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1.
Front Pharmacol ; 12: 711004, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630086

RESUMO

Background: Shen-sui-tong-zhi formula (SSTZF) has been used to treat osteoporosis for decades and shows excellent clinical efficacy. This article aims to explore the optimal anti-osteoporotic ingredient and its precise mechanisms in mice models. Methods: In this study, we first screened the optimal anti-osteoporosis fraction of SSTZF extract in vivo, and then further explored the mechanism of its effects both in vivo and in vitro. Ten-week-old female C57BL/6J mice were administrated with each fraction of SSTZF. At 10 weeks after ovariectomy (OVX), femurs were collected for tissue analyses, including histology, micro-CT, biomechanical tests, and immunohistochemistry for ALP, FABP4, and ß-catenin. Additionally, we also evaluated the mRNA expression level of ALP and FABP4 and the protein expression level of ß-catenin after being treated with SSTZF extract in C3H10T1/2 cells. Moreover, we investigated the anti-osteoporosis effect of SSTZF extract on mice with ß-catenin conditional knockout in growth plate chondrocytes (ß-catenin Gli1ER mice) through µCT, histology, and immunohistochemistry analyzes. Results: At 10 weeks after treatment, osteoporosis-like phenotype were significantly ameliorated in SSTZF n-butanol extract (SSTZF-NB) group mice, as indicated by increased trabecular bone area and ALP content, and decreased lipid droplet area and FABP4 content. No such improvements were observed after being treated with other extracts, demonstrating that SSTZF-NB is the optimal anti-osteoporosis fraction. Additionally, the elevated ß-catenin was revealed in both OVX mice and C3H10T1/2 cells with SSTZF-NB administered. Furthermore, a significant osteoporosis-like phenotype was observed in ß-catenin Gli1ER mice as expected. However, SSTZF-NB failed to rescue the deterioration in ß-catenin Gli1ER mice, no significant re-upregulated ALP and downregulated FABP4 were observed after being treated with SSTZF-NB, demonstrating that SSTZF-NB prevents bone loss mainly via ß-catenin signaling. Conclusion: SSTZF-NB enhances osteogenesis mainly via activation of ß-catenin signaling in growth plate chondrocytes. SSTZF-NB is the optimal anti-osteoporosis fraction of SSTZF and it can be considered a salutary alternative therapeutic option for osteoporosis.

2.
Mater Sci Eng C Mater Biol Appl ; 128: 112326, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474877

RESUMO

Bone defects remain a challenging problem for doctors and patients in clinical practice. Processed pyritum is a traditional Chinese medicine that is often used to clinically treat bone fractures. It contains mainly Fe, Zn, Cu, Mn, and other elements. In this study, we added the extract of processed pyritum to ß-tricalcium phosphate and produced a porous composite TPP (TCP/processed pyritum) scaffold using digital light processing (DLP) 3D printing technology. Scanning electron microscopy (SEM) analysis revealed that TPP scaffolds contained interconnected pore structures. When compared with TCP scaffolds (1.35 ± 0.15 MPa), TPP scaffolds (5.50 ± 0.24 MPa) have stronger mechanical strength and can effectively induce osteoblast proliferation, differentiation, and mineralization in vitro. Meanwhile, the in vivo study showed that the TPP scaffold had better osteogenic capacity than the TCP scaffold. Furthermore, the TPP scaffold had good biosafety after implantation. In summary, the TPP scaffold is a promising biomaterial for the clinical treatment of bone defects.


Assuntos
Fosfatos de Cálcio , Tecidos Suporte , Humanos , Porosidade , Impressão Tridimensional
3.
Medicine (Baltimore) ; 100(20): e26040, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011115

