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1.
Pathol Oncol Res ; 28: 1610633, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091939

RESUMO

Due to the relatively high recurrence rate and the destructive nature of the tumor, the treatment of giant cell tumor is still a challenge. Denosumab appeared to be a promising candidate as a therapeutic drug. However, several studies have reported that tumors can recur during/after treatment with denosumab. Based on activated receptor tyrosine kinase signaling pattern of the stromal/tumor cells, a combination treatment with denosumab and sunitinib has recently been proposed to inhibit recurrences. This prompted us to investigate the PDGFRß expression of five denosumab treated cases using both primary and recurrent tumors during and after denosumab treatment. In addition, to recognise morphological changes, immunohistochemical analysis of H3F3A and PDGFRß was also performed. As an effect of denosumab treatment, the permanent absence of giant cells associated with severe to mild fibrosis was the most consistent morphological change, but H3F3A positive stromal/tumor cells were observed in all cases. Furthermore, an increased immunopositivity of PDGFRß in stromal/tumor cells was evident in all recurrent cases during denosumab treatment. Upon tumor recurrence (after the discontinuation of denosumab treatment) the intensity of PDGFRß immunostaining in stromal/tumor cells was restored/decreased. Our results confirm (for the first time) the activation of PDGFRß on mononuclear stromal/tumor cells at protein level as an effect of denosumab treatment, which has so far only been demonstrated by phosphoprotein array analysis (protein lysates). The decreased PDGFRß activity after the discontinuation of denosumab treatmeant and the increased PDGFRß activity during denosumab treatment underlines the need for denosumab and sunitinib combination therapy.


Assuntos
Neoplasias Ósseas , Tumor de Células Gigantes do Osso , Neoplasias de Tecidos Moles , Neoplasias Ósseas/patologia , Osso e Ossos/patologia , Denosumab/uso terapêutico , Tumor de Células Gigantes do Osso/tratamento farmacológico , Tumor de Células Gigantes do Osso/patologia , Humanos , Sunitinibe/uso terapêutico
2.
Arthritis Res Ther ; 24(1): 223, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115996

RESUMO

BACKGROUND: Subchondral bone plays an important role in the pathogenesis of radiographic osteoarthritis (OA). However, the bony changes that occur in hand OA (HOA) are much less understood. This study aimed to describe the association between radiographic HOA and high-resolution peripheral quantitative computed tomography (HRpQCT) measures of the hand and radius in a population-based sample. METHODS: A total of 201 participants (mean age 72, 46% female) from the Tasmanian Older Adult Cohort (TASOAC) study underwent HRpQCT assessment of the 2nd distal and proximal interphalangeal (DIP, PIP), 1st carpometacarpal (CMC) joint, and distal radius. Radiographic HOA was assessed at the 2nd DIP, PIP joints, and the 1st CMC joint using the OARSI atlas. RESULTS: Proximal osteophyte and joint space narrowing (JSN) scores were consistently more strongly associated with HRpQCT measures compared to the distal site with positive associations for indices of bone size (total and trabecular bone area and cortical perimeter but inconsistent for cortical area) and negative associations for volumetric bone mineral density (vBMD). There was a decrease in trabecular number and bone volume fraction with increasing osteophyte and JSN score as well as an increase in trabecular separation and inhomogeneity. Osteophyte and JSN scores in the hand were not associated with HRpQCT measures at the distal radius. CONCLUSIONS: This hypothesis generating data suggests that bone size and trabecular disorganization increase with both osteophyte formation and JSN (proximal more than distal), while local vBMD decreases. This process appears to be primarily at the site of pathology rather than nearby unaffected bone.


Assuntos
Articulação da Mão , Osteoartrite , Osteófito , Idoso , Compostos de Anilina , Osso e Ossos/patologia , Feminino , Articulação da Mão/diagnóstico por imagem , Articulação da Mão/patologia , Humanos , Masculino , Osteoartrite/diagnóstico por imagem , Osteoartrite/patologia , Osteófito/diagnóstico por imagem , Osteófito/patologia
3.
Front Immunol ; 13: 959575, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36072576

