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1.
Langmuir ; 37(14): 4137-4146, 2021 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-33813823

RESUMEN

Hydroxyapatite (HA) is the main inorganic component of human bones and teeth. It has good biocompatibility and bioactivity, which promotes its good application prospects in the field of bone drug carriers. In this study, tetraethylenepentamine-graphene (rGO-TEPA)/CaCO3:HA composite microspheres were prepared via microwave hydrothermal synthesis using rGO-TEPA/CaCO3 solid microspheres as intermediates. Furthermore, the incompletely transformed CaCO3 was removed by soaking in a citric acid buffer to obtain rGO-TEPA/HA hollow composite microspheres. The two types of as-prepared composite microspheres exhibited sea urchin-like structures, large BET surface areas, and good dispersibility. Mouse preosteoblast cells (MC3T3-E1) were used for in vitro cytotoxicity experiments. The in vitro cell viability test showed that the two composite drug carriers exhibited noncytotoxicity. Moreover, the doxorubicin (DOX) loading and releasing investigations revealed that the two types of prepared carriers had mild storage-release behaviors and good pH responsiveness. Hence, these rGO-TEPA/HA hollow microspheres have promising applications as bone drug carriers.


Asunto(s)
Materiales Biomiméticos , Huesos/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Durapatita , Grafito , Microesferas , Erizos de Mar , Animales , Huesos/citología , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/farmacología , Etilenodiaminas , Concentración de Iones de Hidrógeno , Ratones , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Células Madre/efectos de los fármacos
2.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805833

RESUMEN

A large British study, with almost 3000 patients, identified diabetes as main risk factor for delayed and nonunion fracture healing, the treatment of which causes large costs for the health system. In the past years, much progress has been made to treat common complications in diabetics. However, there is still a lack of advanced strategies to treat diabetic bone diseases. To develop such therapeutic strategies, mechanisms leading to massive bone alterations in diabetics have to be well understood. We herein describe an in vitro model displaying bone metabolism frequently observed in diabetics. The model is based on osteoblastic SaOS-2 cells, which in direct coculture, stimulate THP-1 cells to form osteoclasts. While in conventional 2D cocultures formation of mineralized matrix is decreased under pre-/diabetic conditions, formation of mineralized matrix is increased in 3D cocultures. Furthermore, we demonstrate a matrix stability of the 3D carrier that is decreased under pre-/diabetic conditions, resembling the in vivo situation in type 2 diabetics. In summary, our results show that a 3D environment is required in this in vitro model to mimic alterations in bone metabolism characteristic for pre-/diabetes. The ability to measure both osteoblast and osteoclast function, and their effect on mineralization and stability of the 3D carrier offers the possibility to use this model also for other purposes, e.g., drug screenings.


Asunto(s)
Huesos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Redes y Vías Metabólicas/genética , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Resorción Ósea/genética , Resorción Ósea/metabolismo , Resorción Ósea/patología , Huesos/patología , Calcificación Fisiológica/genética , Anhidrasa Carbónica II/genética , Anhidrasa Carbónica II/metabolismo , Catepsina K/genética , Catepsina K/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Técnicas de Cocultivo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Regulación de la Expresión Génica , Humanos , Modelos Biológicos , Osteoblastos/patología , Osteoclastos/patología , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , Células THP-1 , Fosfatasa Ácida Tartratorresistente/genética , Fosfatasa Ácida Tartratorresistente/metabolismo , Andamios del Tejido
3.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809315

RESUMEN

Patients with advanced breast cancer are at high risk of developing bone metastasis. Despite treatment advances for primary breast cancer, metastatic bone disease remains incurable with a low relative survival. Hence, new therapeutic approaches are required to improve survival and treatment outcome for these patients. Bone is among the most frequent sites of metastasis in breast cancer. Once in the bone, disseminated tumor cells can acquire a dormant state and remain quiescent until they resume growth, resulting in overt metastasis. At this stage the disease is characterized by excessive, osteoclast-mediated osteolysis. Cells of the bone microenvironment including osteoclasts, osteoblasts and endothelial cells contribute to the initiation and progression of breast cancer bone metastasis. Direct cell-to-cell contact as well as soluble factors regulate the crosstalk between disseminated breast cancer cells and bone cells. In this complex signaling network interleukins (ILs) have been identified as key regulators since both, cancer cells and bone cells secrete ILs and express corresponding receptors. ILs regulate differentiation and function of bone cells, with several ILs being reported to act pro-osteoclastogenic. Consistently, the expression level of ILs (e.g., in serum) has been associated with poor prognosis in breast cancer. In this review we discuss the role of the most extensively investigated ILs during the establishment of breast cancer bone metastasis and highlight their potential as therapeutic targets in preventing metastatic outgrowth in bone.