RESUMO

BACKGROUND: Tumor-specific DNA methylation can potentially be a useful indicator in cancer diagnostics and monitoring. Sarcomas comprise a heterogeneous group of mesenchymal neoplasms which cause life-threatening tumors occurring throughout the body. Therefore, potential molecular detection and prognostic evaluation is very important for early diagnosis and treatment. METHODS: We performed a retrospective study analyzing DNA methylation of 261 patients with sarcoma from The Cancer Genome Atlas (TCGA) database. Cox regression analyses were conducted to identify a signature associated with the overall survival (OS) of patients with sarcoma, which was validated in a validation dataset. RESULTS: Three DNA methylation signatures were identified to be significantly associated with OS. Kaplan-Meier analysis showed that the 3-DNA methylation signature could significantly distinguish the high- and low-risk patients in both training (first two-thirds) and validation datasets (remaining one-third). Receiver operating characteristic (ROC) analysis confirmed that the 3-DNA methylation signature exhibited high sensitivity and specificity in predicting OS of patients. Also, the Kaplan-Meier analysis and the area under curve (AUC) values indicated that the 3-DNA methylation signature was independent of clinical characteristics, including age at diagnosis, sex, anatomic location, tumor residual classification, and histological subtypes. CONCLUSIONS: The current study showed that the 3-DNA methylation model could efficiently function as a novel and independent prognostic biomarker and therapeutic target for patients with sarcoma.


Assuntos
Metilação de DNA/fisiologia , Sarcoma/diagnóstico , Sarcoma/metabolismo , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Sarcoma/mortalidade , Neoplasias de Tecidos Moles/mortalidade , Adulto Jovem
5.
J Orthop Translat ; 26: 39-44, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33437621

RESUMO

Objective: To evaluate change in bone mineral density (BMD) during development of knee osteoarthritis (OA) in elderly Chinese community residents. Further, to monitor disease progression by recording speed of sound (SOS), one parameter of BMD provided by quantitative ultrasound measurement. Methods: A total of 4173 community residents of the Chinese mainland were organized to complete questionnaires and relevant measurements, including anthropometry, radiology and quantitative ultrasound (QUS). SOS measurements of the distal radius were acquired using QUS measurements. The Kellgren-Lawrence (KL) grade of knee OA was evaluated by two experienced radiographers using X-rays. Finally, a general linear models analysis was performed to determine potential relationships. Further, the area under the receiver operating characteristic curve (ROC AUC) was applied to assess the distinction model. Results: The SOS score in the OA group was significantly lower than that in the control group (p â€‹< â€‹0.001). However, after adjustment for age and body mass index (BMI), no significant difference was observed in the male population (p â€‹ï¼ â€‹0.841), while a significantly lower SOS score presented in knee OA participants in the female population (p â€‹ï¼ â€‹0.033). A turning point in SOS scores, from increasing to decreasing trends, occurred around KL grade 2; the SOS score gradually increased with progression in participants from KL grades 0 to 2, whereas the SOS score presented a significant decrease in participants with KL grades 3 and 4. The AUC for the model to distinguish OA progression was 0.891. Conclusion: There was a non-linear and stage-specific association between SOS score and knee OA, which presented a positive relationship in early stages, but a negative relationship in advanced stages. A decline of SOS score in knee OA patients in early stages should alert clinicians to the possibility of disease progression. The Translational potential of this article: In the present study, the relationship between OA and BMD had established by SOS. The results suggested that close monitoring of SOS in elderly Chinese communities residents with knee OA could alert disease progression involvement by an easily accessible method, and help early referral to orthopedist consultation for further examination and treatment.

6.
Cell Prolif ; 53(11): e12904, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32997394

RESUMO

OBJECTIVES: Most bone fracture heals through enchondral bone formation that relies on the involvement of periosteal progenitor cells. However, the identity of periosteal progenitor cells and the regulatory mechanism of their proliferation and differentiation remain unclear. The aim of this study was to investigate whether Gli1-CreERT2 can identify a population of murine periosteal progenitor cells and the role of TGF-ß signalling in periosteal progenitor cells on fracture healing. MATERIALS AND METHODS: Double heterozygous Gli1-CreERT2 ;Rosa26-tdTomatoflox/wt mice were sacrificed at different time points for tracing the fate of Gli1+ cells in both intact and fracture bone. Gli1-CreERT2 -mediated Tgfbr2 knockout (Gli1-CreERT2 ;Tgfbr2flox/flox ) mice were subjected to fracture surgery. At 4, 7, 10, 14 and 21 days post-surgery, tibia samples were harvested for tissue analyses including µCT, histology, real-time PCR and immunofluorescence staining. RESULTS: Through cell lineage-tracing experiments, we have revealed that Gli1-CreER T2 can be used to identify a subpopulation of periosteal progenitor cells in vivo that persistently reside in periosteum and contribute to osteochondral elements during fracture repair. During the healing process, TGF-ß signalling is continually activated in the reparative Gli1+ periosteal cells. Conditional knockout of Tgfbr2 in these cells leads to a delayed and impaired enchondral bone formation, at least partially due to the reduced proliferation and chondrogenic and osteogenic differentiation of Gli1+ periosteal cells. CONCLUSIONS: TGF-ß signalling plays an essential role on fracture repair via regulating enchondral bone formation process of Gli1+ periosteal cells.


