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1.
Hum Mol Genet ; 32(7): 1090-1101, 2023 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-36300303

RESUMEN

Cysteamine is currently the only therapy for nephropathic cystinosis. It significantly improves life expectancy and delays progression to end-stage kidney disease; however, it cannot prevent it. Unfortunately, compliance to therapy is often weak, particularly during adolescence. Therefore, finding better treatments is a priority in the field of cystinosis. Previously, we found that genistein, an isoflavone particularly enriched in soy, can revert part of the cystinotic cellular phenotype that is not sensitive to cysteamine in vitro. To test the effects of genistein in vivo, we fed 2-month-old wild-type and Ctns-/- female mice with either a control diet, a genistein-containing diet or a cysteamine-containing diet for 14 months. Genistein (160 mg/kg/day) did not affect the growth of the mice or hepatic functionality. Compared with untreated mice at 16 months, Ctns-/- mice fed with genistein had lower cystine concentrations in their kidneys, reduced formation of cystine crystals, a smaller number of LAMP1-positive structures and an overall better-preserved parenchymal architecture. Cysteamine (400 mg/kg/day) was efficient in reverting the lysosomal phenotype and in preventing the development of renal lesions. These preclinical data indicate that genistein ameliorates kidney injury resulting from cystinosis with no side effects. Genistein therapy represents a potential treatment to improve the outcome for patients with cystinosis.


Asunto(s)
Cistinosis , Enfermedades Renales , Animales , Femenino , Ratones , Cisteamina/uso terapéutico , Cistina/uso terapéutico , Cistinosis/tratamiento farmacológico , Cistinosis/genética , Modelos Animales de Enfermedad , Genisteína/farmacología , Genisteína/uso terapéutico , Riñón
2.
Cell ; 142(2): 296-308, 2010 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-20655470

RESUMEN

The broad expression of the insulin receptor suggests that the spectrum of insulin function has not been fully described. A cell type expressing this receptor is the osteoblast, a bone-specific cell favoring glucose metabolism through a hormone, osteocalcin, that becomes active once uncarboxylated. We show here that insulin signaling in osteoblasts is necessary for whole-body glucose homeostasis because it increases osteocalcin activity. To achieve this function insulin signaling in osteoblasts takes advantage of the regulation of osteoclastic bone resorption exerted by osteoblasts. Indeed, since bone resorption occurs at a pH acidic enough to decarboxylate proteins, osteoclasts determine the carboxylation status and function of osteocalcin. Accordingly, increasing or decreasing insulin signaling in osteoblasts promotes or hampers glucose metabolism in a bone resorption-dependent manner in mice and humans. Hence, in a feed-forward loop, insulin signals in osteoblasts activate a hormone, osteocalcin, that promotes glucose metabolism.


Asunto(s)
Remodelación Ósea , Metabolismo Energético , Insulina/metabolismo , Osteoblastos/metabolismo , Transducción de Señal , Animales , Células Cultivadas , Matriz Extracelular , Glucosa/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Osteocalcina/metabolismo
3.
Am J Hum Genet ; 108(1): 115-133, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33308444

RESUMEN

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.


Asunto(s)
Huesos/metabolismo , Proteínas de Unión al Calcio/metabolismo , Discapacidades del Desarrollo/metabolismo , Osteogénesis/fisiología , Transducción de Señal/fisiología , Animales , Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 4/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Línea Celular , Línea Celular Tumoral , Femenino , Regulación del Desarrollo de la Expresión Génica/fisiología , Células HEK293 , Células Hep G2 , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Células MCF-7 , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL
4.
Arch Biochem Biophys ; 734: 109489, 2023 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-36526001

