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This study investigated treatment trends and major adverse events in patients hospitalized for osteoporotic vertebral fracture (OVF). The frequency of surgical interventions for OVF increased significantly, but this did not decrease major adverse events. The findings underscore the necessity for reevaluating OVF management strategies. PURPOSE: Osteoporotic vertebral fracture (OVF) is a common condition in the aging population, often leading to increased morbidity and mortality. Here, we analyzed treatment trends and incidence of major adverse events in patients hospitalized for OVF. METHODS: We conducted a cross-sectional descriptive study, using a large Japanese hospital administrative database. The cohort included hospitalized patients aged 65 years or older, admitted for OVF from January 2015 to December 2021. The primary outcomes were the trend in the proportion of the patients undergoing surgery for OVF and the incidence of major adverse events within 30 days of admission. As a secondary outcome, we evaluated the trend in hospitalization costs. RESULTS: The study cohort consisted of 14,714 patients, with a mean age of 82.4 years. There was a significant increase in surgical interventions for OVF, from 3.7% of patients in 2015 to 9.8% in 2021 (p < 0.001). The incidence of major adverse events remained unchanged, with a risk ratio of 1.09 (95% confidence interval, 0.88 to 1.35) in 2021 compared to 2015. Average hospitalization costs increased significantly, from $7,570.6 (SD 6,047.0) in 2015 to $9,502.9 (SD 7,231.5) in 2021 (p < 0.001). CONCLUSION: Despite a significant increase in the proportion of surgical intervention for OVF, no reduction in the risk of major adverse events was observed between 2015 and 2021. Surgeons and policy makers need to interpret these findings and work towards an optimized approach to the management of OVF in the aging population.
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Hospitalização , Fraturas por Osteoporose , Complicações Pós-Operatórias , Fraturas da Coluna Vertebral , Humanos , Masculino , Idoso , Feminino , Idoso de 80 Anos ou mais , Fraturas da Coluna Vertebral/cirurgia , Fraturas da Coluna Vertebral/epidemiologia , Incidência , Fraturas por Osteoporose/cirurgia , Fraturas por Osteoporose/epidemiologia , Estudos Transversais , Japão/epidemiologia , Hospitalização/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologiaRESUMO
The regeneration of the mammalian skeleton's craniofacial bones necessitates the action of intrinsic and extrinsic inductive factors from multiple cell types, which function hierarchically and temporally to control the differentiation of osteogenic progenitors. Single-cell transcriptomics of developing mouse calvarial suture recently identified a suture mesenchymal progenitor population with previously unappreciated tendon- or ligament-associated gene expression profile. Here, we developed a Mohawk homeobox (MkxCG; R26RtdT) reporter mouse and demonstrated that this reporter identifies an adult calvarial suture resident cell population that gives rise to calvarial osteoblasts and osteocytes during homeostatic conditions. Single-cell RNA sequencing (scRNA-Seq) data reveal that Mkx+ suture cells display a progenitor-like phenotype with expression of teno-ligamentous genes. Bone injury with Mkx+ cell ablation showed delayed bone healing. Remarkably, Mkx gene played a critical role as an osteo-inhibitory factor in calvarial suture cells, as knockdown or knockout resulted in increased osteogenic differentiation. Localized deletion of Mkx in vivo also resulted in robustly increased calvarial defect repair. We further showed that mechanical stretch dynamically regulates Mkx expression, in turn regulating calvarial cell osteogenesis. Together, we define Mkx+ cells within the suture mesenchyme as a progenitor population for adult craniofacial bone repair, and Mkx acts as a mechanoresponsive gene to prevent osteogenic differentiation within the stem cell niche.