Assuntos
Consolidação da Fratura , Osteogênese , Periósteo/citologia , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Diferenciação Celular , Feminino , Masculino , Camundongos , Periósteo/metabolismo , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismo , Tíbia/lesões , Tíbia/fisiologia
7.
Platelets ; : 1-10, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32835568

RESUMO

Steroid-associated necrosis of the femoral head (SANFH) is one of the most common and refractory chronic diseases with increasing incidence. The typical pathological changes of SANFH include decreased osteogenic differentiation, enhanced intramedullary adipocytes deposition and impaired osseous circulation. In this study, we investigated the effects and potential mechanisms of Platelet-rich plasma (PRP) on SANFH. Sixty Sprague-Dawley rats were randomly divided into the control, PRP donor, model, and PRP groups. Compared to the model group, PRP treatment significantly increased the hemorheological indexes and serum levels of bone gla-protein (BGP) and vascular endothelial growth factor (VEGF), while decreased the levels of triglyceride (TG) and total cholesterol (TC). Meanwhile, Micro-CT and histopathological stain (Hematoxylin-eosin and Alcian blue-hematoxylin/orange G staining) were performed on the femoral head for morphological and histopathological evaluation, indicating that bone trabecular microstructure and bone mineral density (BMD) were significantly improved after PRP treatment. Immunohistochemical analysis revealed that PRP remarkably up-regulated the expression of osteogenic markers including ß-catenin and alkaline phosphatase (ALP), angiogenic markers containing VEGF and platelet endothelial cell adhesion molecule-1 (CD31), while down-regulated adipogenic markers involving fatty acid-binding protein (FABP-4), and peroxisome proliferator-activated receptor gamma (PPAR-γ) in SANFH rat models. In summary, for the first time, PRP was demonstrated to prevent the development of SANFH through stimulating bone formation and vascularization as well as retarding adipogenesis.

8.
Biomed Pharmacother ; 130: 110581, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32745914

RESUMO

BACKGROUND: Radix Rehmanniae Praeparata (RR), the steamed roots of Rehmannia glutinosa, is a traditional Chinese medicine with the function of kidney-nourishing, and it has been safety used for centuries to treat bone-related disorders. The aim of this study is to investigate the positive effect and underlying mechanism of RR enhancing bone fracture healing in mouse model. METHODS: Ten-week-old C57BL/6J mice were subjected to a unilateral open transverse tibial fracture and provided a daily treatment of RR. Bone samples were harvested for tissue analyses including x-ray, µCT, histology, histomorphometry, biomechanical testing, immunohistochemical (IHC) and quantitative gene expression analysis. To determine the role of TGF-ß in accelerating fracture healing effect of RR, aforementioned experiments were performed on Gli1-CreER; Tgfbr2 flox/flox (Tgfbr2Gli1ER) conditional knockout mice. RESULTS: RR promoted bone fracture healing and strengthened bone intensity in wild-type and Cre- mice with the activation of TGF-ß/Smad2 signaling, on the contrary, RR failed to accelerating fracture healing in Tgfbr2Gli1ER mice. CONCLUSION: RR promotes bone fracture healing by intensify the contribution of Gli1+ cells on bone and cartilage formation mainly in TGF-ß-dependent manner. RR is an alternative option for clinical treatment of fracture.