RESUMO

Chronic recurrent and multifocal osteomyelitis (CRMO) is a nonsporadic autoinflammatory disorder. Currently, it is diagnosed based on clinical, radiologic, pathological, and longitudinal data. Numerous aspects should be highlighted due to increased knowledge in imaging and immunology. We emphasize the use of whole-body MRI, which is a non-invasive diagnostic strategy. A literature review was carried out on longitudinal studies. Commonly, the mean age at diagnosis is 11 years, ranging between 3 and 17. The most common sites are the long bone metaphysis, particularly femoral and tibial metaphysis. In addition, the pelvis, spine, clavicle, and mandible may be involved. In long bones, the radiologic appearance can show typical structure, mixed lytic and sclerotic, sclerotic or lytic. It is frequently metaphyseal or juxta-physeal, with hyperostosis or periosteal thickening. The involvement of the vertebral skeleton is often multifocal. Therefore, whole-body MRI is essential in identifying subclinical lesions. CRMO is a polymorphic disorder in which whole-body MRI is beneficial to demonstrate subclinical edema. Vertebral collapse requires long-term monitoring.


Assuntos
Osteomielite , Osso e Ossos/patologia , Criança , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Osteomielite/diagnóstico por imagem , Osteomielite/patologia
4.
BMJ Case Rep ; 15(9)2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127032

RESUMO

Paget disease often presents as a rare asymptomatic lesion of the bone until it progresses into the advanced stages. A senile man was diagnosed with Paget disease of bone on routine dental radiographic analysis. His history of fractures, periodical ill-fitting dentures and frequent pain in the long bones were contributing to the diagnosis. The patient was referred to a general physician where whole body radiographs were taken, which showed several of the classic features of Paget disease. Biochemical analysis was also done in which serum alkaline phosphatase was elevated with all other values within normal limits, confirming the diagnosis. The patient was treated with single-infusion bisphosphonate followed by other required dental procedures. Early diagnosis and prompt management gave a good prognosis, preventing the potential complications.


Assuntos
Adenocarcinoma , Osteíte Deformante , Adenocarcinoma/complicações , Fosfatase Alcalina , Osso e Ossos/patologia , Difosfonatos/uso terapêutico , Humanos , Masculino , Osteíte Deformante/diagnóstico , Radiografia
5.
J Bone Miner Res ; 37(9): 1623-1641, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35949115

RESUMO

Early-onset osteoporosis (EOOP), characterized by low bone mineral density (BMD) and fractures, affects children, premenopausal women and men aged <50 years. EOOP may be secondary to a chronic illness, long-term medication, nutritional deficiencies, etc. If no such cause is identified, EOOP is regarded primary and may then be related to rare variants in genes playing a pivotal role in bone homeostasis. If the cause remains unknown, EOOP is considered idiopathic. The scope of this review is to guide through clinical and genetic diagnostics of EOOP, summarize the present knowledge on rare monogenic forms of EOOP, and describe how analysis of bone biopsy samples can lead to a better understanding of the disease pathogenesis. The diagnostic pathway of EOOP is often complicated and extensive assessments may be needed to reliably exclude secondary causes. Due to the genetic heterogeneity and overlapping features in the various genetic forms of EOOP and other bone fragility disorders, the genetic diagnosis usually requires the use of next-generation sequencing to investigate several genes simultaneously. Recent discoveries have elucidated the complexity of disease pathogenesis both regarding genetic architecture and bone tissue-level pathology. Two rare monogenic forms of EOOP are due to defects in genes partaking in the canonical WNT pathway: LRP5 and WNT1. Variants in the genes encoding plastin-3 (PLS3) and sphingomyelin synthase 2 (SGMS2) have also been found in children and young adults with skeletal fragility. The molecular mechanisms leading from gene defects to clinical manifestations are often not fully understood. Detailed analysis of patient-derived transiliac bone biopsies gives valuable information to understand disease pathogenesis, distinguishes EOOP from other bone fragility disorders, and guides in patient management, but is not widely available in clinical settings. Despite the great advances in this field, EOOP remains an insufficiently explored entity and further research is needed to optimize diagnostic and therapeutic approaches. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Colágeno Tipo I , Osteoporose , Densidade Óssea/genética , Osso e Ossos/patologia , Criança , Colágeno Tipo I/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Osteoporose/genética , Osteoporose/patologia , Via de Sinalização Wnt , Adulto Jovem
6.
Front Endocrinol (Lausanne) ; 13: 907914, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35966102

