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1.
Calcif Tissue Int ; 107(6): 603-610, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32875378

RESUMO

We compared the effects of a nitrogen-containing bisphosphonate (N-BP), zoledronic acid (ZA), and an anti-mouse RANKL antibody (anti-mRANKL Ab) on the bone tissue pathology of a transgenic mouse model of human fibrous dysplasia (FD). For comparison, we also reviewed the histological samples of a child with McCune-Albright syndrome (MAS) treated with Pamidronate for 3 years. EF1α-GsαR201C mice with FD-like lesions in the tail vertebrae were treated with either 0.2 mg/kg of ZA at day 0, 7, and 14 or with 300 µg/mouse of anti-mRANKL Ab at day 0 and 21. All mice were monitored by Faxitron and histological analysis was performed at day 42. ZA did not affect the progression of the radiographic phenotype in EF1α-GsαR201C mice. FD-like lesions in the ZA group showed the persistence of osteoclasts, easily detectable osteoclast apoptotic activity and numerous "giant osteoclasts". In contrast, in the anti-mRANKL Ab-treated mice, osteoclasts were markedly reduced/absent, the radiographic phenotype reverted and the FD-like lesions were extensively replaced by newly formed bone. Numerous "giant osteoclasts" were also detected in the samples of the child with MAS. This study supports the hypothesis that osteoclasts per se, independently of their resorptive activity, are essential for development and expansion of FD lesions.


Assuntos
Displasia Fibrosa Óssea/tratamento farmacológico , Células Gigantes , Osteoclastos , Ácido Zoledrônico/uso terapêutico , Animais , Difosfonatos , Modelos Animais de Doenças , Displasia Fibrosa Óssea/patologia , Camundongos , Camundongos Transgênicos
2.
J Cell Physiol ; 233(2): 1658-1670, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28671269

RESUMO

Osteosarcoma is the most common malignant bone tumor in children and young adults. The identification of proteins which exhibit different subcellular localization in low- versus high-risk osteosarcoma can be instrumental to obtain prognostic information and to develop innovative therapeutic strategies. Beside the well-characterized membrane and cytoplasmic localization of Src protein, this study evaluated the prognostic relevance of its so-far unknown nuclear compartmentalization. We analyzed the subcellular distribution of total and activated (pY418) Src in a tissue microarray including 60 osteosarcoma samples. Immunohistochemical analyses revealed a variable pattern of Src expression and localization, ranging from negative to high-stained nuclei combined with a substantial cytoplasmic staining for total and activated forms. The analysis of Kaplan-Meier survival curves in relationship to the diverse permutations of cytoplasmic and nuclear staining suggested a correlation between Src subcellular localization and the overall survival (OS) of osteosarcoma patients. In order to explain this different subcellular localization, normal osteoblasts and three osteosarcoma cell lines were used to investigate the molecular mechanism. Once confirmed a variable Src localization also in these cell lines, we demonstrated a correlation between the N-myristoyltransferase enzymes expression and activity and the Src nuclear content. In conclusion, these results described a so-far unknown Src nuclear localization in osteosarcoma cells, suggesting that the combined detection of nuclear and cytoplasmic Src levels can be used as a prognostic marker for osteosarcoma patient survival. A correlation between the N-myristoyltransferase enzymes and the Src subcellular localization was described as well.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/enzimologia , Núcleo Celular/enzimologia , Osteossarcoma/enzimologia , Quinases da Família src/metabolismo , Aciltransferases/metabolismo , Adolescente , Adulto , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Linhagem Celular Tumoral , Criança , Ativação Enzimática , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Osteossarcoma/terapia , Prognóstico , Processamento de Proteína Pós-Traducional , Fatores de Tempo , Análise Serial de Tecidos , Adulto Jovem
3.
Front Endocrinol (Lausanne) ; 13: 882379, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757418