Assuntos
Fraturas Ósseas/terapia , Células-Tronco Mesenquimais/metabolismo , Raízes de Plantas , Rehmannia , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Fraturas Ósseas/metabolismo , Masculino , Medicina Tradicional Chinesa , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Transdução de Sinais , Tíbia/lesões
9.
Phytomedicine ; 76: 153256, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534359

RESUMO

BACKGROUND: Although Bushenhuoxue formula (BSHXF) is successfully used as a non-traumatic therapy in treating bone fracture in China, the molecular mechanism underlying its effects remains poorly understood. PURPOSE: The present study aims to explore the therapeutic effects of BSHXF on fracture healing in mice and the underlying mechanism. METHODS: We performed unilateral open transverse tibial fracture procedure in C57BL/6 mice which were treated with or without BSHXF. Fracture callus tissues were collected and analyzed by X-ray, micro-CT, biomechanical testing, histopathology and quantitative gene expression analysis. Tibial fracture procedure was also performed in Cre-negative and Gli1-CreER; Tgfbr2flox/flox conditional knockout (KO) mice (Tgfbr2Gli1ER) to determine if BSHXF enhances fracture healing in a TGF-ß-dependent manner. In addition, scratch-wound assay and cell counting kit-8 (CCK-8) assay were used to evaluate the effect of BSHXF on cell migration and cell proliferation in C3H10T1/2 mesenchymal stem cells, respectively. RESULTS: BSHXF promoted endochondral ossification and enhanced bone strength in wild-type (WT) or Cre- control mice. In contrast, BSHXF failed to promote bone fracture healing in Tgfbr2Gli1ER conditional KO mice. In the mice receiving BSHXF treatment, TGF-ß/Smad2 signaling was significantly activated. Moreover, BSHXF enhanced cell migration and cell proliferation in C3H10T1/2 cells, which was strongly attenuated by the small molecule inhibitor SB525334 against TGF-ß type I receptor. CONCLUSION: These data demonstrated that BSHXF promotes fracture healing by activating TGF-ß/Smad2 signaling. BSHXF may be used as a type of alternative medicine for the treatment of bone fracture healing.

10.
Clin Auton Res ; 30(3): 197-205, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32232688

RESUMO

Identifying individuals at the earliest disease stage becomes crucial as we aim to develop disease-modifying treatments for neurodegenerative disorders. Prodromal diagnostic criteria were recently developed for Parkinson's disease (PD) and are forthcoming for dementia with Lewy bodies (DLB). The latest 2008 version of diagnostic criteria for multiple system atrophy (MSA) have improved diagnostic accuracy in early disease stages compared to previous criteria, but we do not yet have formal criteria for prodromal MSA. Building on similar approaches as for PD and DLB, we can identify features on history-taking, clinical examination, and ancillary clinical testing that can predict the likelihood of an individual developing MSA, while also distinguishing it from PD and DLB. The main clinical hallmarks of MSA are REM sleep behavior disorder (RBD) and autonomic dysfunction (particularly orthostatic hypotension and urogenital symptoms), and may be the primary means by which patients with potential prodromal MSA are identified. Preserved olfaction, absence of significant cognitive deficits, urinary retention, and respiratory symptoms such as stridor and respiratory insufficiency can be clinical features that help distinguish MSA from PD and DLB. Finally, ancillary test results including neuroimaging as well as serological and cerebrospinal fluid (CSF) biomarkers may lend further weight to quantifying the likelihood of phenoconversion into MSA. For prodromal criteria, the primary challenges are MSA's lower prevalence, shorter lead time to diagnosis, and strong overlap with other synucleinopathies. Future prodromal criteria may need to first embed the diagnosis into a general umbrella of prodromal alpha-synucleinopathies, followed by identification of features that suggest prodromal MSA as the specific cause.

11.
Biomed Pharmacother ; 127: 110170, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32334373

RESUMO

BACKGROUND: Bushenhuoxue formula (BSHXF) has shown excellent clinical effects on the treatment of osteoporosis in China. The aim of this study is to determine the anti-osteoporosis effects and precise molecular mechanisms of BSHXF on mouse models. METHODS: Ten-week-old female C57BL/6 J mice were subjected to ovariectomy and provided a daily treatment of BSHXF. At 8 weeks post-surgery, the femurs were harvested for tissue analyses including µCT, histology, qRT-PCR and immunohistochemical (IHC) staining of ß-catenin, ALP and FABP4. To investigate the role of ß-catenin in the anti-osteoporosis effects of BSHXF, relative experiments mentioned above were performed in ß-catenin conditional knockout mice. RESULTS: Ovariectomized (OVX) mice presented severe bone loss and excessive fat accumulation in the chondro-osseous junction underneath the growth plate, with decreased expression of ALP and increased expression of FABP4. BSHXF significantly recovered the OVX-induced abnormal osteogenesis and adipogenesis with the activation of ß-catenin in growth plate chondrocytes. Further, we generated growth plate chondrocyte-specific ß-catenin knockout (ß-cateninGli1ER) mice that exhibited bone loss and fat accumulation in the chondro-osseous junction, similar to the OVX mice. However, BSHXF failed to rescue the osteoporosis-like phenotype in ß-cateninGli1ER mice, indicating the anti-osteoporosis effects of BSHXF act mainly through ß-catenin signaling. No significant restoration of ALP and FABP4 was observed in ß-cateninGli1ER mice after the treatment of BSHXF. CONCLUSIONS: BSHXF attenuates osteoporosis by promoting osteogenic differentiation of growth plate chondrocytes mainly in ß-catenin-dependent manner. BSHXF is considered as a new candidate for the treatment of osteoporosis.