Asunto(s)
Neoplasias Óseas/genética , Neoplasias de la Mama/genética , Comunicación Celular/genética , Interleucinas/genética , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Huesos/metabolismo , Huesos/patología , Neoplasias de la Mama/patología , Linaje de la Célula/genética , Femenino , Humanos , Metástasis de la Neoplasia
4.
Life Sci ; 276: 119469, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33811892

RESUMEN

AIMS: Breast cancer-induced chronic pain is usually treated with opioids, but these compounds cause various adverse effects. Transient receptor potential ankyrin 1 (TRPA1) is involved in cancer pain; also, endogenous TRPA1 agonists are associated with cancer pain development. The aim of this study was to observe the antinociceptive effect of a repeated-dose TRPA1 antagonist administration and the production of endogenous TRPA1 agonists and TRPA1 expression in bone tissue in a model of breast cancer pain in mice. Second, we used a sequence reading archive (SRA) strategy to observe the presence of this channel in the mouse bone and in mouse bone cell lines. MAIN METHODS: We used BALB/c mice for experiments. The animals were subjected to the tumor cell inoculation (4 T1 strain). HC-030031 (a TRPA1 antagonist) treatment was done from day 11 to day 20 after tumor inoculation. TRPA1 expression and biochemical tests of oxidative stress were performed in the bone of mice (femur). SRA strategy was used to detect the TRPA1 presence. KEY FINDINGS: Repeated treatment with the TRPA1 antagonist produced an antinociceptive effect. There was an increase in hydrogen peroxide levels, NADPH oxidase and superoxide dismutase activities, but the expression of TRPA1 in the bone tissue was not altered. SRA did not show TRPA1 residual transcription in the osteoblast and osteoclast cell lines, as well as for mice cranial tissue and in mouse osteoclast precursors. SIGNIFICANCE: The TRPA1 receptor is a potential target for the development of new painkillers for the treatment of bone cancer pain.


Asunto(s)
Acetanilidas/farmacología , Huesos/efectos de los fármacos , Dolor en Cáncer/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Neoplasias Mamarias Animales/complicaciones , Nocicepción/efectos de los fármacos , Purinas/farmacología , Canal Catiónico TRPA1/antagonistas & inhibidores , Acetanilidas/administración & dosificación , Animales , Huesos/metabolismo , Dolor en Cáncer/etiología , Dolor en Cáncer/metabolismo , Dolor en Cáncer/patología , Femenino , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Hiperalgesia/patología , Ratones , Ratones Endogámicos BALB C , Purinas/administración & dosificación
5.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652598

RESUMEN

The search for the perfect bone graft material is an important topic in material science and medicine. Despite human bone being the ideal material, due to its composition, morphology, and familiarity with cells, autografts are widely considered demanding and cause additional stress to the patient because of bone harvesting. However, human bone from tissue banks can be used to prepare materials in eligible form for transplantation. Without proteins and fats, the bone becomes a non-immunogenic matrix for human cells to repopulate in the place of implantation. To repair bone losses, the granulate form of the material is easy to apply and forms an interconnected porous structure. A granulate composed of ß-tricalcium phosphate, pulverized human bone, and chitosan-a potent biopolymer applied in tissue engineering, regenerative medicine, and biotechnology-has been developed. A commercial encapsulator was used to obtain granulate, using chitosan gelation upon pH increase. The granulate has been proven in vitro to be non-cytotoxic, suitable for MG63 cell growth on its surface, and increasing alkaline phosphatase activity, an important biological marker of bone tissue growth. Moreover, the granulate is suitable for thermal sterilization without losing its form-increasing its convenience for application in surgery for guided bone regeneration in case of minor or non-load bearing voids in bone tissue.