RESUMO

The bone marrow adipose tissue constitutes more than two-thirds of the bone marrow volume in adult life and is known to have unique metabolic and functional properties. In neoplastic disorders, bone marrow adipocytes (BMAds) contribute to create a favorable microenvironment to survival and proliferation of cancer cells. Many studies explored the molecular crosstalk between BMAds and neoplastic cells, predominantly in ex-vivo experimental systems or in animal models. However, little is known on the features of BMAds in the human neoplastic marrow. The aim of our study was to analyze the in situ changes in morphology and immunophenotype of BMAds in two different types of neoplastic marrow conditions. We selected a series of archival iliac crest and vertebral bone biopsies from patients with bone marrow metastasis (MET), patients with myeloproliferative neoplasia with grade-3 myelofibrosis (MPN-MF) and age-matched controls (CTR). We observed a significant reduction in the number of BMAds in MET and MPN-MF compared to CTR. Accordingly, in the same groups, we also detected a significant reduction in the mean cell diameter and area. Immunolocalization of different adipocyte markers showed that, compared to CTR, in both MET and MPN-MF the percentages of adiponectin- and phosphorylated hormone sensitive lipase-positive BMAds were significantly reduced and increased respectively. No statistically significant difference was found between MET and MPN-MF. Interestingly, in one MET sample, "remodeled" BMAds containing a large lipid vacuole and multiple, smaller and polarized lipid droplets were identified. In conclusion, our data show that in different types of marrow cancers, BMAds undergo significant quantitative and qualitative changes, which need to be further investigated in future studies.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Mielofibrose Primária , Adipócitos/patologia , Medula Óssea/patologia , Humanos , Transtornos Mieloproliferativos/patologia , Neoplasias/patologia , Mielofibrose Primária/patologia , Microambiente Tumoral
4.
Bone Res ; 10(1): 50, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35853852

RESUMO

The Gsα/cAMP signaling pathway mediates the effect of a variety of hormones and factors that regulate the homeostasis of the post-natal skeleton. Hence, the dysregulated activity of Gsα due to gain-of-function mutations (R201C/R201H) results in severe architectural and functional derangements of the entire bone/bone marrow organ. While the consequences of gain-of-function mutations of Gsα have been extensively investigated in osteoblasts and in bone marrow osteoprogenitor cells at various differentiation stages, their effect in adipogenically-committed bone marrow stromal cells has remained unaddressed. We generated a mouse model with expression of GsαR201C driven by the Adiponectin (Adq) promoter. Adq-GsαR201C mice developed a complex combination of metaphyseal, diaphyseal and cortical bone changes. In the metaphysis, GsαR201C caused an early phase of bone resorption followed by bone deposition. Metaphyseal bone formation was sustained by cells that were traced by Adq-Cre and eventually resulted in a high trabecular bone mass phenotype. In the diaphysis, GsαR201C, in combination with estrogen, triggered the osteogenic activity of Adq-Cre-targeted perivascular bone marrow stromal cells leading to intramedullary bone formation. Finally, consistent with the previously unnoticed presence of Adq-Cre-marked pericytes in intraosseous blood vessels, GsαR201C caused the development of a lytic phenotype that affected both cortical (increased porosity) and trabecular (tunneling resorption) bone. These results provide the first evidence that the Adq-cell network in the skeleton not only regulates bone resorption but also contributes to bone formation, and that the Gsα/cAMP pathway is a major modulator of both functions.

5.
Bone Rep ; 16: 101156, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34950753

RESUMO

Identifying the molecular networks that underlie Fibrous Dysplasia (FD) is key to understand the pathogenesis of the disease, to refine current diagnostic approaches and to develop efficacious therapies. In this study, we used the NanoString nCounter Analysis System to investigate the gene signature of a series of nine Formalin Fixed Decalcified and Paraffin-Embedded (FFDPE) bone biopsies from seven FD patients. We analyzed the expression level of 770 genes. Unsupervised clustering analysis demonstrated partitioning into two clusters with distinct patterns of gene expression. Differentially expressed genes included growth factors, components of the Wnt signaling system, interleukins and some of their cognate receptors, ephrin ligands, matrix metalloproteinases, neurotrophins and genes encoding components of the cAMP-dependent protein kinase. Interestingly, two tissue samples obtained from the same skeletal site of one patient one year apart failed to segregate in the same cluster. Retrospective histological review of the samples revealed different microscopic aspects in the two groups. The results of our pilot study suggest that the genetic signature of FD is heterogeneous and varies according to the histology and, likely, to the age of the lesion. In addition, they show that the Nanostring technology is a valuable tool for molecular translational studies on archival FFDPE material in FD and other rare bone diseases.

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