Assuntos
Condrócitos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Condrócitos/citologia , Feminino , Lâmina de Crescimento/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoporose/patologia , Ovariectomia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética , beta Catenina/metabolismo
12.
Biomed Pharmacother ; 120: 109520, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629251

RESUMO

OBJECTIVE: To investigate the effect and underlying mechanism of Yougui pills (YGPs) on steroid-related osteonecrosis of the femoral head (SONFH). METHODS: Male New Zealand white rabbits were divided into three groups: control group, SONFH group and YGPs group. Rabbit SONFH was induced by methylprednisolone (MPS) combined with lipopolysaccharide (LPS). At 6 weeks post induction, the femoral heads were harvested for tissue analyses, including histopathology, mechanical test of femoral heads, micro-CT, tartrate-resistant acid phosphatase (TRAP) staining, and immunohistochemistry for osteocalcin (OCN), vascular endothelial growth factor (VEGF) and ß-catenin. Protein levels of cathepsin K (CTSK), phospho-glycogen synthase kinase-3 beta (p-Ser9 GSK-3ß) and total glycogen synthase kinase-3 beta (GSK-3ß) in femoral heads were also detected. Additionally, the serum TRAP activity was measured using enzyme-linked immunosorbent assay (ELISA). Finally, the effects of YGPs treatment on osteoclast differentiation and osteoblast formation were evaluated in vitro. RESULTS: The ratio of empty lacuna was markedly lower in YGPs group than SONFH group. Micro-CT evaluation indicated that YGPs has a preventive effect on bone loss in rabbit SONFH. YGPs treatment could suppress bone resorption by reducing TRAP+ osteoclast and serum TRACP5b levels in necrotic femoral heads. Moreover, YGPs treatment could promote bone formation by up-regulating the expression of OCN, VEGF and ß-catenin, while increasing load-bearing capacity of femoral heads. Interestingly, p-Ser9 GSK-3ß downregulation, and CTSK upregulation in necrotic femoral head could be reversed by YGPs treatment, which also effectively inhibited RANKL-induced osteoclast differentiation and promoted osteoblast formation in vitro. CONCLUSION: YGPs could suppress osteoclastogenesis and promote bone formation during SONFH in rabbits by activating ß-catenin.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Necrose da Cabeça do Fêmur/prevenção & controle , Lipopolissacarídeos/toxicidade , Metilprednisolona/toxicidade , Osteonecrose/prevenção & controle , beta Catenina/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/toxicidade , Lipopolissacarídeos/administração & dosagem , Masculino , Metilprednisolona/administração & dosagem , Camundongos , Osteogênese/efeitos dos fármacos , Coelhos , Distribuição Aleatória , beta Catenina/genética
13.
J Cell Physiol ; 234(12): 21877-21888, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31049977