Asunto(s)
Regeneración Ósea/efectos de los fármacos , Huesos/metabolismo , Fosfatos de Calcio , Quitosano , Ensayo de Materiales , Fosfatos de Calcio/química , Fosfatos de Calcio/farmacología , Línea Celular , Quitosano/química , Quitosano/farmacología , Humanos
6.
Poult Sci ; 100(3): 100808, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33518301

RESUMEN

Blood biochemistry and bone metabolism were evaluated to investigate the etiology and mechanism of spontaneous femoral head necrosis (FHN) in broilers. According to the femoral head score of the fourth, fifth, and sixth week old FHN-affected broilers, they were divided into 3 groups, namely Normal group, femoral head separation group, and femoral head separation with growth plate lacerations group, and then carried out a comparative study. The results showed that the liver function (alanine aminotransferase and aspartate aminotransferase) and lipid metabolism (high-density lipoprotein and triglyceride) levels of broilers with spontaneous FHN were significant changed compared with the normal group. At the same time, accumulation of lipid droplets appeared in the liver, which illustrated that the occurrence of FHN may be related to lipid metabolism disorders. Tibia and femur parameters showed significant changes in bone mineral density and bone strength. The distribution of chondrocytes in the articular cartilage of broilers with FHN was irregular and vacuoles appeared, which indicated that cartilage homeostasis was destroyed. TUNEL staining showed that the apoptosis rate of articular chondrocytes in broilers with FHN in 6-week-old was significantly higher than that of normal broilers. Meanwhile, the bone markers (bone glaprotein and bone-specific alkaline phosphatase) changed significantly, indicating that the articular chondrocyte apoptosis and bone metabolism disorder may occur in FHN-affected birds. Therefore, FHN in broilers may be caused by dyslipidemia and abnormal bone metabolism.


Asunto(s)
Huesos , Necrosis de la Cabeza Femoral , Metabolismo de los Lípidos , Enfermedades de las Aves de Corral , Animales , Huesos/metabolismo , Pollos , Necrosis de la Cabeza Femoral/fisiopatología , Necrosis de la Cabeza Femoral/veterinaria , Enfermedades de las Aves de Corral/etiología
7.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33572704

RESUMEN

Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/ß-catenin, BMP and RANKL/OPG, are outlined.


Asunto(s)
Regeneración Ósea , Huesos/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Animales , Huesos/citología , Humanos , Osteoblastos/citología , Osteoblastos/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Osteocitos/citología , Osteocitos/metabolismo
8.
Life Sci ; 272: 119204, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33581127

RESUMEN

AIMS: The involvement of several microRNAs (miRNAs) in osteogenic differentiation has been indicated recently. Also, exosomes, derived from different cells, could shuttle specific miRNAs to other cell systems. Nevertheless, the effect and mechanism of microRNA-935 (miR-935)-containing exosomes in osteoblasts remain basically unclear. The current work was set to inspect the relevance of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSC-exo) carrying miR-935 to osteoporotic rats. METHODS: The extracted BMSCs and purchased osteoblasts were cultured, followed by exosome isolation and identification. After cell grouping, osteoblasts were co-cultured with BMSCs. CCK-8, alizarin red staining as well as ALP staining were performed to detect osteoblast proliferation and activity. The binding connection between miR-935 and signal transducer and activator of transcription 1 (STAT1) was measured by dual-luciferase reporter gene assays. The expression profiles of miR-935, STAT1 and osteoblast-related proteins were assessed by RT-qPCR and Western blot. A rat model with osteoporosis was induced, and the BMD, BV/TV, Tb.N, Tb.Th and Tb.Sp values in rat bone tissues were observed by Micro-CT. RESULTS: BMSC-exo inhibited STAT1 levels by the delivery of miR-935 into osteoblasts, while STAT1 silencing promoted ALP activity in osteoblasts and mineralized nodules. STAT1 was identified as a target gene of miR-935. Moreover, in vivo experiments showed that in ovariectomized rats, silencing of miR-935 significantly reduced BMD, BV/TV, Tb.N, Tb.Th and increased Tb.Sp. CONCLUSION: BMSC-exo carry miR-935 to promote osteoblast proliferation and differentiation through targeting STAT1.


