RESUMEN
Neuromuscular inhibitors have been quickly advanced from being used only for aesthetic purposes to being used as a treatment for musculoskeletal pain and muscle spasticity. This phenomenon stems from the diminished force exerted by muscles, which are essential for bone remodeling. In this context, it is hypothesized that botulinum toxin (BTX) might exert a direct influence on bone resorption. Although such treatments have the potential to provide patients with significant relief, bone loss occurring due to elective muscle paralysis has yet to be examined in clinical trials. The disuse model resulting from spinal cord injury, characterized by the absence of ground reaction and muscle forces, provides an ideal context for exploring the skeletal ramifications of intramuscular BTX injection. This approach enables an investigation into the intricate interplay between muscle and bone, encompassing the impact of spasticity on bone preservation, the potential positive and negative outcomes of BTX on bone metabolism, and the involvement of the autonomic nervous system in bone remodeling regulation. This paper presents a narrative review of research findings on the disturbance of the typical balance between muscles and bones caused by acute muscle paralysis from BTX, resulting in osteopenia and bone resorption.
Asunto(s)
Toxinas Botulínicas , Espasticidad Muscular , Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/tratamiento farmacológico , Espasticidad Muscular/tratamiento farmacológico , Espasticidad Muscular/etiología , Toxinas Botulínicas/administración & dosificación , Toxinas Botulínicas/uso terapéutico , Fármacos Neuromusculares/administración & dosificación , Fármacos Neuromusculares/uso terapéutico , Animales , Huesos/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Remodelación Ósea/fisiología , Resorción Ósea , Músculo Esquelético/efectos de los fármacos , Enfermedades Óseas Metabólicas/tratamiento farmacológicoRESUMEN
Active children and adolescents have unique risk factors for musculoskeletal injuries compared with adults. Physes and developing bones are at higher risk of injury than tendons and ligaments. Children's bone remodeling is robust, allowing most clavicle fractures and torus fractures of the forearm to be managed conservatively. Radial head subluxation is managed with reduction. Apophyseal injuries are traction or overuse injuries that typically can be managed nonoperatively. Osteochondritis dissecans and other osteochondroses require frequent monitoring and occasionally surgical intervention.
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Fracturas Óseas , Humanos , Adolescente , Niño , Fracturas Óseas/terapia , Factores de Riesgo , Sistema Musculoesquelético/lesiones , Trastornos de Traumas Acumulados/terapia , Trastornos de Traumas Acumulados/diagnóstico , Remodelación ÓseaRESUMEN
Reliable gene expression analysis in bone remodeling studies requires an appropriate selection of internal controls, i.e. stable reference genes for the normalization of quantitative real-time PCR (RT-qPCR), the most common method used for quantifying gene expression measurements. Even the most widely used reference genes can have variable expression under different experimental conditions, or in different tissue types or treatment regimes, so selecting appropriate controls is a key step in ensuring reliable results. The aim of this research was to identify the most stable reference gene(s) for the study of olanzapine modulated bone remodeling in rats. RNA was isolated from the maxillary alveolar and femoral bones of olanzapine or placebo-treated Wistar rats and transcribed to cDNA. The expression of 12 candidate reference genes was assessed by RT-qPCR. Their expressions were analysed using GeNorm, NormFinder, BestKeeper and delta Ct algorithms, and by the comprehensive ranking method. PPIA, HRPT1 and PGK1 were the most stably expres sed reference genes and the combination of the three genes was optimal for normalization. This study is the first to identify the optimal reference genes for research in olanzapine-exposed rats, which serve as a pivotal benchmark for enhancing the accuracy and reliability of future RT-qPCR expression in bone studies.
