Development Of Bone Tumors Research Articles

The clinical significance of CD44v6 in malignant and benign primary bone tumors

BackgroundThe objective of this study was to assess the expression profile of CD44v6, a potential cancer stem cell marker, and its diagnostic and predictive significance in three distinct types of primary bone tumors.MethodsIn this study, we utilized real-time qRT-PCR and immunohistochemistry to examine the gene and protein levels of CD44v6 in a total of 138 fresh bone tissues. This included 69 tumor tissues comprising osteosarcoma (N = 23), chondrosarcoma (N = 23), and GCT (N = 23), as well as 69 corresponding non-cancerous tumor margins. Furthermore, we investigated the circulating level of CD44v6 by isolating peripheral blood mononuclear cells from 92 blood samples. Among these, 69 samples were obtained from patients diagnosed with primary bone tumors, while the remaining 23 samples were from healthy donors. The primary objectives of our investigation were to assess the correlation between CD44v6 expression levels and clinic-pathological features of the patients, as well as to evaluate the diagnostic and predictive values of CD44v6 in this context.ResultsIn patients with osteosarcoma and chondrosarcoma tumors, both the gene and protein expression of CD44v6 were found to be significantly higher compared to the GCT group. Furthermore, the circulating level of CD44v6 was notably elevated in patients diagnosed with osteosarcoma and chondrosarcoma in comparison to the GCT group and patients with malignant tumor characteristics. Additionally, we observed a strong correlation between the gene and protein levels of CD44v6 and important tumor indicators such as tumor grade, metastasis, recurrence, and size at the tumor site. CD44v6 shows potential in differentiating patients with bone tumors from both control groups and tumor groups with severe and invasive characteristics from those with non-severe features. Importantly, the expression level of CD44v6 also demonstrated predictive value for determining tumor grade and the likelihood of recurrence.ConclusionCD44v6 is likely to play a role in the development of primary bone tumors and has the potential to serve as a diagnostic biomarker for bone cancer. However, to obtain more accurate and conclusive findings, further mechanistic investigations involving larger population samples are necessary.

Signal Pathways and microRNAs in Osteosarcoma Growth and the Dual Role of Mesenchymal Stem Cells in Oncogenesis.

The major challenges in Osteosarcoma (OS) therapy are its heterogeneity and drug resistance. The development of new therapeutic approaches to overcome the major growth mechanisms of OS is urgently needed. The search for specific molecular targets and promising innovative approaches in OS therapy, including drug delivery methods, is an urgent problem. Modern regenerative medicine focuses on harnessing the potential of mesenchymal stem cells (MSCs) because they have low immunogenicity. MSCs are important cells that have received considerable attention in cancer research. Currently, new cell-based methods for using MSCs in medicine are being actively investigated and tested, especially as carriers for chemotherapeutics, nanoparticles, and photosensitizers. However, despite the inexhaustible regenerative potential and known anticancer properties of MSCs, they may trigger the development and progression of bone tumors. A better understanding of the complex cellular and molecular mechanisms of OS pathogenesis is essential to identify novel molecular effectors involved in oncogenesis. The current review focuses on signaling pathways and miRNAs involved in the development of OS and describes the role of MSCs in oncogenesis and their potential for antitumor cell-based therapy.

Clinical case of treatment of secondary chondrosarcoma developed due to Ollier disease

Ollier disease is a rare non-hereditary disorder of the bone tissue characterized by development of multiple benign bone tumors – enchondromas. One of the dangerous complications of this pathology is tumor transition into chondrosarcoma. Currently, there are no drug therapies for Ollier disease. Surgical treatment is performed in case of complications (chondrosarcoma, pathological fracture).The article presents a clinical case of chondrosarcoma treatment in a 42-year-old male with Ollier disease diagnosed when the patient was 8 years old. Since 2021, the patient noted intensive tumor growth on the right foot and left calf. In August of 2022, the patient sought medical help at the Republican Clinical Oncological Dispensary of the Bashkortostan Ministry of Health. Examination showed synchronous malignant transformation of enchondromas of the right foot and left calf confirmed by histological exam. Due to tumor advancement, surgical treatment was performed. Other enchondroma lesions are being watched.