RESUMO

Despite the development of non-invasive methods, bone histomorphometry remains the only method to analyze bone at the tissue and cell levels. Quantitative analysis of transiliac bone sections requires strict methodologic conditions but since its foundation more 60 years ago, this methodology has progressed. Our purpose was to review the evolution of bone histomorphometry over the years and its contribution to the knowledge of bone tissue metabolism under normal and pathological conditions and the understanding of the action mechanisms of therapeutic drugs in humans. The two main applications of bone histomorphometry are the diagnosis of bone diseases and research. It is warranted for the diagnosis of mineralization defects as in osteomalacia, of other causes of osteoporosis as bone mastocytosis, or the classification of renal osteodystrophy. Bone biopsies are required in clinical trials to evaluate the safety and mechanism of action of new therapeutic agents and were applied to anti-osteoporotic agents such as bisphosphonates and denosumab, an anti-RANKL, which induces a marked reduction of the bone turnover with a consequent elongation of the mineralization period. In contrast, an increased bone turnover with an extension of the formation site is observed with teriparatide. Romosozumab, an anti-sclerostin, has a dual effect with an early increased formation and reduced resorption. Bone histomorphometric studies allow us to understand the mechanism of coupling between formation and resorption and to evaluate the respective role of bone modeling and remodeling. The adaptation of new image analysis techniques will help bone biopsy analysis in the future.


Assuntos
Osso e Ossos , Osteoporose , Remodelação Óssea , Osso e Ossos/patologia , Difosfonatos , Humanos , Osteoporose/patologia
7.
Clin Nucl Med ; 47(9): e613-e615, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35930716

RESUMO

ABSTRACT: Incidental concomitant second primary malignancy may be detected on PET/CT imaging. We present an 18F-fluciclovine PET/CT of a patient undergoing evaluation of biochemically recurrent prostate cancer with incidental radiotracer uptake within lytic osseous lesions confirmed to be multiple myeloma. We present the 18F-fluciclovine PET/CT images of an 83-year-old man with prostate cancer treated in 2005 who presented with back pain and a CT scan revealing multiple lytic osseous lesions concerning for metastases versus a plasma cell neoplasm. Prostate-specific antigen at the time of evaluation was 0.1 ng/mL.


Assuntos
Ciclobutanos , Mieloma Múltiplo , Neoplasias da Próstata , Idoso de 80 Anos ou mais , Osso e Ossos/patologia , Ácidos Carboxílicos , Humanos , Masculino , Mieloma Múltiplo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Próstata/patologia , Tomografia Computadorizada por Raios X
8.
Artigo em Inglês | MEDLINE | ID: mdl-35954639

RESUMO

(1) Background: Avascular necrosis (AVN) may affect every part of the bone. Epiphyseal infarcts are likely to be treated early because most are symptomatic. However, meta- and diaphyseal infarcts are silent and are diagnosed incidentally. Sarcomas developing in the necrotic bone are extremely rare, but they have been reported in the literature. (2) Methods: We conducted a mapping review of recent evidence regarding these malignancies. Methods: A mapping review using a systematic search strategy was conducted to answer research questions. We limited our research to the last ten years (2012-2022). (3) Results: A total of 11 papers were identified, including 9 case reports and 3 case series. The pathomechanism of carcinogenesis in AVN was not investigated to date. Histologically, most tumors were malignant fibrous histiocytoma. The prognosis is relatively poor, especially for patients with metastases, but adjuvant chemotherapy may increase short- and long-term survival. (4) Conclusions: Since AVN-related malignancies are sporadic, no prospective studies have been conducted. The majority of evidence comes from small case series. More research is needed to identify the risk factors that would justify follow-up of patients after bone infarcts at higher risk of developing a malignancy.


Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Osso e Ossos/patologia , Carcinogênese , Humanos , Infarto/patologia
9.
Cartilage ; 13(3): 19476035221118166, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36004407

RESUMO

OBJECTIVE: To evaluate pathological changes in cartilage and subchondral bone MRI biomarkers in a rabbit model of osteoarthritis (OA) and correlate these with histological variations. DESIGN: Transection of the anterior cruciate ligament was performed on the right knee of eighteen 12-week-old New Zealand white rabbits to induce OA. 3-Tesla MR images were obtained from 18 healthy control knees (left) and 18 knees with OA (right). Imaging biomarkers included volume, thickness, T1 and T2* cartilage parametric maps, and several subchondral bone features: bone volume to total volume ratio, trabecular thickness, trabecular spacing, trabecular number (TbN), 2D and 3D fractal dimensions, and quality of trabecular score (QTS). Microscopic analysis of the lateral femoral condyles was set as the ground truth. RESULTS: When healthy and osteoarthritic knees were compared, significant differences were seen in the T1 and T2* values of the femur and tibia cartilage and in the subchondral bone volume to total volume, TbN, and QTS of both the lateral and medial aspects of the femur and tibia. Histological findings revealed significant osteoarthritic changes between healthy and osteoarthritic knees in stain, structure, chondrocyte density, total score, and subchondral bone biomarker levels. A positive correlation was found between histological staining, structure, chondrocyte density, and total score variables in T1 and T2* cartilage biomarkers. A negative correlation was observed between histological subchondral bone variables and magnetic resonance D2D and QTS biomarkers. CONCLUSION: Quantification of several cartilage and subchondral bone imaging biomarkers in a rabbit model of OA allows the detection of significant changes, which are correlated with histological findings.