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Remodelación Ósea , Fémur , Olanzapina , Fosfoglicerato Quinasa , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Animales , Olanzapina/farmacología , Ratas , Fémur/efectos de los fármacos , Fémur/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/normas , Masculino , Remodelación Ósea/efectos de los fármacos , Remodelación Ósea/genética , Fosfoglicerato Quinasa/genética , Perfilación de la Expresión Génica/métodos , Reproducibilidad de los Resultados , Antipsicóticos/farmacologíaRESUMEN
BACKGROUND: Bone regeneration is a well-regulated dynamic process, of which the prominent role of the immune system on bone homeostasis is more and more revealed by recent research. Before fully activation of the bone remodeling cells, the immune system needs to clean up the microenvironment in facilitating the bone repair initiation. Furthermore, this microenvironment must be maintained properly by various mechanisms over the entire bone regeneration process. OBJECTIVE: This review aims to summarize the role of the T-helper 17/Regulatory T cell (Th17/Treg) balance in bone cell remodeling and discuss the relevant progress in bone tissue engineering. RESULTS: The role of the immune response in the early stages of bone regeneration is crucial, especially the impact of the Th17/Treg balance on osteoclasts, mesenchymal stem cells (MSCs), and osteoblasts activity. By virtue of these knowledge advancements, innovative approaches in bone tissue engineering, such as nano-structures, hydrogel, and exosomes, are designed to influence the Th17/Treg balance and thereby augment bone repair and regeneration. CONCLUSION: Targeting the Th17/Treg balance is a promising innovative strategy for developing new treatments to enhance bone regeneration, thus offering potential breakthroughs in bone injury clinics.
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Regeneración Ósea , Huesos , Linfocitos T Reguladores , Células Th17 , Ingeniería de Tejidos , Humanos , Linfocitos T Reguladores/inmunología , Ingeniería de Tejidos/métodos , Regeneración Ósea/inmunología , Animales , Células Th17/inmunología , Huesos/inmunología , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Remodelación Ósea/inmunología , Osteoblastos/inmunología , Osteoclastos/inmunología , Osteoclastos/metabolismoRESUMEN
High dose bolus cholecalciferol supplementation has been associated with falls and fracture, and this does not appear to be due to hypercalcaemia. The primary aim of this study was to determine the change in free vitamin D and metabolites after high dose bolus supplementation. This was a single centre, double-blinded, randomised, controlled trial of three different oral bolus doses of vitamin D3 (50,000 IU, 150,000 IU, and 500,000 IU) in otherwise healthy, vitamin D deficient (total 25-hydroxylated vitamin 25(OH)D < 30 nmol/L) postmenopausal women. Thirty-three women were randomized to one of the three treatment groups. Twenty-seven vitamin D sufficient (25(OH)D > 50 nmol/L) postmenopausal women were recruited as a concurrent control group. Participants attended five study visits over three months. We measured total 25(OH)D3 and free 25(OH)D, total and free 1,25(OH)2D, parathyroid hormone, fibroblast-growth factor-23, serum calcium, ionised calcium, urinary calcium excretion, and bone turnover markers (procollagen I N-propeptide (PINP), serum C-telopeptides of type I collagen (CTX-I) and Osteocalcin (OC)). We assessed muscle strength and function with grip strength and a short physical performance battery. Postural blood pressure and aldosterone:renin ratio (ARR) was also measured. Total 25(OH)D3 and free 25(OH)D increased in response to dose, and there were proportionate increases in total and free metabolites. Treatment did not affect serum calcium, postural blood pressure, ARR, or physical function. Bone turnover markers increased transiently one week after administration of 500,000 IU. High dose bolus cholecalciferol supplementation does not cause disproportionate increases in free vitamin D or metabolites. We did not identify any effect on blood pressure regulation or physical function that would explain increased falls after high dose treatment. A transient increase in bone turnover markers one week after a 500,000 IU bolus suggests that very high doses can have acute effects on bone metabolism, but the clinical significance of this transient increase is uncertain.