Effects of Interferon-γ and Interleukin-4 on Proliferating Cell Nuclear Antigen Expression in Transplanted Bone Tumor Tissue

The rabbit VX2 bone tumor model is an ideal animal model for studying malignant bone tumors. Cytokines have been reported to play a role in tumor initiation and promotion, angiogenesis, and metastasis. However, few studies have investigated the relationship between cytokines and VX2 bone tumor development. This study investigated the effect of interferon-γ (IFN-γ) and interleukin-4 (IL-4) on proliferating cell nuclear antigen (PCNA) expression in tumor tissue. Thirty Japanese white rabbits were randomly divided into group A (n = 15) and group B (n = 15). The rabbit VX2 bone tumor model was constructed by implanting VX2 tumors on the medial side of the upper tibia. Group A was sacrificed in the first week of implantation, and group B in the second week of implantation. Peripheral venous blood, tumor tissue from the medullary cavity at the implantation site, and surrounding bone and soft tissue were harvested before implantation and execution in both experimental groups. IFN-γ and IL-4 expression levels in peripheral blood and PCNA levels in tumor tissues were measured by enzyme-linked immunosorbent assay (ELISA). The tumor tissue of the medullary cavity and surrounding bone and soft tissue was harvested for pathological examination. By the end of the experiment, 30 rabbits were included in the study. There was no significant difference in IFN-γ, IL-4 and PCNA expression levels in group A compared to group B before implantation (t = 1.187, p value = 0.255; t = 1.282, p value = 0.221; t = 0.499, p value = 0.626). IFN-γ and IL-4 expression levels before execution in group A were not significantly different from those before implantation (t = -1.280, p value = 0.213; t = 0.952, p value = 0.349), and PCNA expression levels were higher than those before implantation (t = 2.469, p value = 0.020). Group B had significantly lower IFN-γ expression levels before execution than before implantation (t = -3.741, p value = 0.001) and significantly higher IL-4 and PCNA expression levels before execution than before implantation (t = 6.279, p value < 0.01; t = 13.031, p value < 0.001). IFN-γ expression levels before execution in group B was significantly lower than those before execution in group A (t = 17.184, p value < 0.001), and IL-4 and PCNA expression before execution in group B was significantly higher than that before execution in group A (t = -26.235, p value < 0.001; t = -24.619, p value < 0.001). The correlation between IFN-γ and PCNA levels before execution in groups A and B was negative (r = -0.566, p value = 0.028; r = -0.604, p value = 0.017), and the correlation between IL-4 and PCNA levels was positive (r = 0.583, p value = 0.023; r = 0.884, p value < 0.001). In the rabbit VX2 bone tumor model, extending the period of time after tumor implantation resulted in a negative correlation between IFN-γ and PCNA levels and a positive correlation between IL-4 and PCNA levels.

A Review on Adaptive Hierarchy Segmentation of Bone Cancer Using Neural Network in MATLAB

Abstract: Medical imaging is critical in the diagnosis and treatment of illness, the detection of tumours and the early detection of malignant cells. Microscopic pictures have traditionally been used to detect bone characteristics as a conventional technique. Using micro radiography, which requires several exposures and is labor-intensive, these pictures were captured. This method is unable to distinguish between malignant and non-cancerous cells since the pictures are filled with noise. Image processing analysis has to be automated and dependable in order to be effective. Denoising is the initial step in image processing, and it must be done without interfering with the diagnostic information in the process. Noise and blur are introduced in the picture during the earlier step. We've built soft and hard threshold with a variety of coefficients and measured the threshold in order to obtain exact picture processing. Pre-processing approaches for removing noise and obtaining smooth pictures were discussed throughout our presentation. The picture quality will be improved and false segments will be removed as a result of this procedure. The K-means method was used to identify the presence of bone cancer and to assess its stage, while edge segmentation was employed to smooth out the image. GA analysis relies heavily on the ability to discriminate between benign and malignant bone tumour development. The primary goal of our study was to accurately forecast or identify bone tumours at the appropriate time and stage. Using our image processing and genetic method, we were able to accurately identify bone tumours, which would then aid in the right treatment of therapy. Keywords: Cancer, bone cancer, osteosarcoma, Ewing, image segmentation, edge based segmentation, region based segmentation

A radiological diagnostic approach to tumours and tumour-like lesions of the calcaneus.