Assuntos
Cartilagem Articular , Osteoartrite do Joelho , Animais , Biomarcadores , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Imageamento por Ressonância Magnética/métodos , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/patologia , Coelhos
10.
ACS Biomater Sci Eng ; 8(8): 3199-3219, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35816626

RESUMO

As bone grafts become more commonly needed by patients and as donors become scarcer, acellularized bone grafts (ABGs) are becoming more popular for restorative purposes. While autogeneic grafts are reliable as a gold standard, allogeneic and xenogeneic ABGs have been shown to be of particular interest due to the limited availability of autogeneic resources and reduced patient well-being in long-term surgeries. Because of the complete similarity of their structures with native bone, excellent mechanical properties, high biocompatibility, and similarities of biological behaviors (osteoinductive and osteoconductive) with local bones, successful outcomes of allogeneic and xenogeneic ABGs in both in vitro and in vivo research have raised hopes of repairing patients' bone injuries in clinical applications. However, clinical trials have been delayed due to a lack of standardized protocols pertaining to acellularization, cell seeding, maintenance, and diversity of ABG evaluation criteria. This study sought to uncover these factors by exploring the bone structures, ossification properties of ABGs, sources, benefits, and challenges of acellularization approaches (physical, chemical, and enzymatic), cell loading, and type of cells used and effects of each of the above items on the regenerative technologies. To gain a perspective on the repair and commercialization of products before implementing new research activities, this study describes the differences between ABGs created by various techniques and methods applied to them. With a comprehensive understanding of ABG behavior, future research focused on treating bone defects could provide a better way to combine the treatment approaches needed to treat bone defects.


Assuntos
Regeneração Óssea , Transplante Ósseo/métodos , Osso e Ossos/patologia , Transplante Heterólogo/normas , Transplante Homólogo/normas , Transplante Ósseo/normas , Osso e Ossos/fisiologia , Osso e Ossos/cirurgia , Humanos , Osteogênese , Transplante Heterólogo/métodos , Transplante Homólogo/métodos
11.
Int J Paleopathol ; 38: 55-63, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35816770

RESUMO

OBJECTIVE: This study explores the validity of Paget's disease of bone (PDB) reported in unpublished skeletal reports, based on macroscopic analysis alone. MATERIALS: The high prevalence of 'suspected' Paget's disease (10.7%) in an early modern sample from St John's the Evangelist Church in Redhill, Surrey is reassessed. METHODS: Signs of PDB were examined in 53 well-preserved adults aged 35 + years using macroscopic, radiographic and histological techniques. RESULTS: Macroscopic features of PDB were identified in 8 individuals (15%), with 5 individuals later rejected using radiography. Two individuals showed classic radiographic features of PDB, with a third presenting possible features in radiography (5.7%). These three cases were confirmed by histological analysis. CONCLUSIONS: PDB should not be suggested as a single diagnosis in cases of bone hypertrophy without confirmation using radiography. SIGNIFICANCE: The growing popularity of 'big data' projects and limited collections access means that unpublished cases of PDB are often included in large scale analyses, impacting our understanding of the evolution of this disease. Using macroscopic analysis alone leads to overdiagnosis. Histological analysis is unnecessary when radiographic features are present, but provides a useful diagnostic step in long bones in advanced cases of PBD. LIMITATIONS: The radiographic sample in this study was limited to three individuals. SUGGESTIONS FOR FURTHER RESEARCH: The conclusion that radiography alone can be used to identify PDB in archaeological cases merits further research on a larger number of cases.


