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1.
Skeletal Radiol ; 53(1): 175-178, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37310481

RESUMO

Paget disease of bone is a metabolic disorder with a strong genetic component, characterised by pronounced disorganised bone remodelling. Complications of this disease include an increased risk of developing bone neoplasms. Here, we describe the case of a 60-year-old Italian patient with Paget disease of bone, presenting with an osteoclast-rich tumour. Our analysis of this entity, based on the clinical, morphological and genetic data (whole exome sequencing), suggests that osteoclast-rich lesions in Paget disease of bone are genetically distinct from classical giant cell tumour of bone. We discuss the importance of differentiating these osteoclast-rich lesions.


Assuntos
Neoplasias Ósseas , Tumores de Células Gigantes , Osteíte Deformante , Humanos , Pessoa de Meia-Idade , Osteoclastos/patologia , Osteíte Deformante/diagnóstico por imagem , Osteíte Deformante/genética , Tumores de Células Gigantes/diagnóstico por imagem , Tumores de Células Gigantes/genética , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Osso e Ossos/patologia , Células Gigantes/patologia
2.
Int J Mol Sci ; 24(21)2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37958864

RESUMO

Abnormal activation of multiple immune and non-immune cells and proinflammatory factors mediate the development of joint inflammation in genetically susceptible individuals. Although specific environmental factors like smoking and infections are associated with disease pathogenesis, until now, we did not know the autoantigens and arthritogenic factors that trigger the initiation of the clinical disease. Autoantibodies recognizing specific post-translationally modified and unmodified antigens are generated and in circulation before the onset of the joint disease, and could serve as diagnostic and prognostic markers. The characteristic features of autoantibodies change regarding sub-class, affinity, glycosylation pattern, and epitope spreading before the disease onset. Some of these antibodies were proven to be pathogenic using animal and cell-culture models. However, not all of them can induce disease in animals. This review discusses the aberrant activation of major immune and non-immune cells contributing to joint inflammation. Recent studies explored the protective effects of extracellular vesicles from mesenchymal stem cells and bacteria on joints by targeting specific cells and pathways. Current therapeutics in clinics target cells and inflammatory pathways to attenuate joint inflammation and protect the cartilage and bones from degradation, but none cure the disease. Hence, more basic research is needed to investigate the triggers and mechanisms involved in initiating the disease and relapses to prevent chronic inflammation from damaging joint architecture.


Assuntos
Artrite Reumatoide , Humanos , Animais , Artrite Reumatoide/patologia , Osso e Ossos/patologia , Inflamação/patologia , Autoanticorpos , Cartilagem/patologia
3.
Nutrients ; 15(21)2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37960236

RESUMO

(1) Background: In the RADIOSA phase II randomized clinical trial (NCT03940235), the biology task entails the identification of predictive and prognostic biomarkers in the context of oligorecurrent, castration-sensitive prostate cancer in order to distinguish polymetastatic from oligometastatic disease. This may lay the groundwork for personalized treatments for those patients who could really benefit from metastasis-directed therapies. (2) Methods: Oligorecurrent PCa pts with three or fewer bone or lymph nodal localizations were randomized 1:1 to receive SBRT alone (arm A) or SBRT + 6 months of ADT (arm B). Common serum-derived biomarkers were collected at baseline, and at 3 months after RT. The prognostic nutritional index, an immune and nutrition-based prognostic score, and the controlling nutritional status (CONUT) score, a scoring system for evaluating patient's nutritional status, were calculated in accordance with the body of available literature. As inflammatory indicators, neutrophil-lymphocyte ratio (NLR) and the NLR-albumin ratio (NLRAR) were assessed. Changes in these parameters between baseline and the 3-month timepoint were evaluated both in absolute and relative values. Changes in these parameters between baseline and the 3-month timepoint were evaluated. Significant differences in the trend of these parameters were assessed using the non-parametric Wilcoxon rank-sum test. A network analysis to analyze the relationships between different features stratifying patients according to the arm of study and site of metastases was performed. (3) Results: The current analysis comprised 88 patients (45 arm A, SBRT only, and 43 arm B, SBRT + ADT). When patients were stratified by ADT administration, cholesterol values showed an increasing trend in the group receiving ADT (p = 0.005) which was no longer significant at 1 year. When patients were stratified by site of metastases (52 lymph nodal, 29 bone localizations), the value of NLR was found to be increased in patients with bone localizations (p < 0.05). In addition, the network analysis showed that BMI and NRI are strongly and directly linked for patients at baseline and that this correlation is no longer found at three months. Finally, when patients were divided according to time from surgery to oligorecurrence (enrollment) the patients with a longer time (>6.7 years) showed an increase in CONUT score from baseline. All the other nutritional and inflammatory scores or parameters investigated in the present analysis showed no statistically significant differences at baseline, three months, 1 year, and in absolute change. (4) Conclusions: The nutritional and inflammatory parameters do not seem to represent valuable candidates for possible use in clinical decision making in our cohort of patients and a reliable biological characterization of the oligometastatic state in prostate cancer still seems far from being achieved. Ongoing molecular analysis will show if there is a role of mutational landscape in the definition of the oligometastatic state.


