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The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).
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Huesos/citología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Intestino Delgado/citología , Células Madre Mesenquimatosas/citología , Animales , Cartílago/metabolismo , Intestino Delgado/metabolismo , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
VISTA (V domain immunoglobulin suppressor of T cell activation, also called PD-1H [programmed death-1 homolog]), a novel immune regulator expressed on myeloid and T lymphocyte lineages, is upregulated in mouse and human idiopathic pulmonary fibrosis (IPF). However, the significance of VISTA and its therapeutic potential in regulating IPF has yet to be defined. To determine the role of VISTA and its therapeutic potential in IPF, the expression profile of VISTA was evaluated from human single-cell RNA sequencing data (IPF Cell Atlas). Inflammatory response and lung fibrosis were assessed in bleomycin-induced experimental pulmonary fibrosis models in VISTA-deficient mice compared with wild-type littermates. In addition, these outcomes were evaluated after VISTA agonistic antibody treatment in the wild-type pulmonary fibrosis mice. VISTA expression was increased in lung tissue-infiltrating monocytes of patients with IPF. VISTA was induced in the myeloid population, mainly circulating monocyte-derived macrophages, during bleomycin-induced pulmonary fibrosis. Genetic ablation of VISTA drastically promoted pulmonary fibrosis, and bleomycin-induced fibroblast activation was dependent on the interaction between VISTA-expressing myeloid cells and fibroblasts. Treatment with VISTA agonistic antibody reduced fibrotic phenotypes accompanied by the suppression of lung innate immune and fibrotic mediators. In conclusion, these results suggest that VISTA upregulation in pulmonary fibrosis may be a compensatory mechanism to limit inflammation and fibrosis, and stimulation of VISTA signaling using VISTA agonists effectively limits the fibrotic innate immune landscape and consequent tissue fibrosis. Further studies are warranted to test VISTA as a novel therapeutic target for the IPF treatment.
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Fibrosis Pulmonar Idiopática , Humanos , Ratones , Animales , Fibrosis Pulmonar Idiopática/metabolismo , Pulmón/patología , Fibrosis , Bleomicina/farmacología , Inflamación/metabolismo , Fibroblastos/metabolismoRESUMEN
Background Osteolytic neoplasms to periacetabular bone frequently cause pain and fractures. Immediate recovery is integral to lifesaving ambulatory oncologic care and maintaining quality of life. Yet, open acetabular reconstructive surgeries are associated with numerous complications that delay cancer treatments. Purpose To determine the effectiveness for short- and long-term pain and ambulatory function following percutaneous ablation, osteoplasty, reinforcement, and internal fixation (AORIF) for periacetabular osteolytic neoplasm. Materials and Methods This retrospective observational study evaluated clinical data from 50 patients (mean age, 65 years ± 14 [SD]; 25 men, 25 women) with osteolytic periacetabular metastases or myeloma. The primary outcome of combined pain and ambulatory function index score (range, 1 [bedbound] through 10 [normal ambulation]) was assessed before and after AORIF at 2 weeks and then every 3 months up to 40 months (overall median follow-up, 11 months [IQR, 4-14 months]). Secondary outcomes included Eastern Cooperative Oncology Group (ECOG) score, infection, transfusion, 30-day readmission, mortality, and conversion hip arthroplasty. Serial radiographs and CT images were obtained to assess the hip joint integrity. The paired t test or Wilcoxon signed-rank test and Kaplan-Meier analysis were used to analyze data. Results Mean combined pain and ambulatory function index scores improved from 4.5 ± 2.4 to 7.8 ± 2.1 (P < .001) and median ECOG scores from 3 (IQR, 2-4) to 1 (IQR, 1-2) (P < .001) at the first 2 weeks after AORIF. Of 22 nonambulatory patients, 19 became ambulatory on their first post-AORIF visit. Pain and functional improvement were retained beyond 1 year, up to 40 months after AORIF in surviving patients. No hardware failures, surgical site infections, readmissions, or delays in care were identified following AORIF. Of 12 patients with protrusio acetabuli, one patient required a conversion hemiarthroplasty at 24 months. Conclusion The ablation, osteoplasty, reinforcement, and internal fixation, or AORIF, technique was effective for short- and long-term improvement of pain and ambulatory function in patients with periacetabular osteolytic neoplasm. © RSNA, 2023.