Asunto(s)
Exosomas/genética , MicroARNs/genética , Osteoblastos/metabolismo , Adulto , Animales , Células de la Médula Ósea/metabolismo , Huesos/metabolismo , Calcificación Fisiológica/genética , Calcificación Fisiológica/fisiología , Diferenciación Celular/genética , Proliferación Celular/genética , Células Cultivadas , Femenino , Humanos , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , Persona de Mediana Edad , Osteoblastos/fisiología , Osteogénesis/efectos de los fármacos , Osteoporosis/genética , Osteoporosis/fisiopatología , Ratas , Factor de Transcripción STAT1/metabolismo
9.
Life Sci ; 272: 119208, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33582177

RESUMEN

AIMS: The efficacy of anti-osteoporotic treatments is still limited. Our study aimed to investigate the effect of extracellular vesicles (EVs) derived from bone marrow-derived MSCs (BMSCs) overexpressing glycoprotein non-melanoma clone B (GPNMB) on osteoporosis (OP). MAIN METHODS: Lentiviral vector for GPNMB overexpression or its negative control was generated and transfected into BMSCs. EVs enriched with GPNMB (GPNMB-EVs) were extracted from GPNMB-modified BMSC-conditioned medium and then identified. Cellular uptake and proliferation were analyzed using the Dil-labeled assay and CCK-8 assay, respectively. Cytochemical staining, western blot, and RT-qPCR analysis were performed to assess the effect of GPNMB-EVs on osteogenic differentiation of BMSCs in vitro. Dickkopf-1 (DKK1) as the inhibitor was applied to explore the Wnt/ß-catenin signaling pathway involved in the GPNMB-EV-induced osteogenic differentiation. In vivo experiments were conducted using an ovariectomized (OVX) rat model of postmenopausal osteoporosis, and then assessed the effect of GPNMB-EVs by micro-CT, and histological and immunohistochemical assays. KEY FINDINGS: GPNMB-EVs were taken up by BMSCs, and they noticeably promoted the proliferation of BMSCs. Additionally, GPNMB-EVs activated the Wnt/ß-catenin signaling to stimulate osteogenesis in BMSCs. In vivo examination showed that GPNMB-EVs remarkably improved trabecular bone regeneration and alleviated the osteoporotic phenotype in the OVX-induced rat model of OP. SIGNIFICANCE: EVs derived from GPNMB-modified BMSCs significantly stimulated the proliferation and osteogenic differentiation of BMSCs via the activation of Wnt/ß-catenin signaling and attenuated the bone loss in the OVX-induced rat model of OP. Our findings suggest the promising potential of GPNMB-EVs as cell-free therapy for the treatment of OP.


Asunto(s)
Vesículas Extracelulares/metabolismo , Glicoproteínas de Membrana/farmacología , Osteoblastos/metabolismo , Animales , Médula Ósea/metabolismo , Células de la Médula Ósea/metabolismo , Huesos/metabolismo , Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Femenino , Glicoproteínas de Membrana/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/fisiología , Osteogénesis/efectos de los fármacos , Osteoporosis/metabolismo , Ovariectomía , Ratas , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo
10.
Int J Mol Med ; 47(4)2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33604678

RESUMEN

Glucosamine (GlcN) functions as a building block of the cartilage matrix, and its multifaceted roles in promoting joint health have been extensively investigated. However, the role of GlcN in osteogenesis and bone tissue is poorly understood, mainly due to the lack of adequate experimental models. As a result, the benefit of GlcN application in bone disorders remains controversial. In order to further elucidate the pharmacological relevance and potential therapeutic/nutraceutic efficacy of GlcN, the effect of GlcN treatment was investigated in human primary osteoclasts (hOCs) and osteoblasts (hOBs) that were cultured with two­dimensional (2D) traditional methods or co­cultured in a 3D dynamic system more closely resembling the in vivo bone microenvironment. Under these conditions, osteoclastogenesis was supported by hOBs and sizeable self­assembling aggregates were obtained. The differentiated hOCs were evaluated using tartrate­resistant acid phosphatase assays and osteogenic differentiation was monitored by analyzing mineral matrix deposition via Alizarin Red staining, with expression of specific osteogenic markers determined via reverse transcription­quantitative PCR. It was found that crystalline GlcN sulfate was effective in decreasing osteoclastic cell differentiation and function. hOCs isolated from patients with OA were more sensitive compared with those from healthy donors. Additionally, GlcN exhibited anabolic effects on hOCs both in 2D conventional cell culture and in hOC/hOB 3D dynamic co­culture. The present study demonstrated for the first time the effectiveness of a 3D dynamic co­culture system for characterizing the spectrum of action of GlcN on the bone microenvironment, which may pave the way for more fully determining the potential applications of a compound such as GlcN, which is positioned between pharmaceuticals and nutraceuticals. Based on the present findings, it is hypothesized that GlcN may have potential benefits in the treatment of osteopenic diseases such as osteoporosis, as well as in bone maintenance.


