Osteolytic Damage Research Articles

Epiberberine inhibits bone metastatic breast cancer-induced osteolysis

Ethnopharmacological relevanceThe anti-tumor related diseases of Coptidis Rhizoma (Huanglian) were correlated with its traditional use of removing damp-heat, clearing internal fire, and counteracting toxicity. In the recent years, Coptidis Rhizoma and its components have drawn extensive attention toward their anti-tumor related diseases. Besides, Coptidis Rhizoma is traditionally used as an anti-inflammatory herb. Epiberberine (EPI) is a significant alkaloid isolated from Coptidis Rhizoma, and exhibits multiple pharmacological activities including anti-inflammatory. However, the effect of epiberberine on breast cancer and the inflammatory factors of metastatic breast cancer-induced osteolysis has not been demonstrated clearly. Aim of the studyBone metastatic breast cancer can lead to osteolysis via inflammatory factors-induced osteoclast differentiation and function. In this study, we try to analyze the effect of epiberberine on breast cancer and the inflammatory factors of metastatic breast cancer-induced osteolysis. MethodsTo evaluate whether epiberberine could suppress bone metastatic breast cancer-induced osteolytic damage, healthy female Balb/c mice were intratibially injected with murine triple-negative breast cancer 4T1 cells. Then, we examined the inhibitory effect and underlying mechanism of epiberberine on breast cancer-induced osteoclastogenesis in vitro. Xenograft assay was used to study the effect of epiberberine on breast cancer cells in vivo. Moreover, we also studied the inhibitory effects and underlying mechanisms of epiberberine on RANKL-induced osteoclast differentiation and function in vitro. ResultsThe results show that epiberberine displayed potential therapeutic effects on breast cancer-induced osteolytic damage. Besides, our results show that epiberberine inhibited breast cancer cells-induced osteoclast differentiation and function by inhibiting secreted inflammatory cytokines such as IL-8. Importantly, we found that epiberberine directly inhibited RANKL-induced differentiation and function of osteoclast without cytotoxicity. Mechanistically, epiberberine inhibited RANKL-induced osteoclastogensis via Akt/c-Fos signaling pathway. Furthermore, epiberberine combined with docetaxel effectively protected against bone loss induced by metastatic breast cancer cells. ConclusionsOur findings suggested that epiberberine may be a promising natural compound for treating bone metastatic breast cancer-induced osteolytic damage by inhibiting IL-8 and is worthy of further exploration in preclinical and clinical trials.

Simulation of cancer progression in bone by a virtual thermal flux with a case study on lumbar vertebrae with multiple myeloma

BackgroundTwo main problems examining the mechanism of cancer progression in the tissues using the computational models are lack of enough knowledge on the effective factors for such events in vivo environments and lack of specific parameters in the available computational models to simulate such complicated reactions. MethodsIn this study, it was tried to simulate the progression of cancerous lesions in the bone tissues by an independent parameter from the anatomical and physiological characteristics of the tissues, so to degrade the orthotropic mechanical properties of the bone tissues, a virtual temperature was determined to be used by a well-known framework for simulation of damages in the composite materials. First, the reliability of the FE model to simulate hyperelastic response in the intervertebral discs (IVDs) and progressive failure in the bony components were verified by simulation of some In-Vitro tests, available in the literature. Then, the progression of the osteolytic damage was simulated in a clinical case with multiple myeloma in the lumbar vertebrae. ResultsThe FE model could simulate stress-shielding and diffusion of lesion in the posterior elements of the damaged vertebra which led to spinal stenosis. The load carrying shares associated with the anterior half and the posterior half of the examined vertebral body and the posterior elements were estimated equal to 41 %, 47 % and 12 %, respectively for the intact condition, that changed to 14 %, 16 % and 70 %, when lesion occupied one third of the vertebral body. ConclusionCorrelation of the FE results with the deformation shapes, observed in the MRIs for the clinical case study, indicated appropriateness of the procedure, proposed for simulation of the progressive osteolytic damage in the vertebral segments. The future studies may follow simulation of tumor growth for various metastatic tissues using the method, established here.