The calcaneus is a rare location for the development of primary bone tumours. The purpose of the study is to review the imaging findings in a cohort of patients presenting with tumours and tumour-like lesions of the calcaneus and to develop a more structured approach to the diagnosis of calcaneal lesions. A retrospective study with a collection of 167 cases of calcaneal tumours and tumour-like lesions from our tertiary orthopaedic oncology institution over a period of 13 years. Cases were reviewed by two consultant musculoskeletal radiologists and the location of the lesion within the calcaneus and demographics of the patient were noted for each case. A diagnostic algorithm, which is based on patient age and tumour location, was then extrapolated. Out of the 167 cases, we identified 24 different calcaneal pathologies which included both tumours and tumour-like lesions. The most common being simple bone cysts (18.3% of cases) and intra-osseous lipoma (15% of cases) sited in the diaphyseal equivalent of the calcaneus. A diagnostic algorithm was formulated, which describes the most common location of the different pathologies including both benign and malignant pathologies, subdivided by age. Our algorithm should help the radiologist narrow down the differential diagnosis when evaluating calcaneal lesions. This article provides a radiological approach to calcaneal lesions.

Gene expression profiling utilizing extremely sensitive CDNA arrays and enrichment-based network study of major bone cancer genes.

Background:The gene interaction network is a set of genes interconnected by functional interactions among the genes. The gene interaction networks are studied to determine pathways and regulatory mechanisms in model organisms. In this research, the enrichment study of bone cancer-causing genes is undertaken to identify several hub genes associated to the development of bone cancer.Materials and Methods:Data on bone cancer is obtained from mutated gene samples; highly mutated genes are selected for the enrichment analysis. Due to certain interactions with each other the interaction network model for the hub genes is developed and simulations are produced to determine the levels of expression. For the array analyses, a total of 100 tumor specimens are collected. Cell cultures are prepared, RNA is extracted, cDNA arrays probes are generated, and the expressions analysis of Hub genes is determined.Results:Out of cDNA array findings, only 7 genes: CDKN2A, AKT1, NRAS, PIK3CA, RB1, BRAF, and TP53 are differentially expressed and shown as significant in the development of bone tumors, approximately 15 pathways have been identified, including pathways for non-small cell lung cancer, prostate cancer, pancreatic cancer, chronic myeloid leukemia, and glioma, consisting of all the identified 7 genes. After clinical validations of tumor samples, the IDH1 and TP53 gene revealed significant number of mutations similar to other genes. Specimens analysis showed that RB1, P53, and NRAS are amplified in brain tumor, while BRAF, CDKN2A, and AKT1 are amplified in sarcoma. Maximum deletion mutations of the PIK3CA gene are observed in leukemia. CDKN2A gene amplifications have been observed in virtually all tumor specimens.Conclusion:This study points to a recognizable evidence of novel superimposed pathways mechanisms strongly linked to cancer.

A Correlation Between Intracellular Zinc Content and Osteosarcoma.

Zinc is a trace element in human body involved in many biological processes. It is critical for cell growth and acts as a cofactor for the structure and function of a wide range of cellular proteins such as enzymes. Mounting evidence has shown the involvement of intracellular zinc in the bone-related biological processes such as bone growth, homeostasis, and regeneration; however, the molecular mechanism(s) whereby zinc impels tumorigenesis in bone remains largely unexplored. In this article, selective outline related to the content of intracellular zinc in osteosarcoma cells was provided, and its correlation with signaling molecules that are activated and consequently guide the cells toward tumorigenesis or osteogenesis was discussed. Based on preclinical and clinical evidence, dysregulation of zinc homeostasis, both at intracellular and tissue level, has the main role in the pathogenesis of osteosarcoma. Based on the intracellular zinc content, this element could have a direct role in the dynamics of bone cell transformation and tumor development and play an indirect role in the modulation of the inflammatory and pro/antitumorigenic responses in immune cells. In this context, zinc transporters and the proteins containing zinc domain are regulated by the availability of zinc, playing a crucial role in bone cell transformation and differentiation. According to recent studies, it seems that intracellular zinc levels could be considered as an early prognosis marker. Besides, identification and targeting of zinc-dependent signaling molecules could tilt the balance of life and death toward the latter in chemoresistant malignant cells and may pave a way for designing of the novel osteosarcoma treatment strategies.