RESUMEN

The therapeutic strategies for osteosarcoma involve both surgical approach and chemotherapy, but the identification of new therapeutic targets is particularly necessary in patients with local chemo-resistance, recurrence and lung metastases. The role of epigenetic regulation in osteosarcoma is largely unknown. Thus, in this study we disclosed the effects of histone deacetylase inhibitor drug PXD-101 on human osteosarcoma (OS) cell lines with different aggressiveness, including Saos-2, HOS and 143B cell lines. XTT assays revealed that treatment of Saos-2, HOS and 143B cells with PXD-101 decreased cell viability in a concentration-dependent manner. Fluorescence-activated cell sorting (FACS) analysis showed that PXD-101 inhibited proliferation and induced cell apoptosis. Wound healing assay indicated that PXD-101 inhibited migration of osteosarcoma cells. Real-Time RT-qPCR and protein analysis highlighted reduced expression of Runx2, Osterix and Mad2, probably due to Cyclin B1 inhibition by PXD-101 treatment. To our knowledge, this is the first study that characterized the anti-tumoral effect of PXD-101 in OS cells, suggesting a potential new therapeutic approach in osteosarcoma patients.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Línea Celular Tumoral , Proliferación Celular , Epigénesis Genética , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Apoptosis , Neoplasias Óseas/genética , Movimiento Celular
5.
Int J Mol Sci ; 24(3)2023 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-36768270

RESUMEN

Primary bone tumors (PBTs) represent a huge variety of rare malignancies that originate in the skeletal system [...].


Asunto(s)
Neoplasias Óseas , Investigación Biomédica Traslacional , Humanos , Neoplasias Óseas/genética , Neoplasias Óseas/patología
6.
FASEB J ; 35(3): e21424, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33609323

RESUMEN

Gorham-Stout disease (GSD) is a very rare disease characterized by increased bone erosion with angiomatous proliferation. The mechanisms underlying this disorder have not been deeply investigated. Due to its rarity, no guidelines are currently available for treatment and management of GSD. We recently evaluated the cellular alterations of the bone remodeling in patients showing that osteoclast precursors displayed increased ability to differentiate into osteoclasts and that affected osteoclasts resorb bone more actively than control cells. Moreover, osteoblasts isolated from a patient showed a defective ability to form mineralized nodules. In this paper, we investigated the molecular pathways involved in the cellular defects of GSD bone cells. For this study, we recruited nine patients and performed miRNome analysis of bone cells. Between the 178 miRNAs robustly expressed in GSD osteoclasts, significant modulation of three miRNAs (miR-1246, miR-1-3p, and miR-137-3p) involved in the regulation of osteoclast formation and activity or in the angiomatous proliferation was found in patients' cells. Interestingly, miR-1246 was also up-regulated in serum exosomes from patients. Analysis of miRNAs from patient osteoblasts suggested alteration of miR-204a-5p, miR-615-3p and miR-378a-3p regulating osteoblast function and differentiation. The resulting miRNA pattern may help to understand better the mechanisms involved in GSD and to identify new potential therapeutic targets for this rare disease.


Asunto(s)
Huesos/citología , MicroARNs/genética , Osteoclastos/metabolismo , Osteocitos/metabolismo , Osteólisis Esencial/sangre , Adolescente , Huesos/metabolismo , Diferenciación Celular/genética , Niño , Exosomas/metabolismo , Femenino , Humanos , Masculino , MicroARNs/sangre , Osteólisis Esencial/fisiopatología
7.
Endocr Pract ; 27(1): 21-26, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33475498

RESUMEN

OBJECTIVE: There are no data regarding echocardiographic parameters in patients with normocalcemic primary hyperparathyroidism (NCPHPT). We compared the echocardiographic findings in postmenopausal women with NCPHPT with those in patients with hypercalcemic primary hyperparathyroidism (PHPT) and controls. METHODS: Seventeen consecutive Caucasian postmenopausal women with NCPHPT were compared with 20 women with hypercalcemic PHPT and 20 controls. Obesity, diabetes, kidney failure, and previous cardiovascular diseases were considered exclusion criteria. Each patient underwent biochemical evaluation, bone mineral density scan, and echocardiographic measurements. Patients with parathyroid disorders underwent kidney ultrasound evaluation. RESULTS: Patients with PHPT had significantly higher mean total serum calcium, ionized calcium, 24-hour urinary calcium, and parathyroid hormone and lower mean phosphorus levels compared with those in the controls (all P < .05). The only differences between patients with NCPHPT and PHPT were significantly lower mean total serum calcium, ionized calcium, and 24-hour urinary calcium and higher phosphorus levels in patients with NCPHPT (all P < .05). The only biochemical difference between patients with NCPHPT and the controls was a higher level of mean parathyroid hormone in patients with NCPHPT. There were no differences in cardiovascular risk factors between patients with NCPHPT and PHPT and the controls. Hypertension was the most frequent cardiovascular risk factor, diagnosed in 65% of patients with PHPT. This high prevalence was not statistically significant compared with that observed in patients with NCPHPT (59%) and in the controls (30%). Echocardiography parameters were not different between patients with NCPHPT and PHPT and the controls when subdivided according to the presence of hypertension (ANOVA followed by Bonferroni correction). CONCLUSION: In a population with a low cardiovascular risk, we found no differences in cardiovascular risk factors and echocardiographic parameters between patients with NCPHPT and PHPT and the controls.