Significance of Tim-3 and Its Ligand Galectin-9 in Th1/Th2 Imbalance in Patients with Multiple Myeloma

To investigate the significance of Tim-3 and Galectin-9 in Th1/Th2 imbalance in patients with multiple myeloma (MM). 55 newly diagnosed MM patients and 20 healthy controls were included. Flow cytometry was used to detect the expression of Tim-3 on CD4+T cells, the proportion of Th1, Th2, Tim-3+Th1 and Tim-3+Th2 cells in peripheral blood. ELISA was used to detect the levels of cytokines IFN-γ and IL-4 in serum, and PCR was used to detect the level of Galectin-9 mRNA. Then the correlations between Galectin-9 mRNA expression and Th-cell subsets and related cytokine levels, as well as the relationship between Tim-3+Th1/Tim-3+Th2 ratio and corresponding clinical features were analyzed. Compared with the control group, the expression of Tim-3 on CD4+T cells in peripheral blood of MM patients was significantly increased (P<0.05), the proportions of Tim-3+Th1 cells, Tim-3+Th2 cells and Tim-3+Th1/Tim-3+Th2 ratio in MM patients were also increased (P<0.05), while the proportion of Th1 cells and Th1/Th2 ratio in MM patients were significantly decreased (P<0.05). The level of cytokine IFN-γ and IFN-γ/IL-4 ratio in MM patients were significantly decreased (P<0.05), while the level of cytokine IL-4 was increased (P<0.05). The mRNA levels of Galectin-9 in MM patients were significantly increased (P<0.05). The levels of Galectin-9 mRNA were positively correlated with Tim-3+CD4+T cells (r=0.663), Tim-3+Th2 cells (r=0.492) and IL-4 (r=0.470), while negatively correlated with IFN-γ (r=-0.593). The ratios of Tim-3+Th1/Tim-3+Th2 in MM patients were positively correlated with ISS stage (r=0.511), osteolytic damage (r=0.556) and chromosome abnormality (r=0.632). These results suggest that Tim-3 and Galectin-9 are involved in Th1/Th2 imbalance in MM patients, and the high ratio of Tim-3+Th1/Tim-3+Th2 is associated with poor clinical prognosis.

Radiation Impacts Microbiota Compositions That Activate Transforming Growth Factor-Beta Expression in the Small Intestine

The composition of the gut microbiota represents an early indicator of chronic post-radiation outcomes in elderly bone and gastrointestinal homeostasis. Fecal microbiota analyses revealed that the relative abundances of Bacteroides massiliensis, Muribaculum sp., or Prevotella denticola were different between conventional microbiota (CM) and anti-inflammatory restricted microbiota (RM). The murine RM was found conditional on mucosa-associated dysbiosis under both, disturbances of interleukin (IL)-17 signaling and exposure to radiation alone. This review discusses the hypothesis that intestinal microbiota induced alterations in DNA repair and expressed transforming growth factor (TGF)-β in the small intestine, thereby impacting bone microstructure and osteoblast dysfunction in silicon ion (1.5 Gy 28Si ions of 850 MeV/u) irradiated mice. Bacterial microbiota compositions influenced therapeutic approaches, correlated with clinical outcomes in radiotherapy and were associated with alterations of the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infections during the last global pandemics. In the absence of TGF-β, functional metagenomics, cytokine profiles, bacterial community analyses in human and murine mucosa cells, and inflammatory markers in rat intestines were analyzed. This research finally showed radiation-induced osteolytic damage to correlated with specific features of intestinal bacterial composition, and these relationships were expatiated together with radiation effects on normal tissue cell proliferation.

In vivo antitumor efficacy of 17-AAG loaded PMMA in a human multiple myeloma xenograft mouse model.