RESUMO

Emerging evidence suggests that microRNAs (miRNAs) may be pathologically involved in osteoarthritis (OA). Subchondral bone (SCB) sclerosis is accounted for the knee osteoarthritis (KOA) development and progression. In this study, we aimed to screen the miRNA biomarkers of KOA and investigated whether these miRNAs regulate the differentiation potential of mesenchymal stem cells (MSCs) and thus contributing to SCB. We identified 48 miRNAs in the blood samples in KOA patients (n = 5) through microarray expression profiling detection. After validation with larger sample number, we confirmed hsa-miR-582-5p and hsa-miR-424-5p were associated with the pathology of SCB sclerosis. Target genes prediction and pathway analysis were implemented with online databases, indicating these two candidate miRNAs were closely related to the pathways of pluripotency of stem cells and pathology of OA. Surprisingly, mmu-miR-582-5p (homology of hsa-miR-582-5p) was downregulated in osteogenic differentiation and upregulated in adipogenic differentiation of mesenchymal progenitor C3H10T1/2 cells, whereas mmu-mir-322-5p (homology of hsa-miR-424-5p) showed no change through the in vitro study. Supplementing mmu-miR-582-5p mimics blocked osteogenic and induced adipogenic differentiation of C3H10T1/2 cells, whereas silencing of the endogenous mmu-miR-582-5p enhanced osteogenic and repressed adipogenic differentiation. Further mechanism studies showed that mmu-miR-582-5p was directly targeted to Runx2. Mutation of putative mmu-miR-582-5p binding sites in Runx2 3' untranslated region (3'UTR) could abolish the response of the 3'UTR-luciferase construct to mmu-miR-582-5p supplementation. Generally speaking, our data suggest that miR-582-5p is an important biomarker of KOA and is able to regulate osteogenic and adipogenic differentiation of MSCs via targeting Runx2. The study also suggests that miR-582-5p may play a crucial role in SCB sclerosis of human KOA.


Assuntos
Articulação do Joelho/metabolismo , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Osteogênese/genética , Adipogenia/fisiologia , Diferenciação Celular/genética , Humanos , Osteoartrite/patologia
14.
J Cell Physiol ; 234(10): 18535-18543, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30912140

RESUMO

Although osteoarthritis (OA) in the hip joint is a common and debilitating degenerative disease, the precise molecular mechanisms underlying its pathological process remains unclear. This study sets out to investigate whether ß-catenin plays a critical role in hip OA pathogenesis. Here, we showed overexpressed ß-catenin protein in human OA cartilage tissues. Then, we analyzed ß-cat(ex3)Col2ER mice, in which ß-catenin gene was conditionally activated in femoral head chondrocytes. At 2 months of age, ß-cat(ex3)Col2ER mice already showed a phenotype of severe cartilage degeneration in the femoral head. More changes observed in ß-cat(ex3)Col2ER mice with age included subchondral sclerosis and osteophyte formation along joint margins, resembling a hip OA phenotype in humans. In addition, cartilage degradation and chondrocyte apoptosis as the results of ß-catenin activation possibly contributed to this hip OA-like phenotype. Overall our findings provide direct evidence about the importance of ß-catenin in hip OA pathogenesis.


Assuntos
Condrócitos/metabolismo , Condrócitos/patologia , Colágeno Tipo II/metabolismo , Articulação do Quadril/patologia , Osteoartrite/metabolismo , Osteoartrite/patologia , beta Catenina/metabolismo , Animais , Apoptose , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Matriz Extracelular/metabolismo , Integrases/metabolismo , Camundongos , Fenótipo
15.
Medicine (Baltimore) ; 98(5): e14318, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30702610

RESUMO

Children with fibrous dysplasia (FD) chronically suffer from pain, pathological fractures, and limb deformities. The most effective methods for managing the associated pathological fractures remain controversial. The purpose of this study was to evaluate the clinical results of the treatment of diaphyseal pathological fractures in children with monostotic fibrous dysplasia (MFD) using cortical strut allografts and internal plating.We retrospectively analyzed outcomes in nine children (5 boys, 4 girls) with diaphyseal pathological fractures due to MFD, who were treated with cortical strut allografts and internal plating (6 femoral fractures and 3 humeral fractures) between July 2007 and November 2012. The median age of patients in our study was 10 years (range 6-14 years). The fracture healing time, pain, extremity function, refracture, graft resorption, and complications were recorded to evaluate treatment effects.The median time of follow-up was 69 months (range 60-75 months). All patients had good postoperative fracture healing with a median healing time of 14 weeks (range 12-16 weeks). None experienced refracture, graft resorption, nerve injury, or limitation of extremity function or other complications. The fixation remained stable in all patients, with no evidence of loosening screws after surgery.In pediatric patients, the described surgical approach is an effective and reliable treatment method for diaphyseal pathological fractures caused by MFD. Cortical strut allografts, which act as biological bone plates, can provide good mechanical support while increasing the rate of fracture union.