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Biomarcadores , Remodelación Ósea , Colecalciferol , Suplementos Dietéticos , Deficiencia de Vitamina D , Vitamina D , Humanos , Femenino , Colecalciferol/administración & dosificación , Remodelación Ósea/efectos de los fármacos , Biomarcadores/sangre , Biomarcadores/orina , Vitamina D/análogos & derivados , Vitamina D/sangre , Vitamina D/administración & dosificación , Persona de Mediana Edad , Método Doble Ciego , Anciano , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/sangre , Posmenopausia , Calcio/sangre , Hormona Paratiroidea/sangre , Factor-23 de Crecimiento de Fibroblastos , Relación Dosis-Respuesta a DrogaRESUMEN
OBJECTIVE: The prevalence of type 2 diabetes mellitus (T2DM) and bone metabolism disorders increase with age. Diabetic kidney disease (DKD) is one of the most serious microvascular complications of T2DM, and bone metabolism disorders are closely linked to the occurrence of DKD. The relationship between bone turnover markers(BTMs) and the kidney disease in elderly patients with T2DM remains unclear. Therefore, this study aims to investigate the association between common BTMs and DKD in a large sample of elderly patients. The goal is to provide a basis for early identification of high-risk individuals for DKD among elderly T2DM patients from a bone metabolism perspective. METHODS: In this cross-sectional study, BTMs were collected from a cohort of 2,051 hospitalized Chinese patients. The relationships between 25-hydroxyvitamin D (25-OH-D), ß-CrossLaps (ß-CTX), osteocalcin (OSTEOC), intact parathyroid hormone (iPTH), and total type I collagen N-terminal propeptide (TP1NP), and DKD, as well as urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) were analyzed using regression analysis and restrictive cubic spline (RCS) curves. RESULTS: Higher 25-OH-D levels were independently linked to a lower incidence of DKD and decreased UACR. The RCS curves showed a linear association of 25-OH-D and DKD, approaching the L-shape. ß-CTX was independently and positively correlated with UACR. There is an independent positive correlation between OSTEOC and UACR and a negative correlation with eGFR. iPTH is independently and positively correlated with DKD incidence and UACR, and negatively correlated with eGFR. Additionally, the RCS curves showed a non-linear association of OSTEOC and iPTH and DKD, approaching the J-shape, and the point of inflection is 10.875 ng/L and 34.15 pg/mL respectively. There is an independent positive correlation between TP1NP and UACR incidence, and a negative correlation with eGFR. Risk estimates significantly increase with higher TP1NP levels in the RCS model. CONCLUSION: BTMs are closely associated with kidney disease in elderly patients with T2DM. These discoveries potentially assist clinicians in establishing more preventive measures and targeted treatment strategies for elderly patients with T2DM.
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Biomarcadores , Remodelación Ósea , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Humanos , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Femenino , Anciano , Biomarcadores/sangre , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/epidemiología , Vitamina D/sangre , Vitamina D/análogos & derivados , Hormona Paratiroidea/sangre , Tasa de Filtración Glomerular , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Osteocalcina/sangre , Pronóstico , China/epidemiología , Estudios de Seguimiento , Procolágeno/sangre , Anciano de 80 o más AñosRESUMEN
The onset of osteonecrosis of the femoral head (ONFH) is intimately associated with the extensive administration of glucocorticoids (GCs). Long-term stimulation of GCs can induce oxidative stress in both osteoclasts (OCs) and osteoblasts (OBs), resulting in the disturbance of bone remodelling. An alkaloid named crebanine (CN) demonstrates pharmacological properties including anti-inflammation and reactive oxygen species (ROS) modulation. Our objective is to assess the therapeutic potential of CN in treating ONFH and elucidate the associated underlying mechanisms. The network pharmacology analysis uncovered that CN played a role in regulating ROS metabolism. In vitro, CN demonstrated its ability to reduce the dexamethasone (DEX)-stimulated generation of OCs and suppress their resorptive function by downregulating the level of osteoclast marker genes. Concurrently, CN also mitigated DEX-induced damage to OBs, facilitating the restoration of osteoblast marker gene expression, cellular differentiation and function. These effects were achieved by CN augmenting the antioxidant system to reduce intracellular ROS levels. Furthermore, in vitro results were corroborated by micro-CT and histological data, which also showed that CN attenuated MPS-induced ONFH in mice. This study highlights the therapeutic potential of CN in counteracting GCs-induced ONFH.