Asunto(s)
Huesos/metabolismo , Glucosamina/farmacología , Osteoblastos/citología , Osteoclastos/citología , Osteogénesis/efectos de los fármacos , Adulto , Anciano , Apoptosis/efectos de los fármacos , Células Cultivadas , Microambiente Celular/efectos de los fármacos , Técnicas de Cocultivo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/tratamiento farmacológico
11.
Nat Commun ; 12(1): 1031, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589620

RESUMEN

The application of physical stimuli to cell cultures has shown potential to modulate multiple cellular functions including migration, differentiation and survival. However, the relevance of these in vitro models to future potential extrapolation in vivo depends on whether stimuli can be applied "externally", without invasive procedures. Here, we report on the fabrication and exploitation of dynamic additive-manufactured Janus scaffolds that are activated on-command via external application of ultrasounds, resulting in a mechanical nanovibration that is transmitted to the surrounding cells. Janus scaffolds were spontaneously formed via phase-segregation of biodegradable polycaprolactone (PCL) and polylactide (PLA) blends during the manufacturing process and behave as ultrasound transducers (acoustic to mechanical) where the PLA and PCL phases represent the active and backing materials, respectively. Remote stimulation of Janus scaffolds led to enhanced cell proliferation, matrix deposition and osteogenic differentiation of seeded human bone marrow derived stromal cells (hBMSCs) via formation and activation of voltage-gated calcium ion channels.


Asunto(s)
Plásticos Biodegradables/farmacología , Mecanotransducción Celular , Células Madre Mesenquimatosas/efectos de los fármacos , Poliésteres/farmacología , Andamios del Tejido , Plásticos Biodegradables/química , Regeneración Ósea/genética , Huesos/citología , Huesos/metabolismo , Canales de Calcio Activados por la Liberación de Calcio/fisiología , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Poliésteres/química , Impresión Tridimensional , Ingeniería de Tejidos/métodos , Ondas Ultrasónicas
12.
Nat Commun ; 12(1): 1022, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589584

RESUMEN

Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid-liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Mieloma Múltiple/tratamiento farmacológico , Coactivador 3 de Receptor Nuclear/genética , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Huesos/efectos de los fármacos , Huesos/metabolismo , Huesos/patología , Bortezomib/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 4 , Resistencia a Antineoplásicos/genética , Femenino , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Coactivador 3 de Receptor Nuclear/antagonistas & inhibidores , Coactivador 3 de Receptor Nuclear/metabolismo , Inhibidores de Proteasoma/farmacología , Recurrencia , Proteínas Represoras/metabolismo , Transducción de Señal , Análisis de Supervivencia , Translocación Genética , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Am J Physiol Endocrinol Metab ; 320(3): E591-E597, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33522399

RESUMEN

Studies in humans and rodents show that probiotic bacteria can protect from bone loss caused by sex steroid deficiency. We showed earlier that a mixture of three probiotic bacteria, Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312, and DSM 15313 (L. mix), protects mice from ovariectomy (ovx)-induced bone loss when treatment was started 2 wk before sham and ovx surgery. In addition, the same probiotic treatment protected against lumbar spine bone loss in early postmenopausal women. In the present study, we wanted to evaluate the therapeutic potential of L. mix by starting treatment 1.5 wk after ovx when most of the rapid bone loss as a result of estrogen deficiency has already occurred. Treatment with L. mix for 5.5 wk increased the trabecular thickness but not the trabecular number in the proximal metaphyseal region of tibia compared with vehicle treatment. Cortical thickness and cortical area of the middiaphyseal part of the tibia were significantly decreased in ovx mice but not in L. mix-treated ovx mice. The bone-protective effects of L. mix in ovx mice were associated with a protection against ovx-induced reduction of the frequency of regulatory T-cells and of the expression of Tgfß in the bone marrow. In conclusion, the probiotic L. mix exerted a mild stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 wk after ovariectomy in mice. This effect was associated with effects on bone-protecting regulatory T-cells. The results suggest that L. mix may exert beneficial effects on bone mass when treatment is started after ovariectomy.NEW & NOTEWORTHY The probiotic L. mix exerted a mild stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 wk after ovariectomy in mice. This effect was associated with effects on bone-protecting regulatory T-cells. The results suggest that L. mix may exert beneficial effects on bone mass when treatment is started after ovariectomy.