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Diferenciação Celular , Proteínas de Homeodomínio , Osteogênese , Crânio , Animais , Camundongos , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Osteogênese/genética , Crânio/metabolismo , Osteoblastos/metabolismo , Osteoblastos/citologia , Suturas Cranianas/metabolismo , Células-Tronco/metabolismo , Células-Tronco/citologia , Biomarcadores/metabolismoRESUMO
BACKGROUND: Patients with spinal meningioma may present preoperatively with paralysis and sensory deficits. However, there is a paucity of detailed evaluations and a lack of consensus regarding imaging findings that are predictive of neurological symptoms in patients with spinal meningioma. METHODS: Herein, a total of 55 patients who underwent surgical resection of spinal meningiomas in eight hospitals between 2011 and 2021 were enrolled. Patient characteristics, degree of muscle weakness, sensory disturbances, and the presence of bowel/bladder dysfunction (BBD) before surgical treatment were evaluated using medical records. Patients with American Spinal Injury Impairment Scale grades A-C and the presence of BBD were classified into the paralysis (+) group. Patients with sensory disturbances were assigned to the sensory disturbance (+) group. Based on magnetic resonance (MR) and computed tomography images, the tumor location was classified according to the spinal level and its attachment to the dura mater. To evaluate tumor size, the tumor occupation ratio (OR) was calculated using the area and distance measurement method in horizontal MR images, and the maximum length and area of the tumor in the sagittal plane were measured. RESULTS: Of all patients, 85 % were women. The mean age of patients at surgery was 69.7 years. Twenty-eight (51 %) and 41 (75 %) patients were classified into the paralysis (+) and sensory disturbance (+) groups, respectively. The average tumor length and area in the sagittal plane were 19.6 mm and 203 mm2, respectively; OR-area and diameters were 70.3 % and 72.3 %, respectively. In univariate analyses, tumor length and area in the sagittal plane were significant risk factors for paralysis. OR-diameter, symptom duration, and a low MIB-1 index correlated with sensory disturbances. Multivariate logistic regression analysis demonstrated that the area and length of the tumor in the sagittal plane were significantly correlated with paralysis, whereas the OR-diameter and symptom duration significantly correlated with sensory disturbances. The cut-off values for the area and length of the tumor in the sagittal plane to predict paralysis were 243 mm2 and 20.1 mm, respectively. CONCLUSIONS: Preoperative paralysis in patients with spinal meningiomas was significantly associated with sagittal tumor size than with high tumor occupancy in the horizontal plane. Sensory disturbances were associated with high occupancy in the horizontal plane. Patients with spinal meningiomas > 20 mm in length or 243 mm2 in area in the sagittal plane are at risk of developing paralysis and could be considered for surgery even in the absence of paralysis.
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Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/cirurgia , Meningioma/diagnóstico por imagem , Meningioma/complicações , Feminino , Masculino , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias Meníngeas/cirurgia , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/complicações , Imageamento por Ressonância Magnética , Idoso de 80 Anos ou mais , Adulto , Paralisia/etiologia , Transtornos de Sensação/etiologiaRESUMO
STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To elucidate the factors related to progression of scoliosis in patients with rheumatoid arthritis (RA) using longitudinal cohort data. SUMMARY OF BACKGROUND DATA: Thirty percent of patients with RA have lumbar scoliosis. However, the effectiveness of current treatment methods in preventing the progression of scoliosis is not well-understood due to a lack of longitudinal studies. METHODS: We enrolled 180 patients with RA who were followed up for over two years, all of whom underwent standing spinal X-rays. These patients were categorized based on their disease activity score-28 with erythrocyte sedimentation rate (DAS28-ESR) into two groups: those in remission (n=76) and those in non-remission (n=104). We evaluated various radiographic measures, including C7 center sacral vertical line (C7-CSVL), pelvic obliquity, major Cobb angle, and curve location. RESULTS: Fifty-three (29.4%) patients presented progression of scoliosis during a mean follow-up period of 4.8 years. Patients in the non-remission showed larger Cobb angle at baseline and final follow-up, compared to those in remission. The annual progression rate of the curve was also greater in the non-remission group (1.04 degree /year), than in the remission group (0.59 degree /year, P=0.001). There was no difference in the incidence of new vertebral fractures. The presence of a baseline cobb angle of 10 degree or more (OR: 3.14; 95% CI: 1.38-7.13; P=0.006), glucocorticoid use (OR: 2.88; 95% CI: 1.18-7.06; P=0.021), and non-remission at baseline (OR: 2.83; 95% CI: 1.25-6.41; P=0.012) were significant risk factors for progression of scoliosis. CONCLUSION: RA disease activity is linked to progression of scoliosis in patients with RA. Patients with RA who present with an initial scoliosis of 10 degrees or greater, require glucocorticoids for treatment and are in non-remission at baseline may be at high risk for scoliosis progression.