Asunto(s)
Remodelación Ósea , Necrosis de la Cabeza Femoral , Glucocorticoides , Osteoblastos , Osteoclastos , Estrés Oxidativo , Especies Reactivas de Oxígeno , Animales , Estrés Oxidativo/efectos de los fármacos , Glucocorticoides/efectos adversos , Glucocorticoides/farmacología , Remodelación Ósea/efectos de los fármacos , Ratones , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/tratamiento farmacológico , Necrosis de la Cabeza Femoral/metabolismo , Necrosis de la Cabeza Femoral/patología , Osteoclastos/metabolismo , Osteoclastos/efectos de los fármacos , Homeostasis/efectos de los fármacos , Dexametasona/farmacología , Dexametasona/efectos adversos , Masculino , Cabeza Femoral/patología , Cabeza Femoral/metabolismo , Cabeza Femoral/efectos de los fármacos , Modelos Animales de Enfermedad , Diferenciación Celular/efectos de los fármacos , Ratones Endogámicos C57BL , HumanosRESUMEN
BACKGROUND: Osteoporosis, a systemic skeletal disease, seriously affects the quality of life in postmenopausal women. As one type of cathepsin K (CatK) inhibitor, odanacatib (ODN) is a fresh medication for osteoporosis. Considering the potential of ODN, we further examined the effect and safety of ODN for postmenopausal osteoporosis (PMOP) with a meta-analysis. METHODS: PubMed, EMBASE, Cochrane Library, and Web of Science were searched for eligible studies from inception to December 29th, 2023. After that, we conducted a comprehensive meta-analysis following PRISMA guidelines. Risk of bias was meticulously investigated with the Cochrane Collaboration's tool. Efficacy was assessed with bone mineral density (BMD) at different sites (lumbar spine, trochanter, radius, femoral neck) and biomarkers of bone turnover (P1NP, uNTx/Cr, s-CTx, BSAP). Safety was evaluated by analyzing total, serious, other, and skin adverse events (AEs). RESULTS: Four random clinical trials (RCTs) were involved in our research. All trials were rated as having high quality and met the eligibility criteria. In the current research, ODN was found to elevate BMD at lumbar spine, femoral neck, total hip, trochanter and forearm, while it decreased the levels of serum C-telopeptides of type I collagen (s-CTx) as well as urinary N-telopeptide/creatinine ratio (uNTx/Cr). No significant differences were observed in AEs between the ODN group and the control group. CONCLUSIONS: ODN is a promising alternative for the treatment of PMOP on account of its excellent efficacy and credible safety. Unclear links between ODN and cardiovascular AEs require further research to clarify.
Asunto(s)
Compuestos de Bifenilo , Densidad Ósea , Osteoporosis Posmenopáusica , Humanos , Femenino , Osteoporosis Posmenopáusica/tratamiento farmacológico , Densidad Ósea/efectos de los fármacos , Resultado del Tratamiento , Compuestos de Bifenilo/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Biomarcadores/sangre , Catepsina K/antagonistas & inhibidores , Persona de Mediana Edad , Anciano , Remodelación Ósea/efectos de los fármacosRESUMEN
We aimed to compare the extent of bone turnover suppression between patients with atypical femoral fractures (AFFs) and osteoporotic hip fractures (typical femur fractures, TFFs) using a one-to-one matching strategy. A single-center retrospective comparison of females aged ≥ 60 years who underwent operative treatment for AFFs and TFFs between January 2010 and March 2021 was conducted. Demographic characteristics and clinical data including fracture site, past medical history, bone mineral density (BMD), bisphosphonate (BP) medication history, and serum bone turnover marker (BTM) levels were examined. Moreover, we performed a logistic regression analysis to determine the risk factors for AFFs and a one-to-one matched-pair analysis to compare various BTMs. Overall, 336 consecutive females were included: 113 with AFFs and 213 with TFFs. The mean age, BMI, and lowest BMD T-score were 78.6 years, 22.8 kg/m2, and -3.3, respectively. Patients with AFF were younger, had lower BMD, higher BMI, higher prevalence of rheumatoid arthritis, a greater proportion with previous steroid or BP use, and a longer history of BP use than patients with TFF. The 48:48 matched-pair analysis revealed higher serum 25(OH) vitamin-D (30.5 vs 18.2 ng/mL, P < 0.001) and calcium levels (8.8 vs 8.3 ng/dL, P = 0.009) and lower serum CTX levels (0.33 vs 0.54 ng/mL, P = 0.010) in the AFF group than in the TFF group, suggesting a more suppressed bone remodeling. No differences in the other BTM levels were found. Despite identical histories and durations of BP use, the AFF group exhibited lower CTX levels, suggesting more suppressed bone remodeling. This observation leads us to infer that more suppressed bone remodeling, indicated by lower CTX levels, could be linked to the occurrence of AFFs.