Asunto(s)
Densidad Ósea/efectos de los fármacos , Ovariectomía , Probióticos/administración & dosificación , Animales , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Huesos/efectos de los fármacos , Huesos/metabolismo , Esquema de Medicación , Femenino , Recuento de Linfocitos , Ratones , Ratones Endogámicos C57BL , Osteoporosis/metabolismo , Osteoporosis/prevención & control , Ovariectomía/efectos adversos , Probióticos/farmacología , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Factores de Tiempo
14.
J Med Chem ; 64(3): 1260-1282, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33522236

RESUMEN

Bisphosphonates, used for a long time in osteoporosis management, are currently the target of intensive research, from pre-formulation studies to more advanced stages of clinical practice. This review presents an overview of the contributions of this family of compounds to human health, starting with the chemistry and clinical uses of bisphosphonates. Following this, their pharmacology is described, highlighting administration-borne handicaps and undesirable effects. The last three sections of the review describe the research efforts that seek to curb delivery-related issues and expand bisphosphonate use. Innovative routes and strategies of administration, such as nano-encapsulation for oral intake or injectable cements for local or in-bone delivery are presented, as well as the latest results of case studies or preclinical studies proposing new therapeutic indications for the clinically approved bisphosphonates. Finally, a selection of anti-infectious bisphosphonate new drug candidates is shown, with focus on the molecules reported in the last two decades.


Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Enfermedades Óseas/tratamiento farmacológico , Difosfonatos/farmacología , Animales , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/uso terapéutico , Huesos/efectos de los fármacos , Huesos/metabolismo , Difosfonatos/administración & dosificación , Difosfonatos/química , Difosfonatos/uso terapéutico , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Humanos
15.
Clin Interv Aging ; 16: 71-81, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33447020

RESUMEN

Background: Aging decreases osteogenic ability, inducing harmful effects on the bone extracellular matrix (ECM), while exercise training has been indicated as a tool to counteract bone disorders related to advancing age. The modulation of bone ECM is regulated by several types of matrix metalloproteinase (MMP); however, MMP-2 activity in different trabecular bones in response to resistance training (RT) has been neglected. Remodeling differs in different bones under the application of the same mechanical loading. Thus, we investigated the effects of 12 weeks of RT on MMP-2 activity in the lumbar vertebra (L6), tibia, and femur of young (3 months) and older rats (21 months). Methods: Twenty Wistar rats were divided into four groups (five animals per group): young sedentary or trained and older sedentary or trained. The 12-week RT consisted of climbing a 1.1-m vertical ladder three times per week with progressive weights secured to the animals' tails. The animals were killed 48 h after the end of the experimental period. The MMP-2 activity was assessed by the zymography method. Results: The aging process induced lower MMP-2 activity in the lumbar vertebrae and tibia (p=0.01). RT upregulated pro, intermediate, and active MMP-2 activity in the tibia of young rats (p=0.001). RT also upregulated pro and active MMP-2 activity in the lumbar vertebrae and tibia with advancing age (p=0.01). There was no significant difference (p>0.05) between groups for MMP-2 of the femur, regardless of age and RT. Conclusion: The aging process impairs MMP-2 activity, but RT is a potential therapeutic approach to minimize the deleterious effects of ECM degeneration in different aged bones. Distinct MMP-2 responses to exercise training may result in specific remodeling processes.


Asunto(s)
Matriz Extracelular/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Condicionamiento Físico Animal/fisiología , Entrenamiento de Resistencia/métodos , Adaptación Fisiológica/fisiología , Animales , Huesos/metabolismo , Hueso Esponjoso/metabolismo , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar
16.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33466312