Antagonistic Functions of Connexin 43 during the Development of Primary or Secondary Bone Tumors

Despite research and clinical advances during recent decades, bone cancers remain a leading cause of death worldwide. There is a low survival rate for patients with primary bone tumors such as osteosarcoma and Ewing’s sarcoma or secondary bone tumors such as bone metastases from prostate carcinoma. Gap junctions are specialized plasma membrane structures consisting of transmembrane channels that directly link the cytoplasm of adjacent cells, thereby enabling the direct exchange of small signaling molecules between cells. Discoveries of human genetic disorders due to genetic mutations in gap junction proteins (connexins) and experimental data using connexin knockout mice have provided significant evidence that gap-junctional intercellular communication (Gj) is crucial for tissue function. Thus, the dysfunction of Gj may be responsible for the development of some diseases. Gj is thus a main mechanism for tumor cells to communicate with other tumor cells and their surrounding microenvironment to survive and proliferate. If it is well accepted that a low level of connexin expression favors cancer cell proliferation and therefore primary tumor development, more evidence is suggesting that a high level of connexin expression stimulates various cellular process such as intravasation, extravasation, or migration of metastatic cells. If so, connexin expression would facilitate secondary tumor dissemination. This paper discusses evidence that suggests that connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and secondary bone tumors as a tumor promoter.

New oncogenic signalling pathway: EWS‐Oct4 mediates bone and soft tissue tumourigenesis by activating fibroblast growth factor‐4

Chromosomal translocations involving the interchange of parts between two non-homologous chromosomes can often lead to cancer by creating new fusion proteins. Here, Kim and co-workers show that a chimeric protein, EWS-Oct-4, transcriptionally activates fibroblast growth factor-4 (FGF-4) and triggers a downstream cascade of oncogenic signalling pathways, thereby facilitating the initiation of human bone and soft tissue tumour development. Comment on: https://doi.org/10.1111/febs.14946.

New Insights about the Wnt/β-Catenin Signaling Pathway in Primary Bone Tumors and Their Microenvironment: A Promising Target to Develop Therapeutic Strategies?

Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for the past decade and remains closely related to the response of tumor cells to chemotherapy, reaching around 75% at 5 years for patients with localized forms of osteosarcoma or Ewing sarcoma but less than 30% in metastatic diseases and patients resistant to initial chemotherapy. Despite Ewing sarcoma being characterized by specific EWSR1-ETS gene fusions resulting in oncogenic transcription factors, currently, no targeted therapy could be implemented. It seems even more difficult to develop a targeted therapeutic strategy in osteosarcoma which is characterized by high complexity and heterogeneity in genomic alterations. Nevertheless, the common point between these different bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Therefore, targeting different actors of the bone tumor microenvironment has been hypothesized to develop new therapeutic strategies. In this context, it is well known that the Wnt/β-catenin signaling pathway plays a key role in cancer development, including osteosarcoma and Ewing sarcoma as well as in bone remodeling. Moreover, recent studies highlight the implication of the Wnt/β-catenin pathway in angiogenesis and immuno-surveillance, two key mechanisms involved in metastatic dissemination. This review focuses on the role played by this signaling pathway in the development of primary bone tumors and the modulation of their specific microenvironment.