Assuntos
Neoplasias da Próstata , Humanos , Masculino , Biomarcadores , Osso e Ossos/patologia , Linfonodos , Estado Nutricional , Neoplasias da Próstata/tratamento farmacológico
4.
Int J Paleopathol ; 43: 106-111, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37918134

RESUMO

OBJECTIVE: The promontory of the middle ear was recently suggested to be an appropriate site for diagnosing otitis media (OM) in archaeological bones by endoscopic inspection. The present study scrutinized the underlying assumption that a bulgy, irregular promontorial surface represents a pathological condition. MATERIALS: We compared an allegedly healthy individual and an allegedly diseased individual in skeletal remains of two human individuals from the early Medieval period in Germany. METHODS: The specimens were studied using microscopic analyses of thin ground sections. RESULTS: The osseous architecture of the three-layered promontorial wall was the same in both specimens. Both the contour of the resorption front of the middle layer and the thickness of the overlying outer periosteal layer showed some variation, resulting in an either smooth or a bulgy promontorial surface, while signs of resorptive or proliferative changes at the periosteal surface were missing in both cases. CONCLUSIONS: Our results suggest that an irregular promontorial surface represents normal variation in the development of the otic capsule rather than a pathological condition. We therefore conclude that the promontory is not an appropriate site for diagnosing OM in archaeological bone. SIGNIFICANCE: The study contributes to evidence-based diagnoses in paleo-otological studies. Our assumption is in line with clinical and experimental findings indicating that the otic capsule is protected against bone remodeling. LIMITATIONS: Only two specimens were studied. SUGGESTIONS FOR FURTHER RESEARCH: SEM-studies to detect more subtle changes to the promontorial surface.


Assuntos
Otite Média , Paleopatologia , Humanos , Otite Média/diagnóstico , Otite Média/patologia , Osso Temporal/patologia , Remodelação Óssea , Osso e Ossos/patologia
5.
J Vis Exp ; (200)2023 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-37870316

RESUMO

Bone erosions are a pathological feature of several forms of inflammatory arthritis including rheumatoid arthritis (RA). The increased presence and size of erosions are associated with poor outcomes, joint function, and disease progression. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides unparalleled in vivo visualization of bone erosions. However, at this resolution, discontinuities in the cortical shell (cortical breaks) that are associated with normal physiological processes and pathology are also visible. The Study grouP for xtrEme Computed Tomography in Rheumatoid Arthritis previously used a consensus process to develop a definition of pathological erosion in HR-pQCT: a cortical break detected in at least two consecutive slices, in at least two perpendicular planes, non-linear in shape, with underlying trabecular bone loss. However, despite the availability of a consensus definition, erosion identification is a demanding task with challenges in inter-rater variability. The purpose of this work is to introduce a training tool to provide users with guidance on identifying pathological cortical breaks on HR-pQCT images for erosion analysis. The protocol presented here uses a custom-built module (Bone Analysis Module (BAM) - Training), implemented as an extension to an open-source image processing software (3D Slicer). Using this module, users can practice identifying erosions and compare their results to erosions annotated by expert rheumatologists.