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Ablación por Catéter , Neoplasias , Masculino , Humanos , Femenino , Anciano , Calidad de Vida , Resultado del Tratamiento , Osteotomía/métodos , Estudios RetrospectivosRESUMEN
Many orthopaedic procedures for osteolytic metastases are performed using surgical techniques and implants that are used in arthroplasties or trauma surgeries. There is a need for development of skeletal metastasis-specific procedures. Massive osteolytic metastases in periacetabular regions are managed with open surgical procedures when radiation and antiresorptive agents fail to prevent development and progression of the lesion. An ideal procedure for osteolytic metastases would decrease cancer burden and stabilize weakened bones for continued ambulatory oncologic care without delay. Therefore, ablation, osteoplasty, reinforcement, and internal fixation (AORIF) is a new alternative percutaneous procedure for osteolytic metastases in pelvis and other periarticular osteolytic metastases. Percutaneously inserted cannulated screws provide a universal portal for catheters for ablation, balloon osteoplasty, and zoledronate-loaded bone cement. AORIF reduces local cancer burden by radiofrequency ablation and improves bone strength immediately with polymethyl methacrylate bone cement for enhanced ambulatory oncologic care. Similar to other reported series of percutaneous reinforcement procedures, AORIF improves ambulatory status for localized bone defects in patients who seek anticancer drug therapies. AORIF does not provide anatomic restoration of established comminuted acetabular fractures or protrusio acetabuli but improves pain and ambulatory status for continued oncologic care. AORIF is a new alternative first-line minimally-invasive procedure for patients with advanced cancers and osteolytic pelvic metastases.
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Neoplasias Óseas , Cementos para Huesos/uso terapéutico , Neoplasias Óseas/cirugía , Fijación Interna de Fracturas/efectos adversos , Humanos , Pelvis , Resultado del TratamientoRESUMEN
The surgical management of acetabular and pelvic lesions due to metastatic bone disease is complex in nature. These patients are typically in a frail state, having severe pain, limited mobility, and impaired wound healing. This causes a potential for complications, a high concern for the surgeon. Compounding these issues is limited life span for these patients given the advancement of the disease. Considerations for patients undergoing surgical treatment are achievement of significant pain relief and restoration of ambulation, all while having minimal complications during the postoperative period. Management may also include nonsurgical and interventional methods. A multidisciplinary approach is required for the successful treatment of these patients. Although there have been various surgical methods described, there is still no standardized modality that has been noted. These lesions often require complex decision making, imaging, and surgical reconstruction.
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Neoplasias Óseas , Procedimientos de Cirugía Plástica , Acetábulo/cirugía , Neoplasias Óseas/cirugía , Humanos , Dolor , Pelvis/cirugíaRESUMEN
Osteoarthritis (OA) is a disease of an entire synovial joint characterized by clinical symptoms and distortion of joint tissues, including cartilage, muscles, ligaments, and bone. Although OA is a disease of all joint tissues, it is a defined accessible compartment and is thus amenable to topical surgical and regenerative therapies, including stem cells. All tissues arise from stem progenitor cells, and the relative capacity of different cellular compartments, and different individuals, to renew tissues into adulthood may be important in the onset of many different degenerative diseases. OA is driven by both mechanical and inflammatory factors, but how these factors affect the proliferation and differentiation of cells into cartilage in vivo is largely unknown. Indeed, our very basic understanding of the physiological cellular kinetics and biology of the stem-progenitor cell unit of the articular cartilage, and how this is influenced by mechano-inflammatory injury, is largely unknown. OA seems, rather deceptively, to be the low-hanging fruit for stem cell therapy. Without the basic understanding of the stem cell and progenitor unit that generate and maintain articular cartilage in vivo, we will continue to waste opportunities to both prevent and manage this disease. In this review, we discuss the biology of chondrogenesis, the stem cell populations that support articular cartilage in health and disease, and future opportunities afforded through the translation of basic articular chondrocyte stem cell biology into new clinical therapies.