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STUDY DESIGN: A retrospective multicenter case series was conducted. PURPOSE: This study aimed to investigate survival and prognostic factors after surgery for a metastatic spinal tumor. OVERVIEW OF LITERATURE: Prognostic factors after spinal metastasis surgery remain controversial. METHODS: A retrospective multicenter study was conducted. The study participants included 345 patients who underwent surgery for spinal metastases from 2010 to 2020 at nine referral spine centers in Japan. Data for each patient were extracted from medical records. To identify the factors predicting survival prognosis after surgery, univariate analyses were performed using a Cox proportional hazards model. RESULTS: The mean age was 65.9 years. Common primary tumors were lung (n=72), prostate (n=61), and breast (n=39), and 67.8% (n=234) presented with osteolytic lesions. The epidural spinal cord compression scale score 2 or 3 was recognized in 79.0% (n=271). Frankel grade A paralysis accounted for 1.4% (n=5), and 73.3% (n=253) were categorized as intermediate or high risk according to the new Katagiri score. The overall survival rates were -71.0% at 6 months, 57.4% at 12, and 43.3% at 24. In the univariate analysis, Frankel grade A (hazard ratio [HR], 3.59; 95% confidence interval [CI], 1.23-10.50; p<0.05), intermediate risk (HR, 3.34; 95% CI, 2.10-5.32; p<0.01), and high risk (HR, 7.77; 95% CI, 4.72-12.8; p<0.01) in the new Katagiri score were significantly associated with poor survival. On the contrary, postoperative chemotherapy (HR, 0.23; 95% CI, 0.15-0.36; p<0.01), radiation therapy (HR, 0.43; 95% CI, 0.26-0.70; p<0.01), and both adjuvant therapy (HR, 0.21; 95% CI, 0.14-0.32; p<0.01) were suggested to improve survival. CONCLUSIONS: Surgical indications for patients with Frankel grade A or intermediate or high risk in the new Katagiri score should be carefully considered because of poor survival. Chemotherapy or radiation therapy should be considered after surgery for better survival.
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STUDY DESIGN: A retrospective observational study. PURPOSE: This study aimed to determine an accurate and convenient screening method for predicting proximal junctional fractures (PJFr) following surgery for adult spinal deformity (ASD) using computed tomography (CT)-based measurement of Hounsfield units (HUs). OVERVIEW OF LITERATURE: CT-based measurement of HUs is an alternative tool for assessing bone mineral density. However, the optimal method for predicting adjacent vertebral fractures following spinal fusion using HUs remains unclear. METHODS: This retrospective observational study included 42 patients who underwent reconstructive surgery for ASD. Elliptical regions of interest (ROIs) on the axial section and rectangular ROIs on the sagittal section were placed at the upper instrumented vertebrae (UIV), UIV+1, and UIV+2. In addition, the HU value of the L2 vertebra was used as the representative. RESULTS: PJFr occurred in 28.6% of patients within 2 years following surgery. The HU values obtained from the axial sections of L2, UIV, UIV+1, and UIV+2 were not significantly associated with the incidence of PJFr within 2 years, except for the ROI set in the lower region of the L2 vertebra. However, the HU value of the anterior third of the UIV in the sagittal section was significantly lower in the PJFr group than in the nonPJFr group (87.0 vs. 160.3, p =0.001). A UIV HU value of <100 was associated with a higher incidence of PJFr than an HU vaue of >100 (p <0.05). CONCLUSIONS: Measurements of HU in the anterior one-third of the UIV in the sagittal section demonstrated predictive ability for PJFr following ASD surgery. A UIV HU value of <100 emerged as a risk factor for PJFr.