Assuntos
Artrite Reumatoide , Articulação Metacarpofalângica , Humanos , Articulação Metacarpofalângica/diagnóstico por imagem , Articulação Metacarpofalângica/patologia , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/patologia , Tomografia Computadorizada por Raios X/métodos , Osso e Ossos/patologia , Progressão da Doença
6.
Hum Pathol ; 139: 126-134, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37805864

RESUMO

Clear cell chondrosarcoma (CCC), an extremely rare primary bone tumor, is currently classified by the World Health Organization as a low-grade malignant cartilaginous neoplasm. Clinically, CCC occurs primarily in males with a peak incidence in the third to fifth decades of life, and occasionally, it presents in skeletally immature patients. Unlike conventional chondrosarcoma, CCC has a predilection for the epiphysis of long bones and often displays radiologic features reminiscent of chondroblastoma. The recommended treatment is wide operative resection. CCC has a local recurrence rate of approximately 30%, and nearly 20% cases metastasize mainly to bone and lung often a decade after surgical intervention. Incomplete excision or curettage is associated with a high rate of recurrence. Histologically, the process is characterized by infiltrative lobules and sheets of round to oval cells with abundant cleared cytoplasm and well-defined cell borders associated with trabecula of osteoid and woven bone, scattered osteoclasts, and foci of conventional low-grade chondrosarcoma in about one-half of cases. Correlation with clinical and radiologic characteristics, such as epiphyseal location and young patient age, assists in establishing a correct diagnosis. Pathologic diagnosis of CCC is complicated by the low diagnostic accuracy of core needle biopsy, overlapping histologic features with other matrix-rich primary bone tumors, and a lack of a specific immunohistochemical and molecular profile. DNA methylation-based profiling classifier (sarcoma classifier) is one recent technologic advancement that may help to confirm the histopathological diagnosis of CCC or indicate the need for thorough reassessment in cases where results contradict previous conventional findings.


Assuntos
Neoplasias Ósseas , Condrossarcoma de Células Claras , Condrossarcoma , Masculino , Humanos , Condrossarcoma de Células Claras/diagnóstico , Diagnóstico Diferencial , Neoplasias Ósseas/patologia , Osso e Ossos/patologia , Condrossarcoma/terapia , Condrossarcoma/patologia
7.
Eur J Med Genet ; 66(11): 104857, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37758164

RESUMO

Pathogenic variants in SPARC cause a rare autosomal recessive form of osteogenesis imperfecta (OI), classified as OI type XVII, which was first reported in 2015. Only six patient cases with this specific form of OI have been reported to date. The SPARC protein plays a crucial role in the calcification of collagen in bone, synthesis of the extracellular matrix, and the regulation of cell shape. In this case report, we describe the phenotype of two patients with SPARC-related OI, including a patient with two novel pathogenic variants in the SPARC gene. Targeted Next Generation Sequencing revealed new compound heterozygous variants (c.484G > A p.(Glu162Lys)) and c.496C > T p.(Arg166Cys)) in one patient and a homozygous nonsense pathogenic variant (c.145C > T p.(Gln49*)) in the other. In line with previously reported cases, the two OI patients presented delayed motor development, muscular weakness, scoliosis, and multiple fractures. Interestingly, our study reports for the first time the occurrence of dentinogenesis imperfecta. The study also reports the effectiveness of bisphosphonate treatment for OI type XVII. This article enhances the genetic, clinical, therapeutic, and radiological understanding of SPARC-related OI.


Assuntos
Osteogênese Imperfeita , Humanos , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia , Mutação , Fenótipo , Homozigoto , Osso e Ossos/patologia , Colágeno Tipo I/genética , Osteonectina/genética
8.
Asian Pac J Cancer Prev ; 24(9): 3087-3097, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37774060

RESUMO

OBJECTIVE: This study aimed to report the metastatic lesions observed in identified skeletons whose deaths were caused by breast cancer complications to provide information and evidence that can be used in cases of human identification forensics. METHODS: The research was conducted at the Centre for Forensic Anthropology Studies of the Faculty of Odontology of the University of Pernambuco (CEAF/FOP/UPE), Recife, Brazil. The data bank of the CEAF/FOP/UPE was searched for skeletons with the cause of death reported as due to breast cancer, resulting in five cases. The skeletons were arranged in anatomical positions and macroscopically inspected to register, describe and measure the lesions present to establish the macroscopic patterns of bone destruction caused by breast cancer. RESULT: Of the five skeletons, two presented metastatic lesions. In the first, lesions were observed in a disseminated form, affecting almost all bones. The lesions were predominantly osteolytic and ellipsoid-shaped; however, mixed and circular lesions were also found. The second skeleton presented four lesions of mixed characteristics. The finding of bone lesions in the macroscopic analysis of skeletons may reveal a more advanced stage of the neoplasm, as well as its dissemination in areas little rich in hematopoietic tissue, such as the diaphyses of long bones, a situation widely observed in the first reported case. CONCLUSION: Besides providing more excellent knowledge of their macroscopic presentation, bone metastatic lesions may act as an individualizing factor in human identification cases, narrowing the sample of possible victims.