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Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Osteoartritis/terapia , Medicina Regenerativa/métodos , HumanosRESUMEN
For osteolytic metastatic disease in the pelvis and acetabulum of patients with unpredictable and limited lifespans, first-line treatment focuses on targeting the primary cancer with anticancer drugs, osteoclastogenesis inhibitors, analgesics, and radiation therapy. Uncontrolled pain and progressive bone destruction refractory to these interventions often warrant surgical stabilization. Conventional open surgical procedures using metal implants or prostheses may provide immediate biomechanical stability but are associated with various complications without local cancer control. Outcomes of conventional open surgical reconstructive procedures depend on local cancer progression and progressive bone loss. Percutaneous cancer ablation and bone augmentation with polymethyl methacrylate cement alone often lack optimal internal fixation and integration with surrounding bone. The current literature demands a multipurpose minimally invasive surgical intervention that provides local cancer control, bone protection, and stabilization. An overview of new, alternative percutaneous procedure consisting of image-guided ablation, balloon osteoplasty, cement reinforcement, and internal fixation, which offers a minimally invasive percutaneous treatment option for patients with osteolytic metastatic cancers with the advantages of concurrent thermal necrotization of cancers, zoledronate-loaded bone cementoplasty, and surgical stabilization in an ambulatory surgery setting, is warranted. Early clinical results have shown that the ablation, balloon osteoplasty, cement reinforcement, and internal fixation is a safe and effective alternative solution for stabilizing and palliating osteolytic lesions in patients seeking new effective therapies in the era of rapidly evolving oncologic care.
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Neoplasias Óseas , Cementoplastia , Osteólisis , Cementos para Huesos/uso terapéutico , Neoplasias Óseas/cirugía , Fijación Interna de Fracturas , Humanos , Osteólisis/etiología , Resultado del TratamientoRESUMEN
PURPOSE: To assess early outcome, safety, and complications of an alternative to open surgical treatments of osteolytic lesions in periarticular load-bearing bones. MATERIALS AND METHODS: A single-center, prospective clinical cohort study of 26 lesions in 23 consecutive patients with painful osteolytic skeletal lesions was performed. Patients were followed for an average of 7 mo (1-18 mo). Lesions were targeted from the most intact bone via minimally invasive percutaneous approach for stable anchorage of internal fixation screws using fluoroscopic guidance. Cannulated screws served as universal portals for ablation, balloon osteoplasty, and delivery of bone cement in addition to internal fixation for cement anchoring and prophylactic stabilization of uninvolved bone. RESULTS: There were 19 osteolytic lesions in the pelvis, 4 in the proximal femur, 2 in the proximal tibia, and 1 in the calcaneus. All defects were associated with severe pain or fractures. There were no conversions to open surgery and no infection or bleeding requiring transfusion, embolization, or additional procedures. There was significant improvement in visual analogue scale (VAS) pain score from 8.32 ± 1.70 to 2.36 ± 2.23, combined pain and functional ambulation score from 4.48 ± 2.84 to 7.28 ± 2.76, and Musculoskeletal Tumor Society score from 45% to 68% (P < .05). CONCLUSIONS: Ablation, osteoplasty, reinforcement, and internal fixation is a safe and effective minimally invasive percutaneous image-guided treatment option for functional improvement or palliation of painful osteolytic lesions in the pelvis and periarticular loadbearing bones.
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Técnicas de Ablación , Cementos para Huesos/uso terapéutico , Neoplasias Óseas/cirugía , Calcáneo/cirugía , Cementoplastia , Fémur/cirugía , Fijación Interna de Fracturas , Osteólisis/cirugía , Huesos Pélvicos/cirugía , Tibia/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Cementos para Huesos/efectos adversos , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/fisiopatología , Remodelación Ósea , Tornillos Óseos , Calcáneo/diagnóstico por imagen , Calcáneo/fisiopatología , Cementoplastia/efectos adversos , Femenino , Neoplasias Femorales/diagnóstico por imagen , Neoplasias Femorales/fisiopatología , Neoplasias Femorales/cirugía , Fémur/diagnóstico por imagen , Fémur/fisiopatología , Fijación Interna de Fracturas/efectos adversos , Fijación Interna de Fracturas/instrumentación , Humanos , Masculino , Persona de Mediana Edad , Osteólisis/diagnóstico por imagen , Osteólisis/fisiopatología , Huesos Pélvicos/diagnóstico por imagen , Huesos Pélvicos/fisiopatología , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Recuperación de la Función , Tibia/diagnóstico por imagen , Tibia/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Soporte de PesoRESUMEN
Advancements in medical and radiation oncology have improved the prognosis for many cancers during the past few decades. As a result, physicians are challenged with managing a greater burden of disease for a longer time. In orthopaedics, bone loss secondary to metastatic tumor places patients at risk of impending and pathologic fractures. These events limit functional independence, lessen the quality of life, and place a financial burden on patients and their families. Thus, it is important for clinicians to be aware of measures capable of mitigating cancer-induced bone loss.