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OBJECTIVE: To investigate S2 alar screw (S2AS) accuracy and factors associated with S2AS loosening and lumbosacral nonunion. METHODS: We retrospectively reviewed patients who underwent lumbosacral fusion surgery with S2AS addition under fluoroscopy. S2AS loosening and lumbosacral nonunion were analyzed using a 1-year postoperative computed tomography. S2AS insertion accuracy was originally classified as accurate, short, anterior perforation, lateral perforation, and sacroiliac joint (SIJ) deviation among lateral perforation. Clinical data including sex, age, body mass index, fused segments, fusion procedure, primary or revision surgery, Japanese Orthopedic Association scores and complications were collected. Factors associated with S2AS loosening and lumbosacral nonunion were analyzed. RESULTS: A total of 37 patients (74 screws, age: 63.78 ± 13.57 years, female/male: 14/23 patients, body mass index: 23.11 ± 2.53, fused segments: 1-4 levels, revision: 38%) were included. S2AS loosening and lumbosacral nonunion were observed in 18 screws (13%) and 8 patients (22%) respectively. Only 35 screws (47%) were inserted accurately in our classification. Short, lateral perforation, and anterior perforation were observed in 14 screws (19%), 22 screws (30%), and 3 screws (4.1%). SIJ deviation was seen in 15 screws (20%) Factors associated with S2AS loosening were older age (P = 0.038), fusion levels (P = 0.011), and SIJ deviation (P < 0.001). S2AS loosening affects S1 pedicle screw (S1PS) loosening (P = 0.001). Furthermore, S2AS loosening is a risk factor for lumbosacral nonunion (P = 0.046). CONCLUSIONS: S2AS insertion under fluoroscopy is inaccurate. S2AS loosening induces S1PS loosening and lumbosacral nonunion. Surgeons should avoid deviating to SIJ, especially in older patients and relatively longer fusion.
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Parafusos Pediculares , Fusão Vertebral , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Fusão Vertebral/métodos , FluoroscopiaRESUMO
CASE: We present a case of a 79-year-old man with degenerative cervical myelopathy treated with anterior cervical discectomy and fusion (ACDF) using a zero-profile cage. Postoperatively, the patient experienced a rare complication of anchoring blade-related adjacent vertebral fracture leading to construct failure and recurrence of myelopathic symptoms, necessitating revision surgery. CONCLUSION: This case emphasizes the importance of precision in the surgical technique, specifically in the placement of Caspar pins and anchoring blades. It also underscores the need for a high index of suspicion for potential hardware-related complications in patients presenting with recurring symptoms post-ACDF, contributing to the understanding of such rare complications.
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Doenças da Medula Espinal , Fraturas da Coluna Vertebral , Fusão Vertebral , Masculino , Humanos , Idoso , Fraturas da Coluna Vertebral/etiologia , Fraturas da Coluna Vertebral/cirurgia , Vértebras Cervicais/cirurgia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos , Discotomia/efeitos adversos , Discotomia/métodos , Doenças da Medula Espinal/etiologia , Pinos OrtopédicosRESUMO
PURPOSE: Previous studies have shown that percutaneous pedicle screw (PPS) posterior fixation without anterior debridement for pyogenic spondylitis can improve patient quality of life compared with conservative treatment. However, data on the risk of recurrence after PPS posterior fixation compared with conservative treatment is lacking. The aim of this study was to compare the recurrence rate of pyogenic spondylitis after PPS posterior fixation without anterior debridement and conservative treatment. METHODS: The study was conducted under a retrospective cohort design in patients hospitalized for pyogenic spondylitis between January 2016 and December 2020 at 10 affiliated institutions. We used propensity score matching to adjust for confounding factors, including patient demographics, radiographic findings, and isolated microorganisms. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence of pyogenic spondylitis during the follow-up period in the matched cohort. RESULTS: 148 patients (41 in the PPS group and 107 in the conservative group) were included. After propensity score matching, 37 patients were retained in each group. PPS posterior fixation without anterior debridement was not associated with an increased risk of recurrence compared with conservative treatment with orthosis (HR, 0.80; 95% CI, 0.18-3.59; P = 0.77). CONCLUSIONS: In this multi-center retrospective cohort study of adults hospitalized for pyogenic spondylitis, we found no association in the incidence of recurrence between PPS posterior fixation without anterior debridement and conservative treatment.