Exosomes Play a Key Role in Multiple Myeloma Bone Disease and Tumor Development

Multiple Myeloma (MM) is an often incurable plasma cell proliferative disorder, representing about 10% of all hematologic malignancies. Osteolysis is one of the hallmarks of this malignancy, meaning that almost every patient will manifest with an osteolytic lesion during their disease course, resulting in increased morbidity and pain with ultimately a severe impact on the quality of life.The development and progression of MM is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles (EVs) takes place. This crosstalk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease.Here we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. This syngeneic murine model highly mimics human MM disease and presents with typical MM characteristics such as osteolysis, angiogenesis and a serum M-spike.We first investigated the effects of 5TGM1 small EVs or exosomes, sized 50-120nm in diameter, on osteoclasts and osteoblasts in vitro. 5TGM1 exosomes were able to enhance the resorptive active of osteoclasts. In contrast, these exosomes induced apoptosis in pre-osteoblasts while also blocking their differentiation to mature osteoblasts. RT-PCR showed a downregulation of Runx2, Osterix and Collagen 1A1 expression, while DKK-1 expression was upregulated. Mechanistically, we confirmed the presence of DKK-1 on the 5TGM1 exosomes, which led to a downregulation of the Wnt pathway in osteoblasts.In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. We injected C57BL/KalwRij intravenously during three weeks with 5TGM1 exosomes, and analyzed the femurs by micro-computed tomography. These mice had a significantly lower trabecular bone volume, as the result of a lower trabecular number combined with a higher trabecular separation.Next, we inhibited exosome secretion in 5TGM1-inoculated mice to prevent bone loss and increase sensitivity to bortezomib. For blocking exosome secretion we used the neutral sphingomyelinase inhibitor GW4869. This increased cortical bone volume and decreased bone resorption markers (C-terminal telopeptide of collagen type I) without significantly affecting tumor load. This indicates that inhibiting exosome secretion in the MM microenvironment has a protective effect on myeloma bone disease, not associated with effects on tumor load. Furthermore, blocking exosome secretion by GW4869 also sensitized the myeloma cells to bortezomib, leading to a strong anti-tumor response in vivo when GW4869 and bortezomib were combined.Altogether, our results indicate a key role for exosomes in the myeloma BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy. DisclosuresNo relevant conflicts of interest to declare.

Exosomes play a role in multiple myeloma bone disease and tumor development by targeting osteoclasts and osteoblasts

Progression of multiple myeloma (MM) is largely dependent on the bone marrow (BM) microenvironment wherein communication through different factors including extracellular vesicles takes place. This cross-talk not only leads to drug resistance but also to the development of osteolysis. Targeting vesicle secretion could therefore simultaneously ameliorate drug response and bone disease. In this paper, we examined the effects of MM exosomes on different aspects of osteolysis using the 5TGM1 murine model. We found that 5TGM1 sEVs, or ‘exosomes’, not only enhanced osteoclast activity, they also blocked osteoblast differentiation and functionality in vitro. Mechanistically, we could demonstrate that transfer of DKK-1 led to a reduction in Runx2, Osterix, and Collagen 1A1 in osteoblasts. In vivo, we uncovered that 5TGM1 exosomes could induce osteolysis in a similar pattern as the MM cells themselves. Blocking exosome secretion using the sphingomyelinase inhibitor GW4869 not only increased cortical bone volume, but also it sensitized the myeloma cells to bortezomib, leading to a strong anti-tumor response when GW4869 and bortezomib were combined. Altogether, our results indicate an important role for exosomes in the BM microenvironment and suggest a novel therapeutic target for anti-myeloma therapy.

EGFR is required for FOS‐dependent bone tumor development via RSK2/CREB signaling

Osteosarcoma (OS) is a rare tumor of the bone occurring mainly in young adults accounting for 5% of all childhood cancers. Because of the limited therapeutic options, there has been no survival improvement for OS patients in the past 40 years. The epidermal growth factor receptor (EGFR) is highly expressed in OS; however, its clinical relevance is unclear. Here, we employed an autochthonous c‐Fos‐dependent OS mouse model (H2‐c‐fosLTR) and human OS tumor biopsies for preclinical studies aimed at identifying novel biomarkers and therapeutic benefits of anti‐EGFR therapies. We show that EGFR deletion/inhibition results in reduced tumor formation in H2‐c‐fosLTR mice by directly inhibiting the proliferation of cancer‐initiating osteoblastic cells by a mechanism involving RSK2/CREB‐dependent c‐Fos expression. Furthermore, OS patients with co‐expression of EGFR and c‐Fos exhibit reduced overall survival. Preclinical studies using human OS xenografts revealed that only tumors expressing both EGFR and c‐Fos responded to anti‐EGFR therapy demonstrating that c‐Fos can be considered as a novel biomarker predicting response to anti‐EGFR treatment in OS patients.