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Fracturas Espontáneas , Procedimientos Ortopédicos , Quimioterapia , Humanos , Pronóstico , Calidad de Vida , Radioterapia/efectos adversosRESUMEN
Metastatic bone disease is a substantial driver of morbidity and mortality in many cancers. The presence of bone metastases often indicates a worse prognosis for patients. The mechanisms underlying bone metastases and bone loss are complex and involve interaction between the local factors controlling bone remodeling, systemic regulators, cancer cells, the immune system, and pharmaceutical agents. Cancer cells hone to and initiate interactions with bone cells, thereby resulting in an increase or decrease of local bone mass. Osteolytic metastases are clinically important because they place patients at risk of skeletally related events. In the era of precision medicine and targeted therapies, several pathways have been identified that can serve as targets for new drugs. Therefore, it becomes necessary to understand the molecular mechanisms governing normal bone homeostasis and cancer-induced bone loss to optimally use available and emerging therapeutic modalities for the benefit of patients with skeletal metastases. When pharmacologic or radiation therapies do not block the pathogenesis of metastatic cancer-induced bone loss, surgical stabilization and reinforcement procedures are performed based on size of the lesion, location, degree of osteolysis, and pain. These interventions are performed with the goal of improving patient function and overall outcome.
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Neoplasias Óseas , Humanos , PronósticoRESUMEN
Skeletal metastases of the femur and tibia leading to pathologic fractures or large skeletal defects can be managed with surgical reconstruction, resulting in improved patient outcomes and functionality. The indications for femoral and tibial reconstruction are dependent on several factors, including goals of management, age, comorbidities, site and extent of the lesion, soft-tissue involvement, and history of radiation or other systemic therapy. The goal of reconstruction of large bone defects is to restore anatomy and function while minimizing the risk of complications, implant failure, and subsequent revision procedure. Common reconstructive options include fixation with plates and screws, intramedullary nails, and endoprosthesis implantation.
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Fracturas del Fémur , Fijación Intramedular de Fracturas , Fracturas de la Tibia , Fracturas Espontáneas , Humanos , Complicaciones Posoperatorias , Tibia , Resultado del TratamientoRESUMEN
Tendon stem/progenitor cells (TSCs) have been found in different anatomic locations and showed a promising regenerative potential. We identified a role of TSCs in the regulation of inflammation during healing of acute tendon injuries. Delivery of connective tissue growth factor (CTGF) into full-transected rat patellar tendons significantly increased the number of CD146+ TSCs, leading to enhanced healing. In parallel, CTGF delivery significantly reduced the number of iNOS+ M1 macrophages and increased the expression of anti-inflammatory IL-10 at 2 d after surgery, with over 85% CD146+ TSCs expressing IL-10. By 1 wk, the elevated IL-10 expression remained, and IL-6 expression was significantly attenuated in CTGF-delivered tendon healing. Matrix metalloproteinase (MMP)-3 expression in CTGF-delivered tendon was organized along with the reorienting collagen fibers by 1 wk after surgery, in comparison with the control group showing the abundant MMP-3 expression localized at healing junction. Tissue inhibitor of metalloprotease (TIMP)-3 was expressed in CD146+ TSCs at 1 wk with CTGF, in contrast to control with no TIMP-3 expression. In vitro, IL-10 expression was detected only when tendon cells were stimulated with IL-1ß, and CTGF and significantly higher in CD146+ TSCs than CD146- tendon cells. Similarly, TIMP-3 expression was detected only when treated with CTGF or CTGF and IL-1ß that is significantly higher in CD146+ TSCs compared to CD146- tendon cells. Signaling study with specific inhibitors and Western blot analysis demonstrated that CTGF-induced expression of IL-10 and TIMP-3 in CD146+ TSCs are regulated by JNK/signal transducer and activator of transcription 3 signaling. Taken together, these findings suggest anti-inflammatory roles of CTGF-stimulated TSCs that are likely associated with improved tendon healing.-Tarafder, S., Chen, E., Jun, Y., Kao, K., Sim, K. H., Back, J., Lee, F. Y., Lee, C. H. Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling.