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Densidad Ósea , Remodelación Ósea , Fracturas del Fémur , Fracturas de Cadera , Fracturas Osteoporóticas , Humanos , Femenino , Anciano , Remodelación Ósea/efectos de los fármacos , Fracturas del Fémur/sangre , Fracturas Osteoporóticas/etiología , Fracturas Osteoporóticas/sangre , Estudios Retrospectivos , Persona de Mediana Edad , Anciano de 80 o más Años , Factores de Riesgo , Biomarcadores/sangre , Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéuticoRESUMEN
Osteoporosis (OP) is a common metabolic bone disease characterized by low bone mass, decreased bone mineral density, and degradation of bone tissue microarchitecture. However, our understanding of the mechanisms of bone remodeling and factors affecting bone mass remains incomplete. Sirtuin1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase that regulates a variety of cellular metabolisms, including inflammation, tumorigenesis, and bone metabolism. Recent studies have emphasized the important role of SIRT1 in bone homeostasis. This article reviews the role of SIRT1 in bone metabolism and OP and also discusses therapeutic strategies and future research directions for targeting SIRT1.
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Huesos , Osteoporosis , Sirtuina 1 , Humanos , Sirtuina 1/metabolismo , Osteoporosis/metabolismo , Osteoporosis/patología , Huesos/metabolismo , Animales , Remodelación Ósea , Densidad ÓseaRESUMEN
Bone-forming osteoblasts, osteocytes, and bone-resorbing osteoclasts are responsible for life-long skeletal remodeling [...].
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Osteoblastos , Osteoclastos , Osteocitos , Humanos , Osteoblastos/metabolismo , Osteoblastos/citología , Osteoclastos/metabolismo , Osteoclastos/citología , Osteocitos/metabolismo , Osteocitos/citología , Animales , Huesos/citología , Huesos/metabolismo , Huesos/patología , Remodelación Ósea , Enfermedades Óseas/patología , Enfermedades Óseas/metabolismoRESUMEN
Bone is a dynamically active tissue whose health status is closely related to its construction and remodeling, and imbalances in bone homeostasis lead to a wide range of bone diseases. The sulfated glycoprotein C-type lectin structural domain family 11 member A (Clec11a) is a key factor in bone mass regulation that significantly promotes the osteogenic differentiation of bone marrow mesenchymal stem cells and osteoblasts and stimulates chondrocyte proliferation, thereby promoting longitudinal bone growth. More importantly, Clec11a has high therapeutic potential for treating various bone diseases and can enhance the therapeutic effects of the parathyroid hormone against osteoporosis. Clec11a is also involved in the stress/adaptive response of bone to exercise via mechanical stimulation of the cation channel Pieoz1. Clec11a plays an important role in promoting bone health and preventing bone disease and may represent a new target and novel drug for bone disease treatment. Therefore, this review aims to explore the role and possible mechanisms of Clec11a in the skeletal system, evaluate its value as a potential therapeutic target against bone diseases, and provide new ideas and strategies for basic research on Clec11a and preventing and treating bone disease.
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Remodelación Ósea , Lectinas Tipo C , Humanos , Lectinas Tipo C/metabolismo , Animales , Remodelación Ósea/fisiología , Osteogénesis/fisiología , Huesos/metabolismo , Huesos/fisiología , Enfermedades Óseas/terapia , Enfermedades Óseas/metabolismo , Osteoblastos/metabolismo , Osteoblastos/fisiología , Diferenciación CelularRESUMEN
Glucocorticoids (GC) and parathyroid hormone (PTH) are widely used therapeutic endocrine hormones where their effects on bone and joint arise from actions on multiple skeletal cell types. In osteocytes, GC and PTH exert opposing effects on perilacunar canalicular remodeling (PLR). Suppressed PLR can impair bone quality and joint homeostasis, including in GC-induced osteonecrosis. However, combined effects of GC and PTH on PLR are unknown. Given the untapped potential to target osteocytes to improve skeletal health, this study sought to test the feasibility of therapeutically mitigating PLR suppression. Focusing on subchondral bone and joint homeostasis, we hypothesize that PTH(1-34), a PLR agonist, could rescue GC-suppressed PLR. The skeletal effects of GC and PTH(1-34), alone or combined, were examined in male and female mice by micro-computed tomography, mechanical testing, histology, and gene expression analysis. For each outcome, females were more responsive to GC and PTH(1-34) than males. GC and PTH(1-34) exerted regional differences, with GC increasing trabecular bone volume but reducing cortical bone thickness, stiffness, and ultimate force. Despite PTH(1-34)'s anabolic effects on trabecular bone, it did not rescue GC's catabolic effects on cortical bone. Likewise, cartilage integrity and subchondral bone apoptosis, tartrate-resistant acid phosphatase (TRAP) activity, and osteocyte lacunocanalicular networks showed no evidence that PTH(1-34) could offset GC-dependent effects. Rather, GC and PTH(1-34) each increased cortical bone gene expression implicated in bone resorption by osteoclasts and osteocytes, including Acp5, Mmp13, Atp6v0d2, Ctsk, differences maintained when GC and PTH(1-34) were combined. Since PTH(1-34) is insufficient to rescue GC's effects on young female mouse bone, future studies are needed to determine if osteocyte PLR suppression, due to GC, aging, or other factors, can be offset by a PLR agonist.