Mechanisms of Bone Metastasis of Malignancies of the Genito-Mammary Area

Abstract Bone metastasis is a frequent complication of advanced genito-mammary cancer patients. Skeletal involvement is particularly common in breast cancer. Bone metastases induce a wide range of symptoms, lowering the quality of life and shortening survival. The normal bone remodeling process is deeply affected in all types of metastases: osteolytic, osteoblastic, and mixed. The main mechanisms involved in bone metastatic dissemination are the expression of adhesion tumor molecules and corresponding receptors within bone marrow and bone matrix cells; local growth factors, molecular mechanisms of remodeling the hematopoietic stem cell activity, and alteration of the expression of the post-transcriptional regulatory microRNAs of the gene expression are the new theories developed from recent studies. Abnormalities in the number of copies of the 16q23 gene explain the increased risk of bone metastasis of breast cancer compared to its dissemination to the other organs; the mutual interaction between tumor cells and the bone microenvironment constitutes the element that stimulates both bone destruction and tumor development. Endothelin -1, bone morphogenic proteins, platelet-derived growth factor, Wnt proteins stimulate proliferation and osteoblastic activity. Genomic and proteomic studies underlie the development of new therapeutic agents for the treatment and prevention of bone metastases.

Transforming Growth Factor-β Signaling Plays a Pivotal Role in the Interplay Between Osteosarcoma Cells and Their Microenvironment.

Osteosarcomas are the most frequent form of primary bone tumors and mainly affect children, adolescents, and young adults. Despite encouraging progress in therapeutic management, including the advent of multidrug chemotherapy, the survival rates have remained unchanged for more than four decades: 75% at 5 years for localized disease, but two groups of patients are still at high risk: metastatic at diagnosis (overall survival around 40% at 5 years) and/or poor responders to chemotherapy (20% at 5 years). Because these tumors are classified as “complex genomic,” it is extremely difficult to determine the signaling pathways that might be targeted by specific therapies. A hypothesis has thus emerged, stating that the particular microenvironment of these tumors may interfere with the tumor cells that promote chemoresistance and the dissemination of metastases. The stroma is composed of a large number of cell types (immune cells, endothelial cells, mesenchymal stromal cells, etc.) which secrete growth factors, such as transforming growth factor-β (TGF-β), which favors the development of primary tumors and dissemination of metastases by constituting a permissive niche at primary and distant sites. Rather than targeting the tumor cells themselves, which are very heterogeneous in osteosarcoma, the hypothesis is instead to target the key actors secreted in the microenvironment, such as TGF-βs, which play a part in tumor progression. In the last decade, numerous studies have shown that overexpression of TGF-β is a hallmark of many cancers, including primary bone tumors. In this context, TGF-β signaling has emerged as a crucial factor in the cross talk between tumor cells and stroma cells in poor-prognosis cancers. Secretion of TGF-β by tumor cells or stroma cells can effectively act in a paracrine manner to regulate the phenotype and functions of the microenvironment to stimulate protumorigenic microenvironmental changes. TGF-β can thus exert its protumorigenic function in primary bone tumors by promoting angiogenesis, bone remodeling and cell migration, and by inhibiting immunosurveillance. This review focuses on the involvement of TGF-β signaling in primary bone tumor development, and the related therapeutic options that may be possible for these tumors.

Musculoskeletal complications following total body irradiation in hematopoietic stem cell transplant patients.

Total body irradiation (TBI) is commonly used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT) to treat benign and malignant disease. Though life-saving, these therapies place patients at risk for important side effects, including musculoskeletal complications such as short stature, osteonecrosis, slipped capital femoral epiphysis, and the development of benign and malignant bone tumors. With an increasing number of HSCT survivors, there is a growing need for awareness of the musculoskeletal complications of HSCT and TBI.

Palovarotene Inhibits Osteochondroma Formation in a Mouse Model of Multiple Hereditary Exostoses.