Asunto(s)
Hipercalcemia , Hiperparatiroidismo Primario , Calcio , Ecocardiografía , Femenino , Humanos , Hipercalcemia/epidemiología , Hiperparatiroidismo Primario/complicaciones , Hiperparatiroidismo Primario/diagnóstico por imagen , Hiperparatiroidismo Primario/epidemiología , Hormona Paratiroidea
8.
Int J Mol Sci ; 22(3)2021 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-33498786

RESUMEN

Bone is a regenerative organ characterized by self-renewal ability. Indeed, it is a very dynamic tissue subjected to continuous remodeling in order to preserve its structure and function. However, in clinical practice, impaired bone healing can be observed in patients and medical intervention is needed to regenerate the tissue via the use of natural bone grafts or synthetic bone grafts. The main elements required for tissue engineering include cells, growth factors and a scaffold material to support them. Three different materials (metals, ceramics, and polymers) can be used to create a scaffold suitable for bone regeneration. Several cell types have been investigated in combination with biomaterials. In this review, we describe the options available for bone regeneration, focusing on tissue engineering strategies based on the use of different biomaterials combined with cells and growth factors.


Asunto(s)
Materiales Biocompatibles , Regeneración Ósea/fisiología , Ingeniería de Tejidos/métodos , Andamios del Tejido , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/uso terapéutico , Trasplante Óseo , Cerámica/química , Humanos , Células Madre Mesenquimatosas , Polímeros/química
9.
Int J Mol Sci ; 22(22)2021 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-34830463

RESUMEN

Osteosarcoma (OS) is a skeletal tumor affecting mainly children and adolescents. The presence of distance metastasis is frequent and it is localized preferentially to the lung, representing the main reason for death among patients. The therapeutic approaches are based on surgery and chemotherapeutics. However, the drug resistance and the side effects associated with the chemotherapy require the identification of new therapeutic approaches. The understanding of the complex biological scenario of the osteosarcoma will open the way for the identification of new targets for its treatment. Recently, a great interest of scientific community is for extracellular vesicles (EVs), that are released in the tumor microenvironment and are important regulators of tumor proliferation and the metastatic process. At the same time, circulating extracellular vesicles can be exploited as diagnostic and prognostic biomarkers, and they can be loaded with drugs as a new therapeutic approach for osteosarcoma patients. Thus, the characterization of OS-related EVs could represent a way to convert these vesicles from antagonists for human health into therapeutic and/or diagnostic agents.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Vesículas Extracelulares/genética , Osteosarcoma/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos/efectos adversos , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Resistencia a Medicamentos/genética , Vesículas Extracelulares/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Metástasis de la Neoplasia , Osteosarcoma/genética
10.
Am J Pathol ; 189(5): 1053-1064, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30794806

RESUMEN

Cystinosis is a rare lysosomal storage disorder caused by loss-of-function mutations of the CTNS gene, encoding cystinosin, a symporter that mediates cystine efflux from lysosomes. Approximately 95% of patients with cystinosis display renal Fanconi syndrome, short stature, osteopenia, and rickets. In this study, we investigated whether the absence of cystinosin primarily affects bone remodeling activity, apart from the influences of the Fanconi syndrome on bone mineral metabolism. Using micro-computed tomography and histomorphometric and bone serum biomarker analysis, we evaluated the bone phenotype of 1-month-old Ctns-/- knockout (KO) male mice without tubulopathy. An in vitro study was performed to characterize the effects of cystinosin deficiency on osteoblasts and osteoclasts. Micro-computed tomography analysis showed a reduction of trabecular bone volume, bone mineral density, and number and thickness in KO mice compared with wild-type animals; histomorphometric analysis revealed a reduction of osteoblast and osteoclast parameters in tibiae of cystinotic mice. Decreased levels of serum procollagen type 1 amino-terminal propeptide and tartrate-resistant acid phosphatase in KO mice confirmed reduced bone remodeling activity. In vitro experiments showed an impairment of Ctns-/- osteoblasts and osteoclasts. In conclusion, cystinosin deficiency primarily affects bone cells, leading to a bone loss phenotype of KO mice, independent from renal failure.


Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/fisiología , Enfermedades Óseas/patología , Cistinosis/patología , Osteoblastos/patología , Osteogénesis , Animales , Enfermedades Óseas/etiología , Enfermedades Óseas/metabolismo , Cistinosis/etiología , Cistinosis/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoblastos/metabolismo
11.
Clin Genet ; 97(2): 362-369, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31600839

RESUMEN

Aymé-Gripp syndrome (AYGRPS) is a recognizable condition caused by a restricted spectrum of dominantly acting missense mutations affecting the transcription factor MAF. Major clinical features of AYGRPS include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. Skeletal abnormalities have also been observed in affected individuals, even though these features have not been assessed systematically. Expanding the series with four additional patients, here we provide a more accurate delineation of the molecular aspects and clinical phenotype, particularly focusing on the skeletal features characterizing this disorder. Apart from previously reported malar flattening and joint limitations, we document that carpal/tarsal and long bone defects, and hip dysplasia occur in affected subjects more frequently than formerly appreciated.


Asunto(s)
Catarata/genética , Predisposición Genética a la Enfermedad , Trastornos del Crecimiento/genética , Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Anomalías Musculoesqueléticas/genética , Proteínas Proto-Oncogénicas c-maf/genética , Adolescente , Adulto , Catarata/patología , Niño , Preescolar , Facies , Femenino , Trastornos del Crecimiento/patología , Pérdida Auditiva Sensorineural/patología , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Anomalías Musculoesqueléticas/patología , Mutación Missense/genética , Adulto Joven
12.
Int J Mol Sci ; 21(4)2020 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-32053970

RESUMEN

Bone and muscle represent a single functional system and are tightly connected to each other. Indeed, diseases characterized by alterations of muscle physiology have effects on bone remodeling and structure and vice versa. Muscle influence on bone has been deeply studied, and recent studies identified irisin as new molecule involved in this crosstalk. Muscle regulation by bone needs to be extensively investigated since in the last few years osteocalcin was recognized as a key molecule in the bone-muscle interaction. Osteocalcin can exist in two forms with different degrees of carboxylation. The undercarboxylated form of osteocalcin is a hormone released by the bone matrix during the osteoclast bone resorption and can bind its G-protein coupled receptor GPRC6A expressed in the muscle, thus regulating its function. Recently, this hormone was described as an antiaging molecule for its ability to regulate bone, muscle and cognitive functions. Indeed, the features of this bone-related hormone were used to test a new therapeutic approach for sarcopenia, since injection of osteocalcin in older mice induces the acquirement of physical abilities of younger animals. Even if this approach should be tested in humans, osteocalcin represents the most surprising molecule in endocrine regulation by the skeleton.


Asunto(s)
Huesos/fisiología , Ejercicio Físico , Músculo Esquelético/fisiología , Fenómenos Fisiológicos Musculoesqueléticos , Osteocalcina/metabolismo , Animales , Resorción Ósea/metabolismo , Humanos , Osteoclastos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
13.
Am J Hum Genet ; 98(2): 275-86, 2016 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-26849110

RESUMEN

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Tumores de Células Gigantes/genética , Osteítis Deformante/genética , Dedos de Zinc/genética , Secuencia de Aminoácidos , Animales , Niño , Exones , Femenino , Efecto Fundador , Humanos , Masculino , Datos de Secuencia Molecular , Mutación Missense , Osteoclastos/metabolismo , Linaje , Regulación hacia Arriba , Pez Cebra/genética
14.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-31514440

RESUMEN

Bone is a peculiar tissue subjected to a continuous process of self-renewal essential to assure the integrity of the skeleton and to explicate the endocrine functions. The study of bone diseases characterized by increased or reduced bone mass due to osteoclast alterations has been essential to understand the great role played by osteocalcin in the endocrine functions of the skeleton. The ability of osteoclasts to regulate the decarboxylation of osteocalcin and to control glucose metabolism, male fertility, and cognitive functions was demonstrated by the use of animal models. In this review we described how diseases characterized by defective and increased bone resorption activity, as osteopetrosis and osteoporosis, were essential to understand the involvement of bone tissue in whole body physiology. To translate this knowledge into humans, recently published reports on patients were described, but further studies should be performed to confirm this complex hormonal regulation in humans.