Multiple myeloma (MM) is a monoclonal malignancy characterized by abnormal proliferation of plasma cells. The disease clinically manifests as anemia, hypercalcemia, renal insufficiencies, and osteolytic damage. Osteolytic damage goes with severe bone pain, spinal instability, and pathological fracture, symptoms that are collectively referred to as multiple myeloma bone disease (MMBD). Polymethylmethacrylate (PMMA) bone cement is widely used for bone repair after MMBD surgery, owing to its excellent biomechanical properties and fast curing. To date, however, efficacy of drug-loading PMMA in inhibition of tumor growth and angiogenesis remains unknown. Here, we report that 17-AAG-loaded PMMA bone cement inhibits MM growth in vivo and suppresses tumor diffusion to peripheral tissues. In addition, 17-AAG-loaded PMMA promotes MM apoptosis by downregulating Bax and active Caspase-3.

Particle Radiation Side-Effects: Intestinal Microbiota Composition Shapes Interferon-γ-Induced Osteo-Immunogenicity.

Microbiota can both negatively and positively impact radiation-induced bone loss. Our prior research showed that compared to mice with conventional gut microbiota (CM), mice with restricted gut microbiota (RM) reduced inflammatory tumor necrosis factor (TNF) in bone marrow, interleukin (IL)-17 in blood, and chemokine (C-C motif) ligand 20 (CCL20) in bone marrow under anti-IL-17 treatment. We showed that Muribaculum intestinale was more abundant in intestinal epithelial cells (IECs) from the small intestine of female RM mice and positively associated with augmented skeletal bone structure. Female C57BL/6J pun RM mice, which were injected with anti-IL-17 antibody one day before exposure to 1.5 Gy 28Si ions of 850 MeV/u, showed high trabecular numbers in tibiae at 6 weeks postirradiation. Irradiated CM mice were investigated for lower interferon-γ and IL-17 levels in the small intestine than RM mice. IL-17 blockage resulted in bacterial indicator phylotypes being different between both microbiota groups before and after irradiation. Analysis of the fecal bacteria were performed in relation to bone quality and body weight, showing reduced tibia cortical thickness in irradiated CM mice (-15%) vs. irradiated RM mice (-9.2%). Correlation analyses identified relationships among trabecular bone parameters (TRI-BV/TV, Tb.N, Tb.Th, Tb.Sp) and Bacteroides massiliensis, Muribaculum sp. and Prevotella denticola. Turicibacter sp. was found directly correlated with trabecular separation in anti-IL-17 treated mice, whereas an unidentified Bacteroidetes correlated with trabecular thickness in anti-IL-17 neutralized and radiation-exposed mice. We demonstrated radiation-induced osteolytic damage to correlate with bacterial indicator phylotypes of the intestinal microbiota composition, and these relationships were determined from the previously discovered dose-dependent particle radiation effects on cell proliferation in bone tissue. New translational approaches were designed to investigate dynamic changes of gut microbiota in correlation with conditions of treatment and disease as well as mechanisms of systemic side-effects in radiotherapy.

Systemic PPARγ Antagonism Reduces Metastatic Tumor Progression in Adipocyte-Rich Bone in Excess Weight Male Rodents.

Primary tumors are widely associated with an excess in body fat. The role of adipose tissue on tumor cell homing to bone is yet poorly defined. In this study, we aimed to assess whether bone colonization by tumor cells is favored by an adipocyte-rich bone marrow. We delineated the accompanying alterations of the bone microenvironment and established a treatment approach that interferes with high fat diet (HFD)-induced bone metastasis formation. We were able to show that adipocytes affect skeletal tumor growth in a metastatic model of breast cancer in male rats and melanoma in male mice as well as in human breast cancer bone biopsies. Indeed, HFD-induced bone marrow adiposity was accompanied by accelerated tumor progression and increased osteolytic lesions. In human bone metastases, bone marrow adiposity correlated with tumor cell proliferation. By antagonization of the adipocyte differentiation and storage pathway linked to the peroxisome proliferator-activated receptor gamma (PPARγ) with bisphenol-A-diglycidylether (BADGE), we were able to decelerate tumor progression and subsequent osteolytic damage in the bones of two distinct metastatic animal models exposed to HFD. Overall these data show that adipose tissue is a critical factor in bone metastases and cancer-induced bone loss. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Contribution of Scanner in the Breast Cancer Extension Assessment in the Radiology Department of CNHU-HKM in Benin