Assuntos
Osteíte Deformante , Adulto , Osso e Ossos/patologia , Humanos , Osteíte Deformante/diagnóstico por imagem , Osteíte Deformante/patologia , Sobrediagnóstico , Prevalência , Radiografia
12.
Clin Exp Metastasis ; 39(5): 727-742, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35907112

RESUMO

Despite the significant progress made over the past decade with combination of molecular profiling data and the development of new clinical strategies, our understanding of metastasis remains elusive. Bone metastasis is a complex process and a major cause of mortality in breast and prostate cancer patients, for which there is no effective treatment to-date. The current review summarizes the routes taken by the metastatic cells and the interactions between them and the bone microenvironment. We emphasize the role of the specified niches and cues that promote cellular adhesion, colonization, prolonged dormancy, and reactivation. Understanding these mechanisms will provide better insights for future studies and treatment strategies for bone metastatic conditions.


Assuntos
Neoplasias Ósseas , Neoplasias da Próstata , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Osso e Ossos/patologia , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Microambiente Tumoral
13.
Cell Commun Signal ; 20(1): 94, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35715847

RESUMO

BACKGROUND: Chemoattractant is critical to recruitment of osteoclast precursors and stimulates tumor bone metastasis. However, the role of chemoattractant in bone metastasis of colorectal cancer (CRC) is still unclear. METHODS: Histochemistry analysis and TRAP staining were utilized to detect the bone resorption and activation of osteoclasts (OCs) after administration of CCL7 neutralizing antibody or CCR1 siRNA. qRT-PCR analysis and ELISA assay were performed to detect the mRNA level and protein level of chemoattractant. BrdU assay and Tunel assay were used to detect the proliferation and apoptosis of osteoclast precursors (OCPs). The migration of OCPs was detected by Transwell assay. Western blots assay was performed to examine the protein levels of pathways regulating the expression of CCL7 or CCR1. RESULTS: OCPs-derived CCL7 was significantly upregulated in bone marrow after bone metastasis of CRC. Blockage of CCL7 efficiently prevented bone resorption. Administration of CCL7 promoted the migration of OCPs. Lactate promoted the expression of CCL7 through JNK pathway. In addition, CCR1 was the most important receptor of CCL7. CONCLUSION: Our study indicates the essential role of CCL7-CCR1 signaling for recruitment of OCPs in early bone metastasis of CRC. Targeting CCL7 or CCR1 could restore the bone volume, which could be a potential therapeutical target. Video Abstract.


Assuntos
Neoplasias Ósseas , Quimiocina CCL7 , Neoplasias Colorretais , Osteoclastos , Osteólise , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Quimiocina CCL7/metabolismo , Fatores Quimiotáticos/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Osteoclastos/patologia , Osteólise/metabolismo , Regulação para Cima
14.
PLoS One ; 17(6): e0269335, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35657923

RESUMO

BACKGROUND: Bone metastases in breast cancer patients are a common concern for medical doctors and dentists. Bone-modifying agents, which are necessary to prevent skeletal-related events (SREs), are associated with osteonecrosis of the jaw as an adverse side effect. Hypersensitivity to alcohol is an unfavorable response caused by deficiency of aldehyde dehydrogenase-2 (ALDH2) activity. Inactive ALDH2 is associated with osteoporosis, but its influence on bone metastases is unclear. The aim of our study was to evaluate the effects of alcohol sensitivity on bone metastases and SREs in primary operable breast cancer patients. METHODS: We retrospectively analyzed patients who were administered docetaxel, an anti-tumor agent, for histologically diagnosed breast cancer between April 2004 and September 2015. Alcohol sensitivity was assessed based on medical records of hypersensitivity to alcohol. The primary endpoint was time to bone metastases and the secondary endpoint was time to first SRE from the initial docetaxel administration. Data were stratified by alcohol sensitivity and tumor stages, and differences were estimated by the Kaplan-Meier method. Prognostic risk factors were analyzed by the multivariate Cox proportional hazards model. RESULTS: The median follow-up period of patients with high sensitivity to alcohol (n = 45) was 54 months and that for those with low sensitivity (n = 287) was 64 months. Stratification by alcohol sensitivity revealed that tumor stage exhibited significant correlations with the cumulative incidence of bone metastases in low-sensitivity patients; however, no differences were found in high-sensitivity patients. In multivariate analysis, alcohol sensitivity was a significant prognostic risk factor for bone metastases (HR 2.721, 95% CI 1.268-5.841, P = 0.010). CONCLUSION: Alcohol sensitivity may be a prognostic risk factor for bone metastases. More detailed genetic investigations and metabolic analyses are needed.


Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Aldeído-Desidrogenase Mitocondrial , Neoplasias Ósseas/secundário , Osso e Ossos/patologia , Neoplasias da Mama/patologia , Difosfonatos/uso terapêutico , Docetaxel/uso terapêutico , Feminino , Humanos , Estudos Retrospectivos
15.
Mol Genet Genomic Med ; 10(9): e2004, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35758145

RESUMO

BACKGROUND: Gnathodiaphyseal dysplasia (GDD) is an ultrarare autosomal dominant bone dysplasia characterized by cementoosseous lesions of the jawbones, bone fragility, frequent bone fractures at the young age, bowing of tubular bones, and diaphyseal sclerosis of long bones associated with generalized osteopenia. GDD is caused by point mutations in anoctamin-5 (ANO5) on chromosome 11p14.3. For the past few years, next generation sequencing (NGS) technology has facilitated the discovery of causative variants in genetically heterogeneous diseases. METHODS: In this study, exome sequencing (ES) was performed using the DNA sample of the proband. Family histories and clinical information were collected through comprehensive medical examination and genetic counseling. RESULTS: ES results identified a heterozygous variant, NM_213599.3:c.1078T>C(p.Cys360Arg) in the ANO5 gene. Sanger sequencing was performed to confirm the detected pathogenic variant in DNA samples of the entire family (except deceased individuals), which segregated with the disease within the family. Finally, in silico analysis was applied to test the pathogenicity of the variant using various online software. CONCLUSION: In summary, our investigation identified a novel pathogenic variant in the ANO5, responsible for gnathodiaphyseal dysplasia in a large Iranian family. Therefore, based on the present study, this variant can be helpful for diagnosis and effective management of GDD patients.


Assuntos
Anoctaminas , Osteogênese Imperfeita , Anoctaminas/genética , Osso e Ossos/patologia , Humanos , Irã (Geográfico) , Osteogênese Imperfeita/patologia
16.
J Bone Miner Res ; 37(9): 1700-1710, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35770824

RESUMO

Osteoarthritis (OA) is the most common joint disease, where articular cartilage degradation is often accompanied with sclerosis of the subchondral bone. However, the association between OA and tissue mineralization at the nanostructural level is currently not understood. In particular, it is technically challenging to study calcified cartilage, where relevant but poorly understood pathological processes such as tidemark multiplication and advancement occur. Here, we used state-of-the-art microfocus small-angle X-ray scattering with a 5-µm spatial resolution to determine the size and organization of the mineral crystals at the nanostructural level in human subchondral bone and calcified cartilage. Specimens with a wide spectrum of OA severities were acquired from both medial and lateral compartments of medial compartment knee OA patients (n = 15) and cadaver knees (n = 10). Opposing the common notion, we found that calcified cartilage has thicker and more mutually aligned mineral crystals than adjoining bone. In addition, we, for the first time, identified a well-defined layer of calcified cartilage associated with pathological tidemark multiplication, containing 0.32 nm thicker crystals compared to the rest of calcified cartilage. Finally, we found 0.2 nm thicker mineral crystals in both tissues of the lateral compartment in OA compared with healthy knees, indicating a loading-related disease process because the lateral compartment is typically less loaded in medial compartment knee OA. In summary, we report novel changes in mineral crystal thickness during OA. Our data suggest that unloading in the knee might be involved with the growth of mineral crystals, which is especially evident in the calcified cartilage. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Cartilagem Articular , Osteoartrite do Joelho , Osteoartrite , Osso e Ossos/patologia , Cartilagem Articular/patologia , Humanos , Articulação do Joelho/patologia , Minerais/metabolismo , Osteoartrite/metabolismo , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/patologia
17.
Bone ; 162: 116451, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35654352