Multiple hereditary exostoses (MHE), also known as multiple osteochondromas (MO), is an autosomal dominant disorder characterized by the development of multiple cartilage-capped bone tumors (osteochondromas). The large majority of patients with MHE carry loss-of-function mutations in the EXT1 or EXT2 gene, which encodes a glycosyltransferase essential for heparan sulfate (HS) biosynthesis. Increasing evidence suggests that enhanced bone morphogenetic protein (BMP) signaling resulting from loss of HS expression plays a role in osteochondroma formation in MHE. Palovarotene (PVO) is a retinoic acid receptor γ selective agonist, which is being investigated as a potential drug for fibrodysplasia ossificans progressiva (FOP), another genetic bone disorder with features that overlap with those of MHE. Here we show that PVO inhibits osteochondroma formation in the Fsp1Cre ;Ext1flox/flox model of MHE. Four-week daily treatment with PVO starting at postnatal day (P) 14 reduced the number of osteochondromas that develop in these mice by up to 91% in a dose-dependent manner. An inhibition of long bone growth observed in animals treated from P14 was almost entirely abrogated by delaying the initiation of treatment to P21. We also found that PVO attenuates BMP signaling in Fsp1Cre ;Ext1flox/flox mice and that aberrant chondrogenic fate determination of Ext1-deficient perichondrial progenitor cells in these mice is restored by PVO. Together, the present data support further preclinical and clinical investigations of PVO as a potential therapeutic agent for MHE. © 2017 American Society for Bone and Mineral Research.

Fibular osteocutaneous free flap reconstruction of the mandible after resection of ossifying fibroma in a seven-year old child

Ossifying fibromas (OSF) belong to a group of benign fibro-osseous neoplasms encountered almost exclusively in the craniofacial skeleton. The clinical course is typically asymptomatic. However, discomfort in the mouth begins to develop once the neoplasm progressively extends, causing an overgrowth of bone resulting in pain and facial asym­metry. The development of craniofacial bone tumors in children is quite a rare occurrence. In international medical literature, the described cases typically involve young adolescent patients, with very few case reports of craniofacial neoplasms in children under the age of seven [1, 2]. In the current case report, we present a seven-year-old patient with a biopsy-proven ossifying fibroma. The patient underwent a resection of the neoplasm with reconstruction. One of the major issues encountered in reconstruction of the mandible using a vascularized fibular flap in children is the growth potential of the fibula in comparison to the mandible, resulting in a symmetrical facial image. The use of a fibular osteocutaneous free flap in reconstruction of mandibular deficits in children is a favourable solution. The use of this type of flap permits functional restoration and significantly improved facial cosmesis. The union of the mandible with the integrated fibula is still a topic of ongoing discussion and one must be prepared for possible further orthognathic procedures after completing the growth of the craniofacial skeleton.

LncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can undergo self-renewal and differentiate into multiple lineages. Osteogenic differentiation from MSCs is a well-orchestrated process and regulated by multiple signaling pathways. We previously demonstrated that BMP9 is one of the most potent osteogenic factors. However, molecular mechanism through which BMP9 governs osteoblastic differentiation remains to be fully understood. Increasing evidence indicates noncoding RNAs (ncRNAs) may play important regulatory roles in many physiological and/or pathologic processes. In this study, we investigate the role of lncRNA H19 in BMP9-regulated osteogenic differentiation of MSCs. We demonstrated that H19 was sharply upregulated at the early stage of BMP9 stimulation of MSCs, followed by a rapid decease and gradual return to basal level. This process was correlated with BMP9-induced expression of osteogenic markers. Interestingly, either constitutive H19 expression or silencing H19 expression in MSCs significantly impaired BMP9-induced osteogenic differentiation in vitro and in vivo, which was effectively rescued by the activation of Notch signaling. Either constitutive H19 expression or silencing H19 expression led to the increased expression of a group of miRNAs that are predicted to target Notch ligands and receptors. Thus, these results indicate that lncRNA H19 functions as an important mediator of BMP9 signaling by modulating Notch signaling-targeting miRNAs. Our findings suggest that the well-coordinated biphasic expression of lncRNA H19 may be essential in BMP9-induced osteogenic differentiation of MSCs, and that dysregulated H19 expression may impair normal osteogenesis, leading to pathogenic processes, such as bone tumor development.