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Fusão Vertebral , Espondilite , Adulto , Humanos , Estudos Retrospectivos , Desbridamento , Pontuação de Propensão , Qualidade de Vida , Resultado do Tratamento , Espondilite/diagnóstico por imagem , Espondilite/cirurgia , Espondilite/complicações , Vértebras Lombares/cirurgiaRESUMO
CASE: The accordion phenomenon is defined as the difference in the disc space observed on x-ray or computed tomography images taken in both standing and supine positions, which results in a discrepancy of local spinal alignment. Oblique lateral interbody fusion (OLIF) is a less invasive method of potentially correcting both coronal and sagittal spinal alignment. We present the case of a 66-year-old woman with rheumatoid arthritis treated with OLIF for degenerative disc disease presenting with hyperlordosis and negative sagittal vertical axis (SVA) because of the accordion phenomenon. CONCLUSION: OLIF for severe degenerative disc disease presenting with hyperlordosis and negative SVA because of the accordion phenomenon may be effective.
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Degeneração do Disco Intervertebral , Lordose , Fusão Vertebral , Idoso , Feminino , Humanos , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/cirurgia , Lordose/diagnóstico por imagem , Vértebras Lombares , Radiografia , Fusão Vertebral/métodosRESUMO
PURPOSE: This study aimed to elucidate the severity of neurological deficits in a large series of patients with acute spontaneous spinal epidural haematoma (SSEH) using magnetic resonance imaging (MRI). METHODS: We included 57 patients treated for acute SSEH at 11 institutions and retrospectively analysed their demographic and MRI data upon admission. We investigated MRI findings, such as the haematoma length and canal occupation ratio (COR). The neurological severity of SSEH was assessed based on the American Spinal Injury Association score on admission. RESULTS: Of the 57 patients, 35 (61%) presented with severe paralysis. The MRI analysis showed that SSEH was often located in the cervical spine, dorsal to the spinal cord, and spread over more than three vertebrae. No differences in age, sex, and aetiology were found between patients with and without severe paralysis. The hypo-intensity layer encircling the haematoma, intra-haematoma heterogeneity, and increased CORs were observed more frequently in the severe paralysis group. Furthermore, pathological examination of a dissected haematoma from one patient with a hypo-intensity layer revealed a collagen layer around the haematoma, and patients with intra-haematoma heterogeneity were more likely to have a bleeding predisposition. CONCLUSIONS: In this large series of patients with SSEH, we identified some MRI features associated with severe paralysis, such as the hypo-intensity layer, intra-haematoma heterogeneity, and increased COR. Accordingly, patients with these MRI characteristics should be considered for early surgical intervention.
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Hematoma Epidural Espinal , Vértebras Cervicais , Hematoma Epidural Espinal/diagnóstico por imagem , Hematoma Epidural Espinal/etiologia , Humanos , Imageamento por Ressonância Magnética , Paralisia/diagnóstico por imagem , Paralisia/etiologia , Estudos RetrospectivosRESUMO
Background and Objectives: Measured blood loss frequently underestimates true blood loss; this discrepancy is called hidden blood loss (HBL). The purpose of the present study was to measure HBL in oblique lateral interbody fusion (OLIF). Materials and Methods: Patients who underwent two-stage OLIF at our institute from September 2017 to September 2021 were retrospectively reviewed. Total blood loss (TBL) and HBL were calculated using the gross formula. The age, sex, body mass index (BMI), operation time, measured blood loss, the number of fused segments, hematocrit (HCT), anticoagulant or platelet medication, blood transfusion, days of hospitalization, pre-/postoperative Japanese Orthopedic Association (JOA) score, and JOA recovery rate were compared. Results: A total of thirteen patients were included in the study. The average age, BMI, number of fused segments, operation time, estimated blood loss, and blood transfusion were 69.5 years, 23.3, 2.5, 250 min, 122 mL, and 230 mL, respectively. Five patients received anticoagulant or platelet therapy. Days of hospitalization, pre-/postoperative JOA score, and JOA recovery rate were 14.9 ± 5.1, 19.9 ± 2.7, and 18.0 ± 43.4%, respectively. The TBL and HBL were 688 and 797 mL, respectively. Stepwise multiple regression analysis revealed that younger age (p = 0.01), female sex (p = 0.01), and number of fused segments (p = 0.02) were significantly associated with higher HBL. Conclusions: The HBL in OLIF was 797 mL, which was more than other previously reported procedures. Therefore, OLIF may not be less invasive in terms of HBL. Blood loss after surgery should be considered, especially when patients are younger, are female, and have a greater number of fused segments.