Objective: Breast cancer is the most common female cancer in the world. The prognosis depends on whether metastasis is present or not. The objective of this study was to provide an overview of the CT scan aspects identified during the evaluation of breast cancer extension in the Radiology department of the Teaching University Hospital of Hubert Koutoukou Maga (CNHU-HKM) in Cotonou in Benin. Materials and methods: It was a descriptive study with retrospective collection, conducted from January 1, 2018 to January 31, 2019 (13 months), in the Radiology department of CNHU-HKM. It focused on patients referred for a chest-abdominal-pelvic computed tomography (PET) scan, as part of an extension assessment for breast cancer. Results: During the period of the study, 40 chest-abdominal-pelvic CT scans were compiled, of which 38 (95%) were women and 02 men (5%), and among which 23 were metastatic, accountings for a prevalence of 57.5%. The average age was 51.22±16.33 with extremes of 30 and 83 years old. Among our patients, 32 (80%) had undergone a CT scan for an initial diagnostic of extension assessment, and 08 (20%) for the therapeutic response assessment. According to the TNM classification, T4 tumors accounted for 27.5% (11 cases). Lymph node involvement was found in 18 cases (43.90%), accounting for 12 (30%) of N1 and 6 (15%) of N3. The most commonly found metastatic sites were the lung in 25% followed by the pleura and the liver with equal percentages (10%). The metastases CT scan aspect was typically a carcinomatous lymphangitis appearance; fluid pleural effusions; hypodenses, hypovascular nodules hepatics; osteolytic or mixed bone damage and peritoneum, especially fluid effusion associated with peritoneal nodules. Conclusion: The frequency of breast cancer metastases is high in Benin. The most commonly found metastatic sites on scanner in descending order are the lungs, liver and bones.

Advancements in nanotechnology for the diagnosis and treatment of multiple myeloma.

Multiple myeloma (MM), known as a tumor of plasma cells, is not only refractory but also has a high relapse rate, and is the second-most common hematologic tumor after lymphoma. It is often accompanied by multiple osteolytic damage, hypercalcemia, anemia, and renal insufficiency. In terms of diagnosis, conventional detection methods have many limitations, such as it is invasive and time-consuming and has low accuracy. Measures to change these limitations are urgently needed. At the therapeutic level, although the survival of MM continues to prolong with the advent of new drugs, MM remains incurable and has a high recurrence rate. With the development of nanotechnology, nanomedicine has become a powerful way to improve the current diagnosis and treatment of MM. In this review, the research progress and breakthroughs of nanomedicine in MM will be presented. Meanwhile, both superiorities and challenges of nanomedicine were discussed. As a new idea for the diagnosis and treatments of MM, nanomedicine will play a very important role in the research field of MM.

Multifunctional melanin-like nanoparticles for bone-targeted chemo-photothermal therapy of malignant bone tumors and osteolysis

Malignant bone tumors associated with aggressive osteolysis are currently hard to be cured by the clinical strategies. Nevertheless, nanomedicine might provide a promising therapeutic opportunity. Here, we developed a multifunctional melanin-like nanoparticle for bone-targeted chemo-photothermal treatment of malignant bone tumors. The particle was originally fabricated from alendronate-conjugated polydopamine nanoparticle (PDA-ALN) that exhibited excellent photothermal effect and high affinity to hydroxyapatite. PDA/Fe-ALN significantly enhanced the magnetic resonance contrast of the bone tumors in vivo, suggesting that more PDA-ALN accumulated at the osteolytic bone lesions in the tumors compared with the non-targeting PDA. Chemodrug SN38 was efficiently loaded on PDA-ALN, and the drug release could be triggered by near-infrared irradiation and acidic stimulus. Finally, the combined chemo-photothermal therapy efficiently suppressed the growth of bone tumors and reduced the osteolytic damage of bones at a mild temperature around 43 °C. This study provides an efficient and robust nanotherapeutics for the treatment of malignant bone tumors.