RESUMEN

Despite modern surgical trauma care, bleeding contributes to one-third of trauma-related death. A significant improvement was obtained through the introduction of tranexamic acid (TXA), which today is widely used in emergency and elective orthopedic surgery to control bleeding. However, concerns remain regarding potential adverse effects on bone turnover and regeneration. Therefore, we employed standardized cell culture systems including primary osteoblasts, osteoclasts, and macrophages to evaluate potential effects of TXA on murine bone cells. While osteoblasts derived from calvarial digestion were not affected, TXA increased cell proliferation and matrix mineralization in bone marrow-derived osteoblasts. Short-term TXA treatment (6 h) failed to alter the expression of osteoblast markers; however, long-term TXA stimulation (10 days) was associated with the increased expression of genes involved in osteoblast differentiation and extracellular matrix synthesis. Similarly, whereas short-term TXA treatment did not affect gene expression in terminally differentiated osteoclasts, long-term TXA stimulation resulted in the potent inhibition of osteoclastogenesis. Finally, in bone marrow-derived macrophages activated with LPS, simultaneous TXA treatment led to a reduced expression of inflammatory cytokines and chemokines. Collectively, our study demonstrates a differential action of TXA on bone cells including osteoanabolic, anti-resorptive, and anti-inflammatory effects in vitro which suggests novel treatment applications.


Asunto(s)
Médula Ósea/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Ácido Tranexámico/farmacología , Animales , Médula Ósea/metabolismo , Huesos/efectos de los fármacos , Huesos/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos
17.
Int J Mol Sci ; 22(2)2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33477897

RESUMEN

Hydroxyapatite (HA) reinforced collagen fibrils serve as the basic building blocks of natural bone and dentin. Mineralization of collagen fibrils play an essential role in ensuring the structural and mechanical functionalities of hard tissues such as bone and dentin. Biomineralization of collagen can be divided into intrafibrillar and extrafibrillar mineralization in terms of HA distribution relative to collagen fibrils. Intrafibrillar mineralization is termed when HA minerals are incorporated within the gap zone of collagen fibrils, while extrafibrillar mineralization refers to the minerals that are formed on the surface of collagen fibrils. However, the mechanisms resulting in these two types of mineralization still remain debatable. In this review, the evolution of both classical and non-classical biomineralization theories is summarized. Different intrafibrillar mineralization mechanisms, including polymer induced liquid precursor (PILP), capillary action, electrostatic attraction, size exclusion, Gibbs-Donnan equilibrium, and interfacial energy guided theories, are discussed. Exemplary strategies to induce biomimetic intrafibrillar mineralization using non-collagenous proteins (NCPs), polymer analogs, small molecules, and fluidic shear stress are discussed, and recent applications of mineralized collagen fibers for bone regeneration and dentin repair are included. Finally, conclusions are drawn on these proposed mechanisms, and the future trend of collagen-based materials for bone regeneration and tooth repair is speculated.


Asunto(s)
Biomineralización/genética , Regeneración Ósea/efectos de los fármacos , Huesos/metabolismo , Colágeno/genética , Dentina/metabolismo , Biomimética , Colágeno/química , Colágeno/metabolismo , Dentina/crecimiento & desarrollo , Durapatita/farmacología , Matriz Extracelular/efectos de los fármacos , Humanos , Polímeros/química , Polímeros/farmacología , Ingeniería de Tejidos , Cicatrización de Heridas/efectos de los fármacos , Difracción de Rayos X
18.
Int J Mol Sci ; 22(3)2021 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-33503906

RESUMEN

Bacterial infection in orthopedic surgery is challenging because cell wall components released after bactericidal treatment can alter osteoblast and osteoclast activity and impair fracture stability. However, the precise effects and mechanisms whereby cell wall components impair bone healing are unclear. In this study, we characterized the effects of lipopolysaccharide (LPS) on bone healing and osteoclast and osteoblast activity in vitro and in vivo and evaluated the effects of ibudilast, an antagonist of toll-like receptor 4 (TLR4), on LPS-induced changes. In particular, micro-computed tomography was used to reconstruct femoral morphology and analyze callus bone content in a femoral defect mouse model. In the sham-treated group, significant bone bridge and cancellous bone formation were observed after surgery, however, LPS treatment delayed bone bridge and cancellous bone formation. LPS inhibited osteogenic factor-induced MC3T3-E1 cell differentiation, alkaline phosphatase (ALP) levels, calcium deposition, and osteopontin secretion and increased the activity of osteoclast-associated molecules, including cathepsin K and tartrate-resistant acid phosphatase in vitro. Finally, ibudilast blocked the LPS-induced inhibition of osteoblast activation and activation of osteoclast in vitro and attenuated LPS-induced delayed callus bone formation in vivo. Our results provide a basis for the development of a novel strategy for the treatment of bone infection.