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Inflamación/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Factor de Transcripción STAT3/metabolismo , Tendones/citología , Animales , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Regulación de la Expresión Génica/fisiología , MAP Quinasa Quinasa 4/genética , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3/genética , Transducción de Señal , Células Madre , Traumatismos de los Tendones , Inhibidor Tisular de Metaloproteinasa-3/genética , Inhibidor Tisular de Metaloproteinasa-3/metabolismoRESUMEN
The future of cancer treatment is promising. Although marred by years of plateau in outcomes, new avenues have been identified that are poised to change how we treat cancer. Molecular targeted therapy or targeted therapy is one of these methods. Molecular targeted therapy involves identifying specific pathways or markers that allow cancer cells to flourish. Once identified, specific molecules can be used to block proliferative pathways, thereby negatively impacting tumor growth. Targeting specific pathways that prolong the survival of the cancer cell can lead to a decreased cancer burden, and improved patient outcomes. This article reviews the tenets of molecular targeted therapy, common pathways, target acquisition for drug development, and the pathways that have been elucidated in musculoskeletal tumors.
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This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.
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Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Benzodiazepinonas/administración & dosificación , Benzodiazepinonas/farmacología , Receptores Notch/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Benzodiazepinonas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Receptores Notch/metabolismo , Relación Estructura-ActividadRESUMEN
Chemotherapy is the mainstay of treatment for numerous cancer types, but resistance to chemotherapy remains a major clinical issue and is one of the driving influences underlying the development of new anticancer medications. One of the most important classes of chemotherapy agents is the taxanes, which target the cytoskeleton and spindle apparatus of tumor cells by binding to the microtubules, thereby disrupting key cellular mechanisms, including mitosis. Taxane resistance, however, limits treatment options and creates a major challenge for clinicians. Ongoing research has identified several newer classes of microtubule-targeting chemotherapies that may retain activity despite clinical resistance to taxanes. Among these classes, the epothilones have been studied most extensively in the clinical setting. Like taxanes, epothilones stabilize microtubulin turnover, and they have properties favoring their development as anticancer agents. The most clinically advanced epothilone analog is ixabepilone, which is currently the only approved epothilone derivative. Ixabepilone is indicated for the treatment of metastatic or locally advanced breast cancer in combination with capecitabine after failure of an anthracycline and a taxane, or as monotherapy after failure of an anthracycline, a taxane, and capecitabine. In phase II and III trials, ixabepilone showed efficacy in several patient subgroups and in various stages of breast cancer. Common adverse reactions include peripheral sensory neuropathy and asthenia. This paper will discuss the preclinical and clinical development of epothilones and their derivatives across a variety of cancer types.