RESUMO

INTRODUCTION: Osteogenesis imperfecta (OI) is a heterogenous group of heritable connective tissue disorders characterized by high bone fragility due to low bone mass and impaired bone material properties. Atypical type VI OI is an extremely rare and severe form of bone dysplasia resulting from a loss-of-function mutation (p.S40L) in IFITM5/BRIL,the causative gene of OI type V and decreased osteoblast secretion of pigment epithelium-derived factor (PEDF), as in OI type VI. It is not yet known which alterations at the material level might lead to such a severe phenotype. We therefore characterized bone tissue at the micrometer level in a novel heterozygous Ifitm5/BRIL p.S42L knock-in murine model at 4 and 8 weeks of age. METHODS: We evaluated in female mice, total body size, femoral and lumbar bone mineral density (BMD) by dual-energy X-ray absorptiometry. In the femoral bone we examined osteoid deposition by light microscopy, assessed bone histomorphometry and mineralization density distribution by quantitative backscattered electron imaging (qBEI). Osteocyte lacunae were examined by qBEI and the osteocyte lacuno-canalicular network by confocal laser scanning microscopy. Vasculature was examined indirectly by qBEI as 2D porosity in cortex, and as 3D porosity by micro-CT in third trochanter. Collagen orientation was examined by second harmonic generation microscopy. Two-way ANOVA was used to discriminate the effect of age and genotype. RESULTS: Ifitm5/BRIL p.S42L female mice are viable, do not differ in body size, fat and lean mass from wild type (WT) littermates but have lower whole-body, lumbar and femoral BMD and multiple fractures. The average and most frequent calcium concentration, CaMean and CaPeak, increased with age in metaphyseal and cortical bone in both genotypes and were always higher in Ifitm5/BRIL p.S42L than in WT, except CaMean in metaphysis at 4 weeks of age. The fraction of highly mineralized bone area, CaHigh, was also increased in Ifitm5/BRIL p.S42L metaphyseal bone at 8 weeks of age and at both ages in cortical bone. The fraction of lowly mineralized bone area, CaLow, decreased with age and was not higher in Ifitm5/BRIL p.S42L, consistent with lack of hyperosteoidosis on histological sections by visual exam. Osteocyte lacunae density was higher in Ifitm5/BRIL p.S42L than WT, whereas canalicular density was decreased. Indirect measurements of vascularity revealed a higher pore density at 4 weeks in cortical bone of Ifitm5/BRIL p.S42L than in WT and at both ages in the third trochanter. Importantly, the proportion of bone area with disordered collagen fibrils was highly increased in Ifitm5/BRIL p.S42L at both ages. CONCLUSIONS: Despite normal skeletal growth and the lack of a collagen gene mutation, the Ifitm5/BRIL p.S42L mouse shows major OI-related bone tissue alterations such as hypermineralization of the matrix and elevated osteocyte porosity. Together with the disordered lacuno-canalicular network and the disordered collagen fibril orientation, these abnormalities likely contribute to overall bone fragility.


Assuntos
Modelos Animais de Doenças , Osteogênese Imperfeita , Animais , Densidade Óssea/genética , Osso e Ossos/patologia , Colágeno , Feminino , Técnicas de Introdução de Genes , Proteínas de Membrana/genética , Camundongos , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia
18.
BMC Musculoskelet Disord ; 23(1): 448, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35550061

RESUMO

BACKGROUND: Hyperplasia of the hematopoietic bone marrow in the appendicular skeleton is common. In contrast, focal hematopoietic islands within the axial skeleton are a rare entity and can confuse with osteoblastic metastases. This study aimed to characterize typical MRI and CT findings of hematopoietic islands in distinction from osteoblastic metastases to help both radiologists and clinicians, on the one hand, not to overdiagnose this entity and, on the other hand, to decide on a reasonable work-up. METHODS: We retrospectively analyzed the imaging findings of 14 hematopoietic islands of the axial skeleton in ten patients (nine females, median age = 65.5 years [range, 49-74]) who received both MRI and CT at initial diagnosis between 2006 and 2020. CT-guided biopsy was performed in five cases to confirm the diagnosis, while the other five patients received long-term MRI follow-up (median follow-up = 28 months [range, 6-96 months]). Diffusion-weighted imaging was available in three, chemical shift imaging respectively 18F- fluorodeoxyglucose PET/CT in two, and Technetium 99 m skeletal scintigraphy in one of the patients. RESULTS: All lesions were small (mean size = 1.72 cm2) and showed moderate hypointense signals on T1- and T2-weighted MRI sequences. They appeared isointense to slightly hyperintense on STIR images and slightly enhanced after gadolinium administration. To differentiate this entity from osteoblastic metastases, CT provides important additional information, as hematopoietic islands do not show sclerosis. CONCLUSIONS: Hematopoietic islands within the axial skeleton can occur and mimic osteoblastic metastases. However, the combination of MRI and CT allows for making the correct diagnosis in most cases.