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Densidad Ósea , Remodelación Ósea , Glucocorticoides , Osteocitos , Hormona Paratiroidea , Animales , Osteocitos/efectos de los fármacos , Osteocitos/metabolismo , Hormona Paratiroidea/farmacología , Femenino , Masculino , Ratones , Glucocorticoides/farmacología , Remodelación Ósea/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Ratones Endogámicos C57BL , Huesos/efectos de los fármacos , Huesos/metabolismo , Microtomografía por Rayos XRESUMEN
Introduction: Changes to bone physiology play a central role in the development of osteoarthritis with the mechanosensing osteocyte releasing factors that drive disease progression. This study developed a humanised in vitro model to detect osteocyte responses to either interleukin-6, a driver of degeneration and bone remodelling in animal and human joint injury, or mechanical loading, to mimic osteoarthritis stimuli in joints. Methods: Human MSC cells (Y201) were differentiated in 3-dimensional type I collagen gels in osteogenic media and osteocyte phenotype assessed by RTqPCR and immunostaining. Gels were subjected to a single pathophysiological load or stimulated with interleukin-6 with unloaded or unstimulated cells as controls. RNA was extracted 1-hour post-load and assessed by RNAseq. Markers of pain, bone remodelling, and inflammation were quantified by RT-qPCR and ELISA. Results: Y201 cells embedded within 3D collagen gels assumed dendritic morphology and expressed mature osteocytes markers. Mechanical loading of the osteocyte model regulated 7564 genes (Padj p<0.05, 3026 down, 4538 up). 93% of the osteocyte transcriptome signature was expressed in the model with 38% of these genes mechanically regulated. Mechanically loaded osteocytes regulated 26% of gene ontology pathways linked to OA pain, 40% reflecting bone remodelling and 27% representing inflammation. Load regulated genes associated with osteopetrosis, osteoporosis and osteoarthritis. 42% of effector genes in a genome-wide association study meta-analysis were mechanically regulated by osteocytes with 10 genes representing potential druggable targets. Interleukin-6 stimulation of osteocytes at concentrations reported in human synovial fluids from patients with OA or following knee injury, regulated similar readouts to mechanical loading including markers of pain, bone remodelling, and inflammation. Discussion: We have developed a reproducible model of human osteocyte like cells that express >90% of the genes in the osteocyte transcriptome signature. Mechanical loading and inflammatory stimulation regulated genes and proteins implicated in osteoarthritis symptoms of pain as well as inflammation and degeneration underlying disease progression. Nearly half of the genes classified as 'effectors' in GWAS were mechanically regulated in this model. This model will be useful in identifying new mechanisms underlying bone and joint pathologies and testing drugs targeting those mechanisms.
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Inflamación , Células Madre Mesenquimatosas , Osteoartritis , Osteocitos , Humanos , Osteocitos/metabolismo , Osteocitos/patología , Osteoartritis/patología , Osteoartritis/metabolismo , Inflamación/patología , Inflamación/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Interleucina-6/metabolismo , Remodelación Ósea , Células Cultivadas , Diferenciación CelularRESUMEN
Bone remodeling and bone regeneration are essential for preserving skeletal integrity and maintaining mineral homeostasis. T cells, as key members of adaptive immunity, play a pivotal role in bone remodeling and bone regeneration by producing a range of cytokines and growth factors. In the physiological state, T cells are involved in the maintenance of bone homeostasis through interactions with mesenchymal stem cells, osteoblasts, and osteoclasts. In pathological states, T cells participate in the pathological process of different types of osteoporosis through interaction with estrogen, glucocorticoids, and parathyroid hormone. During fracture healing for post-injury repair, T cells play different roles during the inflammatory hematoma phase, the bone callus formation phase and the bone remodeling phase. Targeting T cells thus emerges as a potential strategy for regulating bone homeostasis. This article reviews the research progress on related mechanisms of T cells immunity involved in bone remodeling and bone regeneration, with a view to providing a scientific basis for targeting T cells to regulate bone remodeling and bone regeneration.