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Fusão Vertebral , Idoso , Anticoagulantes , Perda Sanguínea Cirúrgica , Feminino , Humanos , Vértebras Lombares/cirurgia , Masculino , Estudos Retrospectivos , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodosRESUMO
Bone regeneration following injury is initiated by inflammatory signals and occurs in association with infiltration by sensory nerve fibers. Together, these events are believed to coordinate angiogenesis and tissue reprogramming, but the mechanism of coupling immune signals to reinnervation and osteogenesis is unknown. Here, we found that nerve growth factor (NGF) is expressed following cranial bone injury and signals via p75 in resident mesenchymal osteogenic precursors to affect their migration into the damaged tissue. Mice lacking Ngf in myeloid cells demonstrated reduced migration of osteogenic precursors to the injury site with consequently delayed bone healing. These features were phenocopied by mice lacking p75 in Pdgfra+ osteoblast precursors. Single-cell transcriptomics identified mesenchymal subpopulations with potential roles in cell migration and immune response, altered in the context of p75 deletion. Together, these results identify the role of p75 signaling pathway in coordinating skeletal cell migration during early bone repair.
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Fator de Crescimento Neural , Receptores de Fator de Crescimento Neural , Transdução de Sinais , Animais , Movimento Celular , Camundongos , Fator de Crescimento Neural/metabolismo , Osteoblastos/metabolismo , Osteogênese/genética , Receptores de Fator de Crescimento Neural/metabolismoRESUMO
Clavicular fractures are common, accounting for 4% of all adult fractures. However, simultaneous medial and lateral fractures occurring in the same clavicle (the so-called 'bipolar clavicle fracture') are rare. Treatment for this type of fracture is not well established. Herein, we report our experience of the operative management of a bipolar clavicle fracture using two anatomical locking plates. The patient was an 82-year-old woman who presented with left-sided clavicle pain after falling to the ground. Plain radiography revealed midshaft and distal clavicular fractures. Open reduction and internal fixation were performed using two different plates, the VA-LCP anterior clavicle plate (DePuy Synthes, West Chester, PA, USA) for the midshaft fracture and the LCP superior anterior clavicle plate with lateral extension (DePuy Synthes) for the distal clavicle fracture. Bony union was achieved 4 months postoperatively without any complications. In conclusion, dual plating is an effective surgical procedure for treating bipolar clavicle fractures.
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Bone repair requires the tightly regulated control of multiple intrinsic and extrinsic cell types and signaling pathways. One of the positive regulatory signaling pathways in membranous and endochondral bone healing is the Hedgehog (Hh) signaling family. Here, a novel therapeutic liposomal delivery vector was developed by self-assembly of an Hh-activating cholesterol analog with an emulsifier, along with the addition of Smoothened agonist (SAG) as a drug cargo, for the enhancement of Hh signaling in bone regeneration. The drug-loaded nanoparticulate agonists of Hh signaling were immobilized onto trabecular bone-mimetic apatite-coated 3D scaffolds using bioinspired polydopamine adhesives to ensure favorable microenvironments for cell growth and local therapeutic delivery. Results showed that SAG-loaded liposomes induced a significant and dose-dependent increase in Hh-mediated osteogenic differentiation, as evidenced by in vitro analysis of bone marrow stromal cells, and in vivo calvarial bone healing, as evidenced using all radiographic parameters and histomorphometric analyses. Moreover, favorable outcomes were achieved in comparison to standards of care, including collagen sponge-delivered rBMP2 or allograft bone. In summary, this study demonstrates using a nanoparticle packaged Hh small molecule as a widely applicable bone graft substitute for robust bone repair.