Concurrent benign metastasizing leiomyoma in the lung and lumbar spine with elevated standardized uptake value level in positron-emission tomography computed tomography

Rationale:Benign metastasizing leiomyoma (BML) is rare condition involving distant metastases secondary to benign uterine leiomyoma, and it is most commonly found in the lungs. It rarely metastasizes to the spine to cause osteolytic damage and spinal canal compression.Patient concerns:A 51-year-old woman with low back and bilateral leg pain and paresthesia was admitted to our ward. She has a previous medical history of uterine leiomyomas. Magnetic resonance imaging of the lumbar spine revealed vertebral body osteolytic destruction and soft tissue mass in the L4/5 with a secondary lumbar spinal stenosis. Positron emission tomography computed tomography showed moderately intense accumulation of 18F-fluorodeoxyglucose in the L4/5 mass, as well as multiple nodules with increased metabolic activity in both lungs.Diagnoses:Pulmonary and spinal BML.Interventions:The patient underwent a computed tomography-guided percutaneous needle biopsy of the lung nodule and lumbar corpectomy, tumor excision, and vertebroplasty in the L4/5.Outcomes:Pathologically, both pulmonary nodule and vertebral mass were diagnosed as leiomyomas without any malignant evidence. Estrogen and progesterone receptors were both positive in the metastatic tumors. The patient's symptoms completely disappeared after the surgery. The patient is currently receiving outpatient anti-estrogen tamoxifen treatment for a BML.Lessons:Through this case, we suggest that BML should be regarded as part of differential diagnosis in female patients with a previous medical history of uterine leiomyomas presenting with multiple nodules in any parts of the body.

Acute Disseminated Talaromyces marneffei in An Immunocompetent Patient

Talaromyces marneffei (also called Penicilliosis Marneffei or T. marneffei) is a rare fungal disease that is prevalent mainly in Southeast Asia and commonly seen in immunocompromised hosts. It was rarely observed in immunocompetent hosts. We report a case of acute disseminated T. marneffei in an immunocompetent patient in the non-prevalent region. This patient had never visited the endemic area. The patient experienced a persistent fever. Brain CT and magnetic resonance imaging (MRI) showed a mass in the right frontal with osteolytic damage. Excessive white blood cell (WBC) count and C-reactive protein content were observed. Antibiotics including meropenem and linezolid could not play an effect, and another two hard masses appeared in his right neck and front chest wall. The aspirates from the right frontal mass and bone marrow were cultured. The final diagnose of this infection was disseminated T. marneffei. After voriconazole treatment, all symptoms improved gradually. We present this case and aim to promote more clinicians and microbiologists in the non-endemic region to recognize this rare disease.

BMP9 inhibits the growth and migration of lung adenocarcinoma A549 cells in a bone marrow stromal cell‑derived microenvironment through the MAPK/ERK and NF-κB pathways.

Bone is the most common distant metastatic site of lung cancer, and is particularly prone to osteolytic damage. Soluble factors secreted from bone marrow-derived cells and tumor cells contribute to the growth and metastasis of cancer cells, and enhance osteolytic damage. BMP9, as the most powerful osteogenetic factor of the bone morphogenetic protein (BMP) family, can regulate the development of various tumors. However, the effects and underlying mechanisms of BMP9 in regards to lung cancer and the bone metastatic microenvironment are poorly understood. Here, we determined the inhibitory effects of BMP9 on the proliferation and migration of lung adenocarcinoma A549 cells. When a co-culture system of A549 cells and bone marrow-derived cells (HS-5) was established, it was shown that HS-5 cells promoted the proliferation and migration of A549 cells, and metastasis and osteoclast-related factors IL-6 and IL-8 were increased in the A549 and HS-5 cells. However, BMP9 inhibited the proliferation and migration of the A549 cells in the bone microenvironment, and decreased the levels of IL-6 andIL-8. In addition, mitogen-activated protein kinase (MAPK/ERK) and nuclear factor-κB (NF-κB) signaling pathway may be involved in these effects.