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Antineoplásicos/uso terapéutico , Epotilonas/uso terapéutico , Neoplasias/tratamiento farmacológico , Moduladores de Tubulina/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Descubrimiento de Drogas , Resistencia a Antineoplásicos , Epotilonas/química , Epotilonas/farmacología , Femenino , Humanos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Mitosis/fisiología , Metástasis de la Neoplasia , Neoplasias/patología , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
Bone extracellular matrix (ECM) has been shown to mimic aspects of the tissue's complex microenvironment, suggesting its potential role in promoting bone repair. However, current ECM-based therapies suffer from limitations such as inefficient scale-up, lack of mechanical integrity, and sub-optimal efficacy. Here, we fabricated hydrogels from decellularized ECM (dECM) from wild type (WT) and thrombospondin-2 knock-out (TSP2KO) mouse bones. TSP2KO bone ECM hydrogel was found to have distinct mechanical properties and collagen fibril assembly from WT. Furthermore, TSP2KO hydrogel promoted mesenchymal stem cell (MSC) attachment, spreading, and invasion in vitro. Similarly, it promoted formation of tube-like structures by human umbilical vein endothelial cells (HUVECs). When applied to a murine calvarial defect model, TSP2KO hydrogel enhanced repair, in part, due to increased angiogenesis. Our study suggests the pro-angiogenic therapeutic potential of TSP2KO bone ECM hydrogel in bone repair. STATEMENT OF SIGNIFICANCE: The study describes the first successful preparation of a novel hydrogel made from decellularized bones from wild-type mice and mice lacking thrombospondin-2 (TSP2). Hydrogels from TSP2 knock-out (TSP2KO) bones have unique characteristics in structure and biomechanics. These gels interacted well with cells in vitro and helped repair damaged bone in a mouse model. Therefore, TSP2KO bone-derived hydrogel has translational potential for accelerating repair of bone defects that are otherwise difficult to heal. This study not only creates a new material with promise for accelerated healing, but also validates tunability of native biomaterials by genetic engineering.
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Intramedullary nailing insertion from the proximal-to-distal femur is frequently performed for impending and complete pathological femur fractures due to osteolytic metastases. After nailing through cancer-laden bone, residual chemotherapy- and/or radiation-resistant tumor may progress. Progression of osteolysis risks future nail failure or pathological fractures. This study assesses the incidence of cancer progression following intramedullary nailing in a femur-only cohort and describes a percutaneous rod-retaining salvage technique. A single-institution, retrospective study was conducted to identify adult patients who underwent intramedullary nailing for femoral osteolytic lesions for complete or impending nail failure from 2016 to 2023. Progression was defined as enlargement of the pre-existing lesion and/or appearance of new lesions on radiographs. Surgical outcomes were assessed with a combined pain and functional score. A total of 113 patients (median age 66.8 years (IQR = 16.4); median follow-up 6.0 months (IQR = 14.5)) underwent intramedullary nailing. Sixteen patients (14.2%) exhibited post-nailing cancer progression. Pre- and postoperative radiation and chemotherapy did not decrease the odds of cancer progression. Three patients underwent initial open surgical salvage consisting of proximal femur replacement arthroplasty, and six patients did not receive salvage due to poor surgical candidacy or patient choice. Seven patients (median follow-up 10.7 months (IQR = 12.9)) received percutaneous salvage. In this group, pain and functional scores improved by 4.0 points (p = 0.0078) at two-week postoperative follow-up and 2.0 points (p = 0.0312) at the most recent follow-up (mean follow-up 13.0 ± 9.4 months). All three nonambulatory patients became ambulatory, and six patients were able to ambulate independently without walking aids. No major complications were reported 30 days postoperatively. Progression of femoral osteolytic metastases may occur following intramedullary nailing. Continued monitoring of the entire femur is needed to maintain improved functional status and to prevent catastrophic progression of pre-existing lesions or appearance of new lesions. In patients with more proximal metastases only, the customary practice of bringing a long nail from the proximal femur to distal metaphysis should be reconsidered. Furthermore, there is concern of mechanical transport of cancer cells during guide wire insertion, reaming, and rod insertion through cancer laden bone to cancer free distal bone.
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Fracture callus formation is a dynamic stage of bone activity and repair with precise, spatially localized gene expression. Metastatic breast cancer impairs fracture healing by disrupting bone homeostasis and imparting an altered genomic profile. Previous sequencing techniques such as single-cell RNA and in situ hybridization are limited by missing spatial context and low throughput, respectively. We present a preliminary approach using the Visium CytAssist spatial transcriptomics platform to provide the first spatially intact characterization of genetic expression changes within an orthopedic model of impaired fracture healing. Tissue slides prepared from BALB/c mice with or without MDA-MB-231 metastatic breast cancer cells were used. Both unsupervised clustering and histology-based annotations were performed to identify the hard callus, soft callus, and interzone for differential gene expression between the wild-type and pathological fracture model. The spatial transcriptomics platform successfully localized validated genes of the hard (Dmp1, Sost) and soft callus (Acan, Col2a1). The fibrous interzone was identified as a region of extensive genomic heterogeneity. MDA-MB-231 samples demonstrated downregulation of the critical bone matrix and structural regulators that may explain the weakened bone structure of pathological fractures. Spatial transcriptomics may represent a valuable tool in orthopedic research by providing temporal and spatial context.