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Regeneración Ósea , Remodelación Ósea , Linfocitos T , Remodelación Ósea/inmunología , Remodelación Ósea/fisiología , Humanos , Regeneración Ósea/inmunología , Linfocitos T/inmunología , AnimalesRESUMEN
Evidence concerning the osteotoxic effects of chemotherapy (doxorubicin) has been previously described. Periodontitis also progressively increases in patients receiving chemotherapy; however, the beneficial effects of melatonin and metformin on the alleviation of doxorubicin-induced osteotoxicity have never been investigated. Therefore, we investigated the negative impact of doxorubicin on alveolar bone homeostasis and the benefits of melatonin and metformin on the attenuation of doxorubicin-induced alveolar bone toxicity. Male Wistar rats were divided into 4 groups to receive either 1 mL of normal saline solution as a control group, 3 mg/kg of doxorubicin, 3 mg/kg of doxorubicin plus 10 mg/kg of melatonin, or 3 mg/kg of doxorubicin plus 250 mg/kg of metformin. Doxorubicin treatment was given on days 0, 4, 8, 15, 22, and 29, while interventions were given daily on days 0 to 29. Following euthanasia, blood and alveolar bones were collected for evaluation of oxidative stress, bone remodeling, inflammation, microarchitecture, and periodontal condition. We found that doxorubicin increased systemic oxidative stress, decreased antioxidative capacity, increased inflammation, decreased bone formation, increased bone reabsorption, impaired microarchitecture, and impaired periodontal condition of the alveolar bone. Although cotreatment with melatonin or metformin resulted in some improvement in these parameters, cotreatment with melatonin was more effective than cotreatment with metformin in terms of decreasing oxidative stress, reducing bone resorption, and improving microarchitecture and periodontal condition. All of these findings highlight the potential for antioxidants, especially melatonin, to ameliorate doxorubicin-induced alveolar bone toxicity.
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Pérdida de Hueso Alveolar , Proceso Alveolar , Antioxidantes , Doxorrubicina , Melatonina , Metformina , Estrés Oxidativo , Ratas Wistar , Melatonina/farmacología , Melatonina/uso terapéutico , Animales , Metformina/farmacología , Metformina/uso terapéutico , Doxorrubicina/toxicidad , Masculino , Ratas , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Pérdida de Hueso Alveolar/prevención & control , Proceso Alveolar/efectos de los fármacos , Antibióticos Antineoplásicos/toxicidad , Remodelación Ósea/efectos de los fármacos , Microtomografía por Rayos XRESUMEN
Macrophages are important regulators of bone remodeling, and M1 polarization is observed in the setting of medication-related osteonecrosis of the jaws (MRONJ). Here, we characterize the phenotype of macrophages during early stages of MRONJ development in zoledronate (ZA)-treated mice with periodontal disease and explore the role of rosiglitazone, a drug that has been reported to lower the M1/M2 macrophage ratio, in MRONJ burden. Mice received ZA, and experimental periodontal disease (EPD) was induced around their second left maxillary molar. The mice were euthanized 1, 2, or 4 wk later. Micro-computed tomography and histologic and immunohistochemical analyses were carried out. In a separate experiment, mice were treated with ZA in the absence or presence of rosiglitazone, EPD was induced for 5 wk, and the MRONJ burden was assessed. An M1 predilection was noted in ZA versus vehicle (Veh) mice at 1, 2, or 4 wk after ligature placement. M1 cells were found to be positive for MMP-13, and their presence coincided with disruption of the surrounding collagen network in ZA mice. Rosiglitazone caused a reversal in the M1/M2 polarization in Veh and ZA mice. Rosiglitazone did not cause significant radiographic changes 5 wk after EPD in Veh or ZA animals. Importantly, percentage osteonecrosis and bone exposure were decreased in the rosiglitazone-treated versus nontreated ZA sites 5 wk after EPD. Our data point to an important role of M1 macrophage polarization with an overexpression of MMP-13 in the early phases of MRONJ development and provide insight into the use of interventional approaches promoting an M2 phenotype as a preventative means to alleviate MRONJ burden.