Assuntos
Transplante Ósseo , Fraturas do Fêmur/cirurgia , Displasia Fibrosa Monostótica/complicações , Fixação Interna de Fraturas/métodos , Fraturas Espontâneas/cirurgia , Fraturas do Úmero/cirurgia , Placas Ósseas , Criança , Diáfises , Feminino , Fraturas do Fêmur/etiologia , Fixação Interna de Fraturas/instrumentação , Fraturas Espontâneas/etiologia , Humanos , Fraturas do Úmero/etiologia , Masculino , Estudos Retrospectivos
16.
Artigo em Inglês | MEDLINE | ID: mdl-30402118

RESUMO

Objective: To investigate the effect and underlying mechanism of Bushenhuoxue (BSHX) formula on articular cartilage repair. Methods: Twenty-four full-thickness cartilage defect rats were divided into two groups: model group and BSHX group (treated with BSHX formula). Macroscopic observation and histopathological study were conducted after 4- and 8-week treatment. Additionally, we also evaluated chondrocyte proliferation, extracellular matrix (ECM) deposition, cartilage degradation, and chondrocyte hypertrophy-related genes expression in chondrogenic ATDC5 cells cultured in BSHX formula-mediated serum. Moreover, we assessed aforementioned genes expression and pSMAD2/3 protein level in Tgfßr2 siRNA transfected chondrogenic ATDC5 cells in order to address whether BSHX formula exerts cartilage repairing effect through TGF-ß signaling. Results: Neocartilage regeneration promotion effect was observed in cartilage defect rats after BSHX formula treatment, with increases in Col2 and pSMAD2 and decreases in Mmp13 and Runx2. Moreover, cell proliferation, the elevated Col2a1, Aggrecan and pSMAD2/3, reduced Mmp13, Adamts5, Col10a1, and Runx2 expression were also observed in chondrogenic ATDC5 cells cultured in BSHX formula-mediated serum. Besides, the expression alteration of ECM deposition, cartilage degradation, chondrocyte hypertrophy-related genes, and pSMAD2/3 protein levels presented in Tgfßr2 downregulated chondrogenic ATDC5 cells couldn't be adjusted by BSHX formula treatment. Conclusion: By activation of TGF-ß signaling, BSHX formula can promote articular cartilage repair by accelerating chondrocyte proliferation and maintaining chondrocyte phenotype, upregulate ECM accumulation, and inhibit matrix degradation.

17.
Artigo em Inglês | MEDLINE | ID: mdl-28983518

RESUMO

Large-scale intrinsic brain systems have been identified for exteroceptive senses (e.g., sight, hearing, touch). We introduce an analogous system for representing sensations from within the body, called interoception, and demonstrate its relation to regulating peripheral systems in the body, called allostasis. Employing the recently introduced Embodied Predictive Interoception Coding (EPIC) model, we used tract-tracing studies of macaque monkeys, followed by two intrinsic functional magnetic resonance imaging samples (N = 280 and N = 270) to evaluate the existence of an intrinsic allostatic/interoceptive system in the human brain. Another sample (N = 41) allowed us to evaluate the convergent validity of the hypothesized allostatic/interoceptive system by showing that individuals with stronger connectivity between system hubs performed better on an implicit index of interoceptive ability related to autonomic fluctuations. Implications include insights for the brain's functional architecture, dissolving the artificial boundary between mind and body, and unifying mental and physical illness.

18.
PET Clin ; 12(3): 351-359, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28576172

RESUMO

Biomarkers of the molecular pathology underpinning dementia syndromes are increasingly recognized as crucial for diagnosis and development of disease-modifying treatments. Amyloid PET imaging is an integral part of the diagnostic assessment of Alzheimer disease. Its use has also deepened understanding of the role of amyloid pathology in Lewy body disorders and aging. Tau PET imaging is an imaging biomarker that will likely play an important role in the diagnosis, monitoring, and treatment in dementias. Using tau PET imaging to examine how tau pathology relates to amyloid and other markers of neurodegeneration will serve to better understand the pathophysiologic cascade that leads to dementia.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Demência/diagnóstico por imagem , Demência/metabolismo , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X , Proteínas tau/metabolismo
19.
CNS Spectr ; 22(6): 439-449, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28196556