Variants of Osteoprotegerin Lacking TRAIL Binding for Therapeutic Bone Remodeling in Osteolytic Malignancies.

Osteolytic bone damage is a major cause of morbidity in several metastatic pathologies. Current therapies using bisphosphonates provide modest improvement, but cytotoxic side effects still occur prompting the need to develop more effective therapies to target aggressive osteoclastogenesis. Increased levels of receptor activator of NF-κB ligand (TNFSF11/RANKL), leading to RANKL-RANK signaling, remain the key axis for osteoclast activation and bone resorption. Osteoprotegerin (TNFRSF11B/OPG), a decoy receptor for RANKL, is significantly decreased in patients who present with bone lesions. Despite its potential in inhibiting osteoclast activation, OPG also binds to TNF-related apoptosis-inducing ligand (TNFSF10/TRAIL), making tumor cells resistant to apoptosis. Toward uncoupling the events of TRAIL binding of OPG and to improve its utility for bone remodeling without inducing tumor resistance to apoptosis, OPG mutants were developed by structural homology modeling based on interactive domain identification and by superimposing models of OPG, TRAIL, and its receptor DR5 (TNFRSF10B) to identify regions of OPG for rational design. The OPG mutants were purified and extensively characterized for their ability to decrease osteoclast damage without affecting tumor apoptosis pathway both in vitro and in vivo, confirming their potential in bone remodeling following cancer-induced osteolytic damage. OPG variants were developed that lack TRAIL binding, yet retain RANKL binding and suggest new possibilities for therapeutic targeting in osteolytic malignancies.

BMP9 regulates cross-talk between breast cancer cells and bone marrow-derived mesenchymal stem cells.

Breast cancer cells frequently metastasize to distant organs, including bone. Interactions between breast cancer cells and the bone microenvironment are known to enhance tumor growth and osteolytic damage. Here we investigated whether BMP9 (a secretary protein) may change the bone microenvironment and, by doing so, regulate the cross-talk between breast cancer cells and bone marrow-derived mesenchymal stem cells. After establishing a co-culture system composed of MDA-MB-231 breast cancer cells and HS-5 bone marrow-derived mesenchymal stem cells, and exposure of this system to BMP9 conditioned media, we assessed putative changes in migration and invasion capacities of MDA-MB-231 cells and concomitant changes in osteogenic marker expression in HS-5 cells and metastases-related genes in MDA-MB-231 cells. We found that BMP9 can inhibit the migration and invasion of MDA-MB-231 cells, and promote osteogenesis and proliferation of HS-5 cells, in the co-culture system. We also found that the BMP9-induced inhibition of migration and invasion of MDA-MB-231 cells may be caused by a decreased RANK ligand (RANKL) secretion by HS-5 cells, leading to a block in the AKT signaling pathway. From our data we conclude that BMP9 inhibits the migration and invasion of breast cancer cells, and promotes the osteoblastic differentiation and proliferation of bone marrow-derived mesenchymal stem cells by regulating cross-talk between these two types of cells through the RANK/RANKL signaling axis.

Primary eosinophilic granuloma presenting as bilateral otitis media and mastoiditis

Background: Simultaneous bilateral involvement of the temporal bones is a rare manifestation of eosinophilic granuloma, a disease characterized by solitary or multiple foci of osteolytic damage. Case Presentation: A young child initially presented with bilateral otitis media, with subsequent rapidly developing bilateral masses in the mastoid region. Computed tomography demonstrated extensive bony destruction which, after a course of vinblastine, methotrexate and prednisolone improved dramatically on follow-up scans. Conclusion: We present an unusual case of bilateral temporal bone destruction due to eosinophilic granuloma in a young child along with the literature review.