Asunto(s)
Lipopolisacáridos/farmacología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Piridinas/farmacología , Animales , Biomarcadores , Huesos/diagnóstico por imagen , Huesos/efectos de los fármacos , Huesos/metabolismo , Huesos/patología , Línea Celular , Modelos Animales de Enfermedad , Inmunohistoquímica , Masculino , Ratones , Osteogénesis/efectos de los fármacos , Cicatrización de Heridas , Microtomografía por Rayos X
19.
Int J Mol Sci ; 22(2)2021 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-33466904

RESUMEN

Reconstruction of segmental bone defects by autologous bone grafting is still the standard of care but presents challenges including anatomical availability and potential donor site morbidity. The process of 3D bioprinting, the application of 3D printing for direct fabrication of living tissue, opens new possibilities for highly personalized tissue implants, making it an appealing alternative to autologous bone grafts. One of the most crucial hurdles for the clinical application of 3D bioprinting is the choice of a suitable cell source, which should be minimally invasive, with high osteogenic potential, with fast, easy expansion. In this study, mesenchymal progenitor cells were isolated from clinically relevant human bone biopsy sites (explant cultures from alveolar bone, iliac crest and fibula; bone marrow aspirates; and periosteal bone shaving from the mastoid) and 3D bioprinted using projection-based stereolithography. Printed constructs were cultivated for 28 days and analyzed regarding their osteogenic potential by assessing viability, mineralization, and gene expression. While viability levels of all cell sources were comparable over the course of the cultivation, cells obtained by periosteal bone shaving showed higher mineralization of the print matrix, with gene expression data suggesting advanced osteogenic differentiation. These results indicate that periosteum-derived cells represent a highly promising cell source for translational bioprinting of bone tissue given their superior osteogenic potential as well as their minimally invasive obtainability.


Asunto(s)
Células de la Médula Ósea/metabolismo , Trasplante Óseo/métodos , Huesos/metabolismo , Células Madre Mesenquimatosas/metabolismo , Biosíntesis de Proteínas , Ingeniería de Tejidos/métodos , Adulto , Bioimpresión/métodos , Células de la Médula Ósea/citología , Huesos/citología , Diferenciación Celular/genética , Células Cultivadas , Humanos , Células Madre Mesenquimatosas/citología , Osteogénesis/genética , Impresión Tridimensional , Andamios del Tejido , Trasplante Autólogo
20.
Int J Mol Sci ; 22(3)2021 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-33498907

RESUMEN

Tissue nonspecific alkaline phosphatase (TNAP/Alpl) is associated with cell stemness; however, the function of TNAP in mesenchymal progenitor cells remains largely unknown. In this study, we aimed to establish an essential role for TNAP in bone and muscle progenitor cells. We investigated the impact of TNAP deficiency on bone formation, mineralization, and differentiation of bone marrow stromal cells. We also pursued studies of proliferation, mitochondrial function and ATP levels in TNAP deficient bone and muscle progenitor cells. We find that TNAP deficiency decreases trabecular bone volume fraction and trabeculation in addition to decreased mineralization. We also find that Alpl-/- mice (global TNAP knockout mice) exhibit muscle and motor coordination deficiencies similar to those found in individuals with hypophosphatasia (TNAP deficiency). Subsequent studies demonstrate diminished proliferation, with mitochondrial hyperfunction and increased ATP levels in TNAP deficient bone and muscle progenitor cells, plus intracellular expression of TNAP in TNAP+ cranial osteoprogenitors, bone marrow stromal cells, and skeletal muscle progenitor cells. Together, our results indicate that TNAP functions inside bone and muscle progenitor cells to influence mitochondrial respiration and ATP production. Future studies are required to establish mechanisms by which TNAP influences mitochondrial function and determine if modulation of TNAP can alter mitochondrial respiration in vivo.


Asunto(s)
Adenosina Trifosfato/biosíntesis , Fosfatasa Alcalina/metabolismo , Huesos/metabolismo , Respiración de la Célula , Células Madre Mesenquimatosas/metabolismo , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/fisiología , Animales , Huesos/fisiología , Calcificación Fisiológica , Diferenciación Celular , Masculino , Células Madre Mesenquimatosas/fisiología , Ratones , Ratones Noqueados , Músculo Esquelético/fisiología , Osteogénesis , Cráneo/metabolismo , Cráneo/fisiología
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