Assuntos
Neoplasias da Mama , Antropologia Forense , Humanos , Feminino , Neoplasias da Mama/patologia , Osso e Ossos/patologia , Brasil , Compostos Radiofarmacêuticos
9.
Exp Cell Res ; 431(1): 113751, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37574037

RESUMO

Primary cilia are non-motile, microtubule-based sensory organelle present in most vertebrate cells with a fundamental role in the modulation of organismal development, morphogenesis, and repair. Here we focus on the role of primary cilia in embryonic and postnatal skeletal development. We examine evidence supporting its involvement in physiochemical and developmental signaling that regulates proliferation, patterning, differentiation and homeostasis of osteoblasts, chondrocytes, and their progenitor cells in the skeleton. We discuss how signaling effectors in mechanotransduction and bone development, such as Hedgehog, Wnt, Fibroblast growth factor and second messenger pathways operate at least in part at the primary cilium. The relevance of primary cilia in bone formation and maintenance is underscored by a growing list of rare genetic skeletal ciliopathies. We collate these findings and summarize the current understanding of molecular factors and mechanisms governing primary ciliogenesis and ciliary function in skeletal development and disease.


Assuntos
Osso e Ossos , Esqueleto , Cílios , Humanos , Animais , Osso e Ossos/citologia , Osso e Ossos/patologia , Esqueleto/crescimento & desenvolvimento , Organogênese , Osteogênese , Transdução de Sinais , Mecanotransdução Celular
10.
Clin Nucl Med ; 48(10): 894-895, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37565820

RESUMO

ABSTRACT: A 23-year-old man was recently diagnosed with Langerhans cell histiocytosis (LCH). 68 Ga-FAPI PET/CT showed multiple lesions with intense FAPI uptake in the axial and appendicular skeleton with lytic or mixed bone destruction, consistent with osseous lesions of LCH. FAPI-avid foci around the right atrium and inferior vena cava, as well as micronodules and thin-walled cysts in the lungs, were also noted, possibly also involvement of LCH. This case suggested that 68 Ga-FAPI PET/CT may have the potential to be applied in evaluation of LCH.


Assuntos
Histiocitose de Células de Langerhans , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Masculino , Humanos , Adulto Jovem , Adulto , Fluordesoxiglucose F18 , Pulmão/patologia , Osso e Ossos/patologia , Histiocitose de Células de Langerhans/diagnóstico por imagem , Histiocitose de Células de Langerhans/patologia
11.
Int J Mol Sci ; 24(15)2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37569810

RESUMO

Up to 80% of castration-resistant prostate cancer (CRPC) patients develop bone metastases during the natural history of disease and about 25% harbor mutations in DNA damage repair (DDR) genes. This retrospective observational study evaluated the prevalence of DDR alterations in CRPC patients and their effect on the clinical outcomes associated with bone metastases. The mutational status of CRPC patients was analyzed per FoundationOne® analysis in tissue biopsy or, when it was not possible, in liquid biopsy performed at the onset of metastatic CRPC (mCRPC). The impact of DDR gene mutations on bone-related efficacy endpoints was evaluated at the time of mCRPC diagnoses. In total, 121 mCRPC patients with bone metastases were included: 38 patients had mutations in at least one DDR gene, the remaining 83 ones had a non-mutated DDR status. DDR mutated status was associated with bone metastases volume (p = 0.006), but did not affect SRE (skeletal-related events) incidence and time to SRE onset. Liquid and tissue biopsies were both available for 61 patients with no statistically significant difference in terms of incidence and type of molecular DDR alterations. Mutated DDR status was associated with higher bone metastasic volume, although a not detrimental effect on the other bone-related efficacy endpoints was observed.