A preliminary comparative clinical study of vertebroplasty with multineedle or single-needle interstitial implantation of 125I seeds in the treatment of osteolytic metastatic vertebral tumors

Percutaneous vertebroplasty (PVP) combined with brachytherapy using the interstitial implantation of (125)I seeds has previously yielded encouraging clinical results in the treatment of metastatic vertebral tumors. However, the bone cement injection volume is very small due to the osteolytic damage to the metastatic vertebrae, and the ideal spatial distribution of the (125)I seeds is difficult to achieve. In the current study, the authors present a clinical method for puncture needle insertion to achieve a greater bone cement injection volume and a more ideal spatial distribution of the (125)I seeds. Twenty-nine patients with osteolytic metastatic vertebral tumors were divided into 2 groups and were treated with either PVP combined with multineedle interstitial implantation of (125)I seeds, or PVP combined with single-needle interstitial implantation of (125)I seeds. Clinical efficacy was evaluated according to a visual analog scale (VAS) of pain, the Karnofsky Performance Scale (KPS), and the Response Evaluation Criteria In Solid Tumors (RECIST). Back pain was significantly alleviated in all patients after surgery. Compared with the preoperative scores, the VAS scores were significantly decreased in both groups at 1 week and 3 months postoperatively (p < 0.05), but there were no significant intergroup differences (p > 0.05). The postoperative quality of life was improved in both groups; the KPS scores increased significantly compared with the preoperative scores (p < 0.05), and the postoperative KPS scores were significantly different between the 2 groups (p < 0.05). No intergroup differences were observed in pain alleviation, but the bone cement injection volume was significantly greater in the multineedle group than in the single-needle group (p < 0.05). The clinical benefit rate and disease control rate at 3 months after the operation were both significantly better for the multineedle group (p < 0.05). The outcomes of PVP combined with multineedle interstitial implantation of (125)I seeds in patients with osteolytic metastatic vertebral tumors appeared to be better than the outcomes of PVP combined with single-needle interstitial implantation of (125)I seeds. These better outcomes may be the result of the greater bone cement injection volume and the more ideal spatial distribution of the (125)I seeds.

Critical role for inflammasome-independent IL-1β production in osteomyelitis (P6211)

Abstract The immune system plays an important role in the pathophysiology of many acute and chronic bone disorders, but the specific inflammatory networks that regulate individual bone disorders remain to be elucidated. Here, we characterized the osteoimmunological underpinnings of osteolytic bone disease in Pstpip2cmo mice. These mice carry a homozygous L98P missense mutation in the Pombe Cdc15 homology (PCH) family phosphatase PSTPIP2 that is responsible for the development of a persistent autoinflammatory disease resembling chronic recurrent multifocal osteomyelitis (CRMO) in humans. We found that improper regulation of IL-1β production resulted in secondary induction of inflammatory cytokines, inflammatory cell infiltration in the bone and unremitting bone inflammation. Aberrant Il1β expression precedes the development of osteolytic damage in young Pstpip2cmo mice, and genetic deletion of Il1β, but not Il1α, rescued osteolytic bone disease in mutant mice. Intriguingly, caspase-1 activation in the inflammasome complex was dispensable for Pstpip2cmo-mediated bone disease. Thus, our findings establish a critical role for inflammasome-independent production of IL-1β in osteolytic bone disease.

Abstract 2240: Structural variant of osteoprotegerin lacking TRAIL binding for therapeutic bone remodeling in osteolytic malignancies.