Assuntos
Neoplasias Ósseas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Idoso , Neoplasias Ósseas/patologia , Osso e Ossos/patologia , Feminino , Fluordesoxiglucose F18 , Gadolínio , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Retrospectivos
19.
Pediatr Diabetes ; 23(6): 773-782, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35603554

RESUMO

OBJECTIVE: To describe bone mineral density (BMD), bone structure, and fracture prevalence in adolescents with type 1 diabetes (T1D) and explore their associations with glycemic control and microvascular complications. RESEARCH DESIGN AND METHODS: Cross sectional study of 64 adolescents (38 males) with T1D duration >10 years who underwent dual-energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), fracture survey, plantar fascia thickness, and microvascular complications assessment. RESULTS: Mean age was 16.6 ± 2.1 years, diabetes duration 12.8 ± 2.2 years and HbA1c 8.9 ± 1.7% (74 mmol/mol). Fracture prevalence was 50%. DXA areal BMD (Z-score) was reduced for femoral neck (-0.5 ± 1.3, p = 0.008) and arm (-0.4 ± 1.0, p < 0.001), while total areal BMD and lumbar spine BMD were normal. In pQCT (Z-score), trabecular volumetric BMD (vBMD) was reduced for tibia (-0.4 ± 0.8, p < 0.001) and radius (-0.8 ± 1.4, p < 0.001) whereas cortical vBMD was increased at both sites (tibia: 0.5 ± 0.6, p < 0.001, radius: 0.7 ± 1.5, p < 0.001). Muscle cross-sectional area (CSA) was reduced for upper (-0.6 ± 1.2, p < 0.001) and lower (-0.4 ± 0.7, p < 0.001) limbs. DXA total areal BMD was positively correlated with BMI (p < 0.01) and age at T1D diagnosis (p = 0.04). Lower radial bone CSA, total and lumbar spine BMD were associated with autonomic nerve dysfunction. HbA1c, diabetes duration, fracture history and other microvascular complications were not significantly associated with bone parameters. CONCLUSIONS: Adolescents with childhood-onset T1D have site-specific bone deficits in upper and lower limbs but normal total and lumbar spine BMD. T1D appears to have differential effects on trabecular and cortical bone compartments. Future longitudinal analysis is warranted to examine whether these changes translate in to increased fracture risk.


Assuntos
Desenvolvimento Ósseo , Osso e Ossos , Diabetes Mellitus Tipo 1 , Absorciometria de Fóton , Adolescente , Densidade Óssea/fisiologia , Osso e Ossos/patologia , Criança , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Hemoglobina A Glicada , Humanos , Masculino
20.
Genes Immun ; 23(3-4): 141-148, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35581496

RESUMO

Enhancer of zeste homolog 2 (EZH2) has been noted to contribute to the pathogenesis of autoimmune diseases. This study sought to investigate the mechanism of EZH2 in osteoclast (OCL) and osteoblast (OBL) differentiation (OCLD/OBLD) and bone destruction in RA. The animal model of collagen-induced arthritis (CIA) was established, followed by arthritis index (AI) scoring and histological staining, and measurements of inflammatory cytokines levels. The number of OCLs was detected via Tartrate-resistant acid phosphatase (TRAP) staining, and levels of OBL markers were determined by Western blot analysis. Trimethylated histone H3 at lysine 27 (H3K27me3) expression and its enrichment in the Ndrg2 promoter were detected. Collaborative experiments were performed with GSK-J1 or sh-Ndrg2 in CIA mice with EZH2 knockdown. EZH2 was upregulated while Ndrg2 was downregulated in knee joint tissues of CIA mice. Silencing EZH2 reduced AI scores, pathological injury of the knee joint, levels of inflammatory cytokines, and TRAP-positive cells, and increased protein levels of RUNX2 and BMP2. EZH2 promoted H3K27me3 level in the Ndrg2 promoter to inhibit Ndrg2 transcription. H3K27me3 upregulation or Ndrg2 downregulation reversed the role of silencing EZH2 in bone destruction. Overall, EZH2 repressed OBLD and promoted OCLD to aggravate bone destruction in CIA mice through H3K27me3/Ndrg2.


Assuntos
Artrite Experimental , Proteína Potenciadora do Homólogo 2 de Zeste , Osteoblastos , Osteoclastos , Animais , Artrite Experimental/complicações , Artrite Experimental/genética , Osso e Ossos/patologia , Diferenciação Celular , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Histonas/metabolismo , Camundongos , Osteoblastos/citologia , Osteoclastos/citologia
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