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Callo Óseo , Fracturas del Fémur , Ratones , Animales , Callo Óseo/metabolismo , Callo Óseo/patología , Fracturas del Fémur/patología , Curación de Fractura , Perfilación de la Expresión GénicaRESUMEN
Tau is a microtubule (MT)-stabilizing protein that is altered in Alzheimer's disease (AD) and other tauopathies. It is hypothesized that the hyperphosphorylated, conformationally altered, and multimeric forms of tau lead to a disruption of MT stability; however, direct evidence is lacking in vivo. In this study, an in vivo stable isotope-mass spectrometric technique was used to measure the turnover, or dynamicity, of MTs in brains of living animals. We demonstrated an age-dependent increase in MT dynamics in two different tau transgenic mouse models, 3xTg and rTg4510. MT hyperdynamicity was dependent on tau expression, since a reduction of transgene expression with doxycycline reversed the MT changes. Treatment of rTg4510 mice with the epothilone, BMS-241027, also restored MT dynamics to baseline levels. In addition, MT stabilization with BMS-241027 had beneficial effects on Morris water maze deficits, tau pathology, and neurodegeneration. Interestingly, pathological and functional benefits of BMS-241027 were observed at doses that only partially reversed MT hyperdynamicity. Together, these data suggest that tau-mediated loss of MT stability may contribute to disease progression and that very low doses of BMS-241027 may be useful in the treatment of AD and other tauopathies.
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Trastornos del Conocimiento/tratamiento farmacológico , Epotilonas/uso terapéutico , Microtúbulos/patología , Degeneración Nerviosa/tratamiento farmacológico , Tauopatías/tratamiento farmacológico , Moduladores de Tubulina/uso terapéutico , Proteínas tau/fisiología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Doxiciclina/farmacología , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/psicología , Epotilonas/farmacología , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microtúbulos/efectos de los fármacos , Tauopatías/complicaciones , Tauopatías/genética , Tauopatías/patología , Tauopatías/psicología , Moduladores de Tubulina/farmacología , Proteínas tau/antagonistas & inhibidores , Proteínas tau/biosíntesis , Proteínas tau/genéticaRESUMEN
The interface between bone tissue and metal implants undergoes various types of mechanical loading, such as strain, compression, fluid pressure, and shear stress, from daily activities. Such mechanical perturbations create suboptimal environments at the host bone-implant junction, causing an accumulation of wear particles and debilitating osseous integration, potentially leading to implant failure. While many studies have focused on the effect of particles on macrophages or osteoprogenitor cells, differential and combined effects of mechanical perturbations and particles on such cell types have not been extensively studied. In this study, macrophages and osteoprogenitor cells were subjected to physiological and superphysiological mechanical stimuli in the presence and absence of Ti particles with the aim of simulating various microenvironments of the host bone-implant junction. Macrophages and osteoprogenitor cells were capable of engulfing Ti particles through actin remodeling and also exhibited changes in mRNA levels of proinflammatory cytokines under certain conditions. In osteoprogenitor cells, superphysiological strain increased proinflammatory gene expression; in macrophages, such mechanical perturbations did not affect gene expression. We confirmed that this phenomenon in osteoprogenitor cells occurred via activation of the ERK1/2 signaling pathway as a result of damage to the cytoplasmic membrane. Furthermore, AZD6244, a clinically relevant inhibitor of the ERK1/2 pathway, mitigated particle-induced inflammatory gene expression in osteoprogenitor cells and macrophages. This study provides evidence of more inflammatory responses under mechanical strains in osteoprogenitor cells than macrophages. Phagocytosis of particles and mechanical perturbation costimulate the ERK1/2 pathway, leading to expression of proinflammatory genes.