Abstract Current treatments for osteolytic cancer pathology include a combination of radiation and chemotherapy, but toxic side effects are still of major concern. Studies have shown that osteoclast activity is increased in patients with osteolytic cancers such as multiple myeloma, breast and prostate cancer through increased expression of Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) leading to RANKL/RANK signaling, resulting in osteoclast activation and ultimately bone resorption. Moreover, Osteoprotegerin (OPG), a decoy receptor for RANKL, is disproportionately expressed in these patients who present with bone lesions. Thus, the use of OPG as a therapeutic molecule would greatly decrease osteolytic damage and reduce morbidity. However, despite the potential of OPG in inhibiting the activation of osteoclast, OPG also binds to tumor necrosis factor related apoptosis-inducing ligand (TRAIL) making tumor cells resistant to apoptosis. TRAIL binds to the Death Receptor 4 and 5 (DR4, DR5) and initiate cell death of transformed cells such as MM. The goals of this study was to designed and develop a therapeutic approach to the treatment of osteolytic bone damage by use of genetically altered OPG retaining RANKL binding but abolished in TRAIL binding. Towards uncoupling the events of TRAIL binding of OPG and to improve its utility for bone remodeling without inducing tumor resistance to apoptosis, we created a genetic variant of OPG through structural homology model based on interactive domain identification and by superimposing structural models of TRAIL, OPG and DR5 to identify regions of OPG for rational design. The mutant OPG (mut-OPG) was purified and extensively characterized for its ability for decreasing osteoclast damage without affecting tumor apoptosis pathway both in vivo and in vitro indicating its potential for therapy targeting bone lesions in osteolytic malignancies. Citation Format: Jerome T. Higgs. Structural variant of osteoprotegerin lacking TRAIL binding for therapeutic bone remodeling in osteolytic malignancies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2240. doi:10.1158/1538-7445.AM2013-2240

Abstract 2143: Anti-TGFβ antibody treatment rescues doxorubicin- mediated bone loss in preclinical osteolytic breast cancer metastasis models.

Abstract Anthracyclines (doxorubicin) are one of the most effective and widely used chemotherapeutic agent for the treatment of several cancer types, including early stage and metastatic breast cancer. However, doxorubicin has been known to cause long-term bone damage and growth defects in patients with childhood cancers, which was also confirmed by several preclinical studies. This raises concern regarding the usage of doxorubicin for the treatment of patients with metastatic breast cancer who are already at increased risk of osteolytic bone damage leading to severe bone loss due to. A number of clinical and preclinical studies have indicated that doxorubicin causes both long term and short term bone damages by lowering bone mineral density, increasing bone loss and may disrupt bone homeostasis by directly affecting bone marrow stem cells, however, the underlying mechanism is poorly understood. We have previously reported that treatment with doxorubicin increases circulating levels of TGFβ, a cytokine which has been implicated in the increase in osteoclast differentiation and survival, suppression of osteoblast differentiation and has been associated with advancement of breast cancer to bone metastasis. We hypothesize, breast cancer patients undergoing doxorubicin treatment will experience accelerated bone loss due to an increase in serum TGFβ levels and blocking TGFβ will rescue this bone loss, at least partially. We have tested the efficacy of anti-TGFβ antibody 1D11, in blocking doxorubicin-mediated bone damage in cardiac injection and orthotopic models of breast cancer to bone metastasis. X-ray image analysis revealed that doxorubicin treatment resulted in an eightfold increase in osteolytic lesion areas (P=0.002) and microCT analysis has shown almost 50% decrease in BV/TV (P=0.0005), in a preclinical murine model metastatic breast cancer. Doxorubicin treatment has also decreased BV/TV in non-tumor bearing animals, suggesting a direct damaging effect of this agent to bone at the sites which are not affected by cancer infestation. As anticipated, treatment with anti-TGFβ antibody 1D11 was able to rescue doxorubicin-mediated bone loss in all three preclinical models tested. At the cellular level, direct effect of doxorubicin treatment on the bone marrow microenvironment included decreased osteoblast survival and reduced mineralized matrix formation and increased osteoclast formation, thereby affecting both bone formation and bone resorption. Taken together, we conclude that, doxorubicin therapy decreases bone formation and increases bone resorption causing additional bone loss in patients with osteolytic bone disease and an anti-TGFβ therapy may be affective in controlling that bone loss. Citation Format: Tapasi Rana, Anwesa Chakrabarti, Michael Freeman, Swati Biswas. Anti-TGFβ antibody treatment rescues doxorubicin- mediated bone loss in preclinical osteolytic breast cancer metastasis models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2143. doi:10.1158/1538-7445.AM2013-2143