Asunto(s)
Densidad Ósea , Resorción Ósea/metabolismo , Resorción Ósea/patología , Sistema Endocrino/metabolismo , Osteocalcina/metabolismo , Animales , Fertilidad , Glucosa/metabolismo , Humanos
15.
Tumour Biol ; 40(4): 1010428318771773, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29687745

RESUMEN

Morbidity in advanced prostate cancer patients is largely associated with bone metastatic events. The development of novel therapeutic strategies is imperative in order to effectively treat this incurable stage of the malignancy. In this context, Akt signaling pathway represents a promising therapeutic target able to counteract biochemical recurrence and metastatic progression in prostate cancer. We explored the therapeutic potential of a novel dual PI3 K/mTOR inhibitor, X480, to inhibit tumor growth and bone colonization using different in vivo prostate cancer models including the subcutaneous injection of aggressive and bone metastatic (PC3) and non-bone metastatic (22rv1) cell lines and preclinical models known to generate bone lesions. We observed that X480 both inhibited the primary growth of subcutaneous tumors generated by PC3 and 22rv1 cells and reduced bone spreading of PCb2, a high osteotropic PC3 cell derivative. In metastatic bone, X480 inhibited significantly the growth and osteolytic activity of PC3 cells as observed by intratibial injection model. X480 also increased the bone disease-free survival compared to untreated animals. In vitro experiments demonstrated that X480 was effective in counteracting osteoclastogenesis whereas it stimulated osteoblast activity. Our report provides novel information on the potential activity of PI3 K/Akt inhibitors on the formation and progression of prostate cancer bone metastases and supports a biological rationale for the use of these inhibitors in castrate-resistant prostate cancer patients at high risk of developing clinically evident bone lesions.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Óseas , Compuestos Orgánicos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/prevención & control , Neoplasias Óseas/secundario , Remodelación Ósea/fisiología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia sin Enfermedad , Humanos , Masculino , Ratones , Ratones Desnudos , Neoplasias de la Próstata/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Células RAW 264.7 , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Int J Mol Sci ; 19(6)2018 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-29890702

RESUMEN

Bone is the preferential site of metastasis for breast and prostate tumor. Cancer cells establish a tight relationship with the host tissue, secreting factors that stimulate or inhibit bone cells, receiving signals generated from the bone remodeling activity, and displaying some features of bone cells. This interplay between tumor and bone cells alters the physiological bone remodeling, leading to the generation of a vicious cycle that promotes bone metastasis growth. To prevent the skeletal-related events (SRE) associated with bone metastasis, approaches to inhibit osteoclast bone resorption are reported. The bisphosphonates and Denosumab are currently used in the treatment of patients affected by bone lesions. They act to prevent or counteract the SRE, including pathologic fractures, spinal cord compression, and pain associated with bone metastasis. However, their primary effects on tumor cells still remain controversial. In this review, a description of the mechanisms leading to the onset of bone metastasis and clinical approaches to treat them are described.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Neoplasias Óseas/genética , Resorción Ósea/tratamiento farmacológico , Humanos
17.
Int J Mol Sci ; 19(4)2018 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-29642618

RESUMEN

Multiple types of cancer have the specific ability to home to the bone microenvironment and cause metastatic lesions. Despite being the focus of intense investigation, the molecular and cellular mechanisms that regulate the metastasis of disseminated tumor cells still remain largely unknown. Bone metastases severely impact quality of life since they are associated with pain, fractures, and bone marrow aplasia. In this review, we will summarize the recent discoveries on the role of extracellular vesicles (EV) in the regulation of bone remodeling activity and bone metastasis occurrence. Indeed, it was shown that extracellular vesicles, including exosomes and microvesicles, released from tumor cells can modify the bone microenvironment, allowing the formation of osteolytic, osteosclerotic, and mixed mestastases. In turn, bone-derived EV can stimulate the proliferation of tumor cells. The inhibition of EV-mediated crosstalk between cancer and bone cells could represent a new therapeutic target for bone metastasis.


Asunto(s)
Neoplasias Óseas/metabolismo , Vesículas Extracelulares/metabolismo , Animales , Neoplasias Óseas/secundario , Vesículas Extracelulares/patología , Humanos
18.
Nat Genet ; 39(8): 960-2, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17632511

RESUMEN

Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.


