillectomy. DESIGN: Retrospective cohort. SETTING: Administrative claims data. PATIENTS AND PARTICIPANTS: Patients, aged 13 years and older, with 15-month continuous Medicaid eligibility surrounding index surgery, were selected from single-state Medicaid medical and pharmacy claims data for surgeries performed between 2014 and 2017. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Baseline comorbidities and presurgery opioid use were assessed in the 6 months prior to admission, and patients' opioid use was followed for 9 months post-discharge. Generalized linear model with log link and Poisson distribution was used to determine risk of chronic opioid use for all risk factors. Group-based trajectory models identified groups of patients with similar opioid use trajectories over the 15-month study period. RESULTS: More than one in three (37.7 percent) patients were post-surgery chronic opioid users, defined as the dichotomous outcome of filling an opioid prescription 90 or more days after surgery. Key variables associated with chronic post-surgery opioid use include presurgery opioid use, 30-day post-surgery opioid use, and comorbidities. Latent trajectory modeling grouped patients into six distinct opioid use trajectories. Associates of trajectory group membership are reported. CONCLUSIONS: Findings support the importance of surgeons setting realistic patient expectations for post-surgical opioid use, as well as the importance of coordination of post-surgical care among patients failing to fully taper off opioids within 1-3 months of surgery.
Subject(s)
Analgesics, Opioid , Opioid-Related Disorders , United States/epidemiology , Humans , Analgesics, Opioid/adverse effects , Aftercare , Medicaid , Retrospective Studies , Patient Discharge , Opioid-Related Disorders/epidemiology , PrescriptionsABSTRACT
Bone marrow skeletal stem cells (SSCs) secrete many cytokines including stromal derived factor-1 or CXCL12, which influences cell proliferation, migration, and differentiation. All CXCL12 splice variants are rapidly truncated on their N-terminus by dipeptidyl peptidase 4 (DPP4). This includes the common variant CXCL12 alpha (1-68) releasing a much less studied metabolite CXCL12(3-68). Here, we found that CXCL12(3-68) significantly inhibited SSC osteogenic differentiation and RAW-264.7 cell osteoclastogenic differentiation and induced a senescent phenotype in SSCs. Importantly, pre-incubation of SSCs with CXCL12(3-68) significantly diminished their ability to migrate toward CXCL12(1-68) in transwell migration assays. Using a high-throughput G-protein-coupled receptor (GPCR) screen (GPCRome) and bioluminescent resonance energy transfer molecular interaction assays, we revealed that CXCL12(3-68) acts via the atypical cytokine receptor 3-mediated ß-arrestin recruitment and as a competitive antagonist to CXCR4-mediated signaling. Finally, a reverse phase protein array assay revealed that DPP4-cleaved CXCL12 possesses a different downstream signaling profile from that of intact CXCL12 or controls. The data presented herein provides insights into regulation of CXCL12 signaling. Importantly, it demonstrates that DPP4 proteolysis of CXCL12 generates a metabolite with significantly different and previously overlooked bioactivity that helps explain discrepancies in the literature. This also contributes to an understanding of the molecular mechanisms of osteoporosis and bone fracture repair and could potentially significantly affect the interpretation of experimental outcomes with clinical consequences in other fields where CXCL12 is vital, including cancer biology, immunology, cardiovascular biology, neurobiology, and associated pathologies.
ABSTRACT
Vertebral compression fractures (VCFs) can have a variety of etiologies, including trauma, osteoporosis, or neoplastic infiltration. Osteoporosis related fractures are the most common cause of VCFs and have a high prevalence among all postmenopausal women with increasing incidence in similarly aged men. Trauma is the most common etiology in those >50 years of age. However, many cancers, such as breast, prostate, thyroid, and lung, have a propensity to metastasize to bone, which can lead to malignant VCFs. Indeed, the spine is third most common site of metastases after lung and liver. In addition, primary tumors of bone and lymphoproliferative diseases such as lymphoma and multiple myeloma can be the cause of malignant VCFs. Although patient clinical history could help raising suspicion for a particular disorder, the characterization of VCFs is usually referred to diagnostic imaging. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
Subject(s)
Fractures, Compression , Osteoporosis , Spinal Fractures , Male , Humans , Female , United States , Aged , Spinal Fractures/diagnostic imaging , Spinal Fractures/therapy , Fractures, Compression/diagnostic imaging , Fractures, Compression/therapy , Bone and Bones , Societies, MedicalABSTRACT
PURPOSE: To test absorbable materials as a prelude to development of an absorbable vena cava filter for the prevention of pulmonary embolism (PE). MATERIALS AND METHODS: Three absorbing polymer candidates, poliglecaprone (Monocryl; sizes 4-0 and 1), polyglactin (Vicryl; sizes 4-0 and 1), and polydioxanone (PDSII; sizes 4-0, 2-0, 0, and 1), were fabricated into vascular filters and evaluated in an engineered closed circulation system that replicated human physiologic characteristics. Material performance was determined over a period of 10 weeks via weekly tensile testing, yielding stress-versus-strain parameters. Control samples of the same absorbable polymers were also tested in a static buffer. RESULTS: PDSII (size 2-0) retained 69% strength in circulation versus 86% in control at 6 weeks (P < .0001) and 11% strength in circulation versus 51% in control at 10 weeks (P < .001). It was fully absorbed in circulation by 22 weeks. In contrast, Monocryl and Vicryl absorbed much faster, with Monocryl possessing 6% strength at 2 weeks in circulation and Vicryl reaching 0% strength at 4 weeks. CONCLUSIONS: Polydioxanone appears to be a strong candidate for novel absorbable vascular filters for PE prevention, with sufficient strength retention to catch emboli for at least 6 weeks and sequentially absorb via hydrolysis into CO(2) and H(2)O within 22 weeks.