Assuntos
Neoplasias Ósseas , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Mutação , Osso e Ossos/patologia , Reparo do DNA/genética
13.
Nat Cancer ; 4(8): 1193-1209, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37550517

RESUMO

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK-STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Humanos , Idoso , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/terapia , Transtornos Mieloproliferativos/patologia , Medula Óssea/patologia , Medula Óssea/fisiologia , Células-Tronco Hematopoéticas/patologia , Osso e Ossos/patologia , Microambiente Tumoral/genética
14.
Small ; 19(45): e2303456, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37438648

RESUMO

The pathogenesis of postmenopausal osteoporosis (PMOP) is mainly determined by the adhesion of osteoclasts to the bone matrix and the involvement of various molecules in bone resorption. The dual regulation strategy of the physical barriers of bone matrix and intracellular gene regulation generated by advanced biomaterials is a decent alternative for the treatment of PMOP. Herein, for the first time, it is identified that hsa-miR-378i/mmu-miR-378a-3p are closely associated with PMOP. Then, an osteophilic and dual-regulated alendronate-gene lipoplex (antagomir@Aln-Lipo), composed of medicative alendronate-functionalized liposomal vehicle and encapsulated specific microRNAs is engineered, for bone-targeting delivery of genes to achieve combined mitigation of bone loss. Alendronate targets hydroxyapatite in the bone matrix and occupies the adhesion site of osteoclasts, thus providing the "physical barriers". Antagomir is coupled precisely to specific endogenous microRNAs, thus providing the "genetic signals". These functionalized lipoplexes exhibited long-term stability and good transfection efficiency. It is proven that antagomir@Aln-Lipo could synergistically regulate osteoclastogenesis and bone resorption in vitro and in vivo. Furthermore, intravenous injection of antagomir@Aln-Lipo efficiently reverses bone loss through a dual mechanism driven by alendronate and antagomir-378a-3p. In conclusion, the osteophilic and dual-regulated antagomir@Aln-Lipo offers a brand-new bifunctional strategy for the precise treatment of PMOP.


Assuntos
Reabsorção Óssea , MicroRNAs , Humanos , Alendronato , Antagomirs , Osso e Ossos/patologia , MicroRNAs/genética
15.
Breast Cancer Res Treat ; 202(2): 233-244, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37522998

RESUMO

PURPOSE: Numerous studies had reported the diagnostic value of alkaline phosphatase (ALP) and its bone-specific isoforms (BAP) in the metastases of breast cancer (BC). The purpose of this meta-analysis was to summarize the diagnostic value of serum ALP and BAP in metastatic BC, especially focused on bone metastases. METHODS: We searched comprehensively in the PubMed, Cochrane Library, and EMBASE for studies to explore the diagnostic accuracy of serum ALP/BAP level for metastatic BC. Qualities of including studies were assessed and pooled sensitivity, specificity, and summary receiver operating characteristic curve were calculated. Publication bias was assessed and meta-regression was conducted. RESULTS: We finally included 25 studies with a total of 12,155 BC patients (1681 metastatic cases and 10,474 controls). According to the QUADAS-2 tool to assessment the methodological quality, most of the included studies were judged as high risk of patient selection bias. High serum levels of ALP/BAP in bone metastatic BC patients could be found compared with non-metastatic BC patients. The pooled sensitivity and specificity of ALP for BC bone metastases were 0.62 and 0.86, and the area under the curve (AUC) was 0.80. The pooled sensitivity and specificity of ALP for all site metastases (mainly bone and liver) were 0.56 and 0.91, and the AUC was 0.90. The pooled sensitivity and specificity of BAP for BC bone metastases were 0.66 and 0.92, and the AUC was 0.89. CONCLUSION: Although not promising, serum ALP and BAP could bring useful information for the early detection of BC metastases especially for the bone metastases.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Humanos , Feminino , Fosfatase Alcalina , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Osso e Ossos/patologia , Neoplasias Ósseas/secundário
16.
Int J Mol Sci ; 24(13)2023 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-37446237

RESUMO

The pathogenesis of rheumatoid arthritis (RA) consists of the formation of synovial villi, inflammation, immune abnormalities, and bone-cartilage destruction [...].