Asunto(s)
Osteonecrosis de los Maxilares Asociada a Difosfonatos , Imidazoles , Macrófagos , Rosiglitazona , Tiazolidinedionas , Microtomografía por Rayos X , Ácido Zoledrónico , Animales , Ratones , Rosiglitazona/farmacología , Rosiglitazona/uso terapéutico , Ácido Zoledrónico/farmacología , Macrófagos/efectos de los fármacos , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Osteonecrosis de los Maxilares Asociada a Difosfonatos/patología , Osteonecrosis de los Maxilares Asociada a Difosfonatos/etiología , Imidazoles/farmacología , Difosfonatos/farmacología , Metaloproteinasa 13 de la Matriz/metabolismo , Conservadores de la Densidad Ósea/farmacología , Modelos Animales de Enfermedad , Fenotipo , Masculino , Remodelación Ósea/efectos de los fármacos , Ratones Endogámicos C57BL , Enfermedades Periodontales , Colágeno/metabolismoRESUMEN
Obesity can increase the risk of bone fragility, even when bone mass is intact. This fragility stems from poor bone quality, potentially caused by deficiencies in bone matrix material properties. However, cellular and molecular mechanisms leading to obesity-related bone fragility are not fully understood. Using male mouse models of obesity, we discovered TGF-ß signaling plays a critical role in mediating the effects of obesity on bone. High-carbohydrate and high-fat diets increase TGF-ß signaling in osteocytes, which impairs their mitochondrial function, increases cellular senescence, and compromises perilacunar/canalicular remodeling and bone quality. By specifically inhibiting TGF-ß signaling in mouse osteocytes, some of the negative effects of high-fat and high-carbohydrate diets on bones, including the lacunocanalicular network, perilacunar/canalicular remodeling, senescence, and mechanical properties such as yield stress, were mitigated. DMP1-Cre-mediated deletion of TGF-ß receptor II also blunted adverse effects of high-fat and high-carbohydrate diets on energy balance and metabolism. These findings suggest osteocytes are key in controlling bone quality in response to high-fat and high-carbohydrate diets. Calibrating osteocyte function could mitigate bone fragility associated with metabolic diseases while reestablishing energy balance.
Asunto(s)
Dieta Alta en Grasa , Obesidad , Osteocitos , Factor de Crecimiento Transformador beta , Animales , Osteocitos/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones , Factor de Crecimiento Transformador beta/metabolismo , Masculino , Obesidad/metabolismo , Transducción de Señal , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Remodelación Ósea , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Huesos/metabolismo , Densidad Ósea/efectos de los fármacos , Carbohidratos de la Dieta/efectos adversos , Carbohidratos de la Dieta/administración & dosificaciónRESUMEN
Type 2 diabetes (T2D) is on the rise worldwide and is associated with various complications in the oral cavity. Using an adult-onset diabetes preclinical model, we demonstrated profound periodontal alterations in T2D mice, including inflamed gingiva, disintegrated periodontal ligaments (PDLs), marked alveolar bone loss, and unbalanced bone remodeling due to decreased formation and increased resorption. Notably, we observed elevated levels of the Wnt signaling inhibitor sclerostin in the alveolar bone of T2D mice. Motivated by these findings, we investigated whether a sclerostin-neutralizing antibody (Scl-Ab) could rescue the compromised periodontium in T2D mice. Administering Scl-Ab subcutaneously once a week for 4 weeks, starting 4 weeks after T2D induction, led to substantial increases in bone mass. This effect was attributed to the inhibition of osteoclasts and promotion of osteoblasts in both control and T2D mice, effectively reversing the bone loss caused by T2D. Furthermore, Scl-Ab stimulated PDL cell proliferation, partially restored the PDL fibers, and mitigated inflammation in the periodontium. Our study thus established a T2D-induced periodontitis mouse model characterized by inflammation and tissue degeneration. Scl-Ab emerged as a promising intervention to counteract the detrimental effects of T2D on the periodontium, exhibiting limited side effects on other craniofacial hard tissues.