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Regeneração Óssea/efeitos dos fármacos , Cicloexilaminas/farmacologia , Proteínas Hedgehog/metabolismo , Oxisteróis/administração & dosagem , Tiofenos/farmacologia , Alicerces Teciduais/química , Animais , Apatitas/química , Transplante Ósseo , Diferenciação Celular/efeitos dos fármacos , Cicloexilaminas/química , Modelos Animais de Doenças , Feminino , Humanos , Lipossomos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Camundongos , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Crânio/diagnóstico por imagem , Crânio/lesões , Crânio/cirurgia , Tiofenos/química , Microtomografia por Raio-XRESUMO
Intra-articular injection of mesenchymal stem cells has shown benefit for the treatment of osteoarthritis (OA). However, mesenchymal stem/stromal cells at the origin of these clinical results are heterogenous cell populations with limited cellular characterization. Here, two transgenic reporter mice were used to examine the differential effects of two precisely defined perivascular cell populations (Pdgfrα+ and Pdgfrß+ cells) from white adipose tissue for alleviation of OA. Perivascular mesenchymal cells were isolated from transgenic Pdgfrα-and Pdgfrß-CreERT2 reporter animals and delivered as a one-time intra-articular dose to C57BL/6J mice after destabilization of the medial meniscus (DMM). Both Pdgfrα+ and Pdgfrß+ cell preparations improved metrics of cartilage degradation and reduced markers of chondrocyte hypertrophy. While some similarities in cell distribution were identified within the synovial and perivascular spaces, injected Pdgfrα+ cells remained in the superficial layers of articular cartilage, while Pdgfrß+ cells were more widely dispersed. Pdgfrß+ cell therapy prevented subchondral sclerosis induced by DMM, while Pdgfrα+ cell therapy had no effect. In summary, while both cell therapies showed beneficial effects in the DMM model, important differences in cell incorporation, persistence, and subchondral sclerosis were identified.
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Cartilagem Articular , Osteoartrite , Animais , Cartilagem Articular/patologia , Terapia Baseada em Transplante de Células e Tecidos , Modelos Animais de Doenças , Injeções Intra-Articulares , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoartrite/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Esclerose/metabolismo , Esclerose/patologiaRESUMO
Progenitor cells from adipose tissue are able to induce bone repair; however, inconsistent or unreliable efficacy has been reported across preclinical and clinical studies. Soluble inhibitory factors, such as the secreted Wnt signaling antagonists Dickkopf-1 (DKK1), are expressed to variable degrees in human adipose-derived stem cells (ASCs), and may represent a targetable "molecular brake" on ASC mediated bone repair. Here, anti-DKK1 neutralizing antibodies were observed to increase the osteogenic differentiation of human ASCs in vitro, accompanied by increased canonical Wnt signaling. Human ASCs were next engrafted into a femoral segmental bone defect in NOD-Scid mice, with animals subsequently treated with systemic anti-DKK1 or isotype control during the repair process. Human ASCs alone induced significant but modest bone repair. However, systemic anti-DKK1 induced an increase in human ASC engraftment and survival, an increase in vascular ingrowth, and ultimately improved bone repair outcomes. In summary, anti-DKK1 can be used as a method to augment cell-mediated bone regeneration, and could be particularly valuable in the contexts of impaired bone healing such as osteoporotic bone repair.