Assuntos
Artrite Reumatoide , Humanos , Artrite Reumatoide/genética , Membrana Sinovial/patologia , Inflamação/patologia , Cartilagem/patologia , Osso e Ossos/patologia
17.
Adv Exp Med Biol ; 1405: 477-506, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37452950

RESUMO

Malignant bone tumors affecting the brain and spine are a rare and exceedingly difficult-to-treat group of diseases. Most commonly consisting of chordoma and chondrosarcoma, these tumors also include giant-cell tumors and osteosarcomas. This chapter will cover the background, epidemiology, genetics, molecular biology, histopathology, radiographic features, clinical manifestations, therapeutic approaches, and clinical management of each entity.


Assuntos
Osteossarcoma , Neoplasias da Medula Espinal , Neoplasias da Coluna Vertebral , Humanos , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/epidemiologia , Neoplasias da Coluna Vertebral/genética , Osso e Ossos/patologia , Cartilagem/patologia , Encéfalo/patologia
18.
Nat Commun ; 14(1): 4271, 2023 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-37460553

RESUMO

Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone disease mouse model wherein myeloma cells injected into Pd-1h-/-Rag2-/- results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.


Assuntos
Mieloma Múltiplo , Osteólise , Animais , Camundongos , Osso e Ossos/patologia , Proteínas de Transporte , Metaloproteinase 13 da Matriz , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Osteoclastos/patologia , Osteólise/genética , Osteólise/patologia
19.
Front Immunol ; 14: 1121878, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37475868

RESUMO

Bone is among the main sites of metastasis in breast, prostate and other major cancers. Bone metastases remain incurable causing high mortality, severe skeletal-related effects and decreased quality of life. Despite the success of immunotherapies in oncology, no immunotherapies are approved for bone metastasis and no clear benefit has been observed with approved immunotherapies in treatment of bone metastatic disease. Therefore, it is crucial to consider unique features of tumor microenvironment in bone metastasis when developing novel therapies. The vicious cycle of bone metastasis, referring to crosstalk between tumor and bone cells that enables the tumor cells to grow in the bone microenvironment, is a well-established concept. Very recently, a novel osteoimmuno-oncology (OIO) concept was introduced to the scientific community. OIO emphasizes the significance of interactions between tumor, immune and bone cells in promoting tumor growth in bone metastasis, and it can be used to reveal the most promising targets for bone metastasis. In order to provide an insight into the current immuno-oncology drug development landscape, we used 1stOncology database, a cancer drug development resource to identify novel immunotherapies in preclinical or clinical development for breast and prostate cancer bone metastasis. Based on the database search, 24 immunotherapies were identified in preclinical or clinical development that included evaluation of effects on bone metastasis. This review provides an insight to novel immuno-oncology drug development in the context of bone metastasis. Bone metastases can be approached using different modalities, and tumor microenvironment in bone provides many potential targets for bone metastasis. Noting current increasing interest in the field of OIO, more therapeutic opportunities that primarily target bone metastasis are expected in the future.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Neoplasias da Próstata , Masculino , Humanos , Qualidade de Vida , Neoplasias Ósseas/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Osso e Ossos/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Desenvolvimento de Medicamentos , Microambiente Tumoral
20.
Front Endocrinol (Lausanne) ; 14: 1168306, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37484945

RESUMO

Since our discovery in 2013 that genetic defects in PLS3 lead to bone fragility, the mechanistic details of this process have remained obscure. It has been established that PLS3 variants cause syndromic and nonsyndromic osteoporosis as well as osteoarthritis. PLS3 codes for an actin-bundling protein with a broad pattern of expression. As such, it is puzzling how PLS3 specifically leads to bone-related disease presentation. Our review aims to summarize the current state of knowledge regarding the function of PLS3 in the predominant cell types in the bone tissue, the osteocytes, osteoblasts and osteoclasts. This is related to the role of PLS3 in regulating mechanotransduction, calcium regulation, vesicle trafficking, cell differentiation and mineralization as part of the complex bone pathology presented by PLS3 defects. Considering the consequences of PLS3 defects on multiple aspects of bone tissue metabolism, our review motivates the study of its mechanism in bone diseases which can potentially help in the design of suitable therapy.


Assuntos
Mecanotransdução Celular , Osteoporose , Humanos , Mutação , Osteoporose/patologia , Osso e Ossos/patologia , Homeostase
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