Asunto(s)
Osteopetrosis/genética , Ligando RANK/genética , Animales , Consanguinidad , Femenino , Genes Recesivos , Humanos , Masculino , Ratones , Osteoclastos , Linaje
19.
Lab Invest ; 94(3): 275-85, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24336069

RESUMEN

Autosomal dominant osteopetrosis type II (ADO II) is a rare, heritable bone disorder characterized by a high bone mass and insufficient osteoclast activity. Mutations in the CLCN7 gene have been reported to cause ADO II. To gain novel insights into the pathways dysregulated in ADOII osteoclasts, we identified changes in gene expression in osteoclasts from patients with a heterozygous mutation of CLCN7. To do this, we carried out a transcriptomic study comparing gene expression in the osteoclasts of patients with ADO II and healthy donors. Our data show that, according to our selection criteria, 182 genes were differentially expressed in osteoclasts from patients and controls. From the 18 displaying the highest change in microarray, we confirmed differential expression for seven by qPCR. Although two of them have previously been found to be expressed in osteoclasts (ITGB5 and SERPINE2), the other five (CES1 (carboxyl esterase 1), UCHL1 (ubiquitin carboxy-terminal esterase L1, also known as ubiquitin thiolesterase), WARS (tryptophanyl-tRNA synthetase), GBP4 (guanylate-binding protein 4), and PRF1) are not yet known to have a role in this cell type. At the protein level, we confirmed elevated expression of ITGB5 and reduced expression of WARS, PRF1, and SERPINE2. Transfection of ClC-7 harboring the G215R mutation into osteoclasts resulted in an increased ITGB5 and reduced PRF1 expression of borderline significance. Finally, we observed that the ADO II patients presented a normal or increased serum level of bone formation markers, demonstrating a coupling between dysfunctional osteoclasts and osteoblasts. Sphingosine kinase 1 mRNA was expressed at the same level in ADO II and control osteoclasts. In conclusion, these data suggest that in addition to an acidification dysfunction caused by the CLCN7 mutation, a change in ITGB5, PRF1, WARS, and SERPINE2 expression could be part of the osteoclastic phenotype of ADO II.


Asunto(s)
Osteoclastos/metabolismo , Osteopetrosis/genética , Adulto , Anciano , Anciano de 80 o más Años , Hidrolasas de Éster Carboxílico/genética , Estudios de Casos y Controles , Canales de Cloruro/genética , Canales de Cloruro/metabolismo , Femenino , Proteínas de Unión al GTP/genética , Humanos , Cadenas beta de Integrinas/genética , Cadenas beta de Integrinas/metabolismo , Masculino , Persona de Mediana Edad , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación , Mutación Missense , Osteopetrosis/metabolismo , Perforina , Fenotipo , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Serpina E2/genética , Serpina E2/metabolismo , Transcriptoma , Triptófano-ARNt Ligasa/genética , Triptófano-ARNt Ligasa/metabolismo , Ubiquitina Tiolesterasa/genética , Adulto Joven
20.
Cells ; 13(6)2024 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-38534381

RESUMEN

The identification of new therapeutic targets and the development of innovative therapeutic approaches are the most important challenges for osteosarcoma treatment. In fact, despite being relatively rare, recurrence and metastatic potential, particularly to the lungs, make osteosarcoma a deadly form of cancer. In fact, although current treatments, including surgery and chemotherapy, have improved survival rates, the disease's recurrence and metastasis are still unresolved complications. Insights for analyzing the still unclear molecular mechanisms of osteosarcoma development, and for finding new therapeutic targets, may arise from the study of post-translational protein modifications. Indeed, they can influence and alter protein structure, stability and function, and cellular interactions. Among all the post-translational modifications, ubiquitin-like modifications (ubiquitination, deubiquitination, SUMOylation, and NEDDylation), as well as glycosylation, are the most important for regulating protein stability, which is frequently altered in cancers including osteosarcoma. This review summarizes the relevance of ubiquitin-like modifications and glycosylation in osteosarcoma progression, providing an overview of protein stability regulation, as well as highlighting the molecular mediators of these processes in the context of osteosarcoma and their possible targeting for much-needed novel therapy.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Humanos , Glicosilación , Ubiquitina , Osteosarcoma/patología , Neoplasias Óseas/patología , Estabilidad Proteica
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