RESUMO

Alzheimer's disease (AD) has long been recognized as a heterogeneous illness, with a common clinical presentation of progressive amnesia and less common "atypical" clinical presentations, including syndromes dominated by visual, aphasic, "frontal," or apraxic symptoms. Our knowledge of atypical clinical phenotypes of AD comes from clinicopathologic studies, but with the growing use of in vivo molecular biomarkers of amyloid and tau pathology, we are beginning to recognize that these syndromes may not be as rare as once thought. When a clinician is evaluating a patient whose clinical phenotype is dominated by progressive aphasia, complex visual impairment, or other neuropsychiatric symptoms with relative sparing of memory, the differential diagnosis may be broader and a confident diagnosis of an atypical form of AD may require the use of molecular biomarkers. Despite the evolving sophistication in our diagnostic tools, and the acknowledgment of atypical AD syndromes in the 2011 revised diagnostic criteria for AD, the assessment of such patients still poses substantial challenges. We use a case-based approach to review the clinical and imaging phenotypes of a series of patients with typical and atypical AD, and discuss our current approach to their evaluation. One day, we hope that regardless of whether a patient exhibits typical or atypical symptoms of AD pathology, we will be able to identify the condition at a prodromal phase and institute a combination of symptomatic and disease-modifying therapies to support cognitive processes, function, and behavior, and slow or halt progression to dementia.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Idoso , Encéfalo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos
20.
JAMA Neurol ; 74(4): 427-436, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28241163

RESUMO

Importance: Previous postmortem studies have long demonstrated that neurofibrillary tangles made of hyperphosphorylated tau proteins are closely associated with Alzheimer disease clinical phenotype and neurodegeneration pattern. Validating these associations in vivo will lead to new diagnostic tools for Alzheimer disease and better understanding of its neurobiology. Objective: To examine whether topographical distribution and severity of hyperphosphorylated tau pathologic findings measured by fluorine 18-labeled AV-1451 ([18F]AV-1451) positron emission tomographic (PET) imaging are linked with clinical phenotype and cortical atrophy in patients with Alzheimer disease. Design, Setting, and Participants: This observational case series, conducted from July 1, 2012, to July 30, 2015, in an outpatient referral center for patients with neurodegenerative diseases, included 6 patients: 3 with typical amnesic Alzheimer disease and 3 with atypical variants (posterior cortical atrophy, logopenic variant primary progressive aphasia, and corticobasal syndrome). Patients underwent [18F]AV-1451 PET imaging to measure tau burden, carbon 11-labeled Pittsburgh Compound B ([11C]PiB) PET imaging to measure amyloid burden, and structural magnetic resonance imaging to measure cortical thickness. Seventy-seven age-matched controls with normal cognitive function also underwent structural magnetic resonance imaging but not tau or amyloid PET imaging. Main Outcomes and Measures: Tau burden, amyloid burden, and cortical thickness. Results: In all 6 patients (3 women and 3 men; mean age 61.8 years), the underlying clinical phenotype was associated with the regional distribution of the [18F]AV-1451 signal. Furthermore, within 68 cortical regions of interest measured from each patient, the magnitude of cortical atrophy was strongly correlated with the magnitude of [18F]AV-1451 binding (3 patients with amnesic Alzheimer disease, r = -0.82; P < .001; r = -0.70; P < .001; r = -0.58; P < .001; and 3 patients with nonamnesic Alzheimer disease, r = -0.51; P < .001; r = -0.63; P < .001; r = -0.70; P < .001), but not of [11C]PiB binding. Conclusions and Relevance: These findings provide further in vivo evidence that distribution of the [18F]AV-1451 signal as seen on results of PET imaging is a valid marker of clinical symptoms and neurodegeneration. By localizing and quantifying hyperphosphorylated tau in vivo, results of tau PET imaging will likely serve as a key biomarker that links a specific type of molecular Alzheimer disease neuropathologic condition with clinically significant neurodegeneration, which will likely catalyze additional efforts to develop disease-modifying therapeutics.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Carbolinas/metabolismo , Córtex Cerebral/patologia , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Atrofia/diagnóstico por imagem , Atrofia/etiologia , Córtex Cerebral/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/metabolismo , Estudos Retrospectivos
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