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Tecido Adiposo , Anticorpos Neutralizantes , Diferenciação Celular , Peptídeos e Proteínas de Sinalização Intercelular , Osteogênese , Células-Tronco/citologia , Tecido Adiposo/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCIDRESUMO
Tissue resident mesenchymal stem/stromal cells (MSCs) occupy perivascular spaces. Profiling human adipose perivascular mesenchyme with antibody arrays identified 16 novel surface antigens, including endolysosomal protein CD107a. Surface CD107a expression segregates MSCs into functionally distinct subsets. In culture, CD107alow cells demonstrate high colony formation, osteoprogenitor cell frequency, and osteogenic potential. Conversely, CD107ahigh cells include almost exclusively adipocyte progenitor cells. Accordingly, human CD107alow cells drove dramatic bone formation after intramuscular transplantation in mice, and induced spine fusion in rats, whereas CD107ahigh cells did not. CD107a protein trafficking to the cell surface is associated with exocytosis during early adipogenic differentiation. RNA sequencing also suggested that CD107alow cells are precursors of CD107ahigh cells. These results document the molecular and functional diversity of perivascular regenerative cells, and show that relocation to cell surface of a lysosomal protein marks the transition from osteo- to adipogenic potential in native human MSCs, a population of substantial therapeutic interest.
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Adipogenia/genética , Diferenciação Celular/genética , Proteína 1 de Membrana Associada ao Lisossomo/genética , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Adipócitos/metabolismo , Animais , Humanos , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Ratos , Ratos Nus , Células-Tronco/metabolismoRESUMO
The vascular wall stores mesenchymal progenitor cells which are able to induce bone regeneration, via direct and paracrine mechanisms. Although much is known regarding perivascular cell regulation of osteoblasts, their regulation of osteoclasts, and by extension utility in states of high bone resorption, is not known. Here, human perivascular stem cells (PSCs) were used as a means to prevent autograft resorption in a gonadectomy-induced osteoporotic spine fusion model. Furthermore, the paracrine regulation by PSCs of osteoclast formation was evaluated, using coculture, conditioned medium, and purified extracellular vesicles. Results showed that PSCs when mixed with autograft bone induce an increase in osteoblast:osteoclast ratio, promote bone matrix formation, and prevent bone graft resorption. The confluence of these factors resulted in high rates of fusion in an ovariectomized rat lumbar spine fusion model. Application of PSCs was superior across metrics to either the use of unpurified, culture-defined adipose-derived stromal cells or autograft bone alone. Under coculture conditions, PSCs negatively regulated osteoclast formation and did so via secreted, nonvesicular paracrine factors. Total RNA sequencing identified secreted factors overexpressed by PSCs which may explain their negative regulation of graft resorption. In summary, PSCs reduce osteoclast formation and prevent bone graft resorption in high turnover states such as gonadectomy-induced osteoporosis.
Assuntos
Reabsorção Óssea/prevenção & controle , Osteoclastos/patologia , Osteoporose/fisiopatologia , Transplante de Células-Tronco/métodos , Células-Tronco/metabolismo , Transcriptoma/fisiologia , Animais , Feminino , Humanos , Ratos , Ratos NusRESUMO
Perivascular mural cells surround capillaries and microvessels and have diverse regenerative or fibrotic functions after tissue injury. Subsynovial fibrosis is a well-known pathologic feature of osteoarthritis, yet transgenic animals for use in visualizing perivascular cell contribution to fibrosis during arthritic changes have not been developed. Here, inducible Pdgfra-CreERT2 reporter mice were subjected to joint-destabilization surgery to induce arthritic changes, and cell lineage was traced over an 8-week period with a focus on the joint-associated fat pad. Results showed that, at baseline, inducible Pdgfra reporter activity highlighted adventitial and, to a lesser extent, pericytic cells within the infrapatellar fat pad. Joint-destabilization surgery was associated with marked fibrosis of the infrapatellar fat pad, accompanied by an expansion of perivascular Pdgfra-expressing cellular descendants, many of which adopted α-smooth muscle actin expression. Gene expression analysis of microdissected infrapatellar fat pad confirmed enrichment in membrane-bound green fluorescent protein/Pdgfra-expressing cells, along with a gene signature that corresponded with injury-associated fibro-adipogenic progenitors. Our results highlight dynamic changes in joint-associated perivascular fibro-adipogenic progenitors during osteoarthritis.