RESUMEN
Calcitonin was discovered over 50 yr ago as a new hormone that rapidly lowers circulating calcium levels. This effect is caused by the inhibition of calcium efflux from bone, as calcitonin is a potent inhibitor of bone resorption. Calcitonin has been in clinical use for conditions of accelerated bone turnover, including Paget's disease and osteoporosis; although in recent years, with the development of drugs that are more potent inhibitors of bone resorption, its use has declined. A number of peptides that are structurally similar to calcitonin form the calcitonin family, which currently includes calcitonin gene-related peptides (αCGRP and ßCGRP), amylin, adrenomedullin, and intermedin. Apart from being structurally similar, the peptides signal through related receptors and have some overlapping biological activities, although other activities are peptide specific. In bone, in vitro studies and administration of the peptides to animals generally found inhibitory effects on osteoclasts and bone resorption and positive effects on osteoblasts and bone formation. Surprisingly, studies in genetically modified mice have demonstrated that the physiological role of calcitonin appears to be the inhibition of osteoblast activity and bone turnover, whereas amylin inhibits osteoclast activity. The review article focuses on the activities of peptides of the calcitonin family in bone and the challenges in understanding the relationship between the pharmacological effects and the physiological roles of these peptides.
Asunto(s)
Huesos/metabolismo , Calcitonina/metabolismo , Neuropéptidos/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Animales , Remodelación Ósea/fisiología , Resorción Ósea/metabolismo , HumanosRESUMEN
OBJECTIVES: Basic calcium phosphate (BCP) crystals contribute to several syndromes associated with tendon disease, including acute calcific tendinitis and Milwaukee shoulder syndrome. Interactions between BCP crystals and tenocytes (tendon cells) may contribute to these clinical syndromes. This study aimed to determine the direct effects of BCP crystals on tenocyte function and viability. METHODS: In vitro assays were used to assess changes in human tenocytes cultured with BCP crystals. Real-time PCR was used to determine changes in the expression of tendon-related genes and extracellular matrix remodelling enzymes (MMPs; a disintegrin and metalloproteases, ADAMTS; and tissue inhibitor of metalloproteinases, TIMPs). ELISA was used to measure protein concentrations in tenocyte supernatants. MTT and alamarBlue™ assays were used to determine changes in cell viability. RESULTS: BCP crystals upregulated tenocyte gene expression of MMP-1, MMP-3, ADAMTS-4 and TIMP-1 after 24 h. Time-course experiments showed expression peaked at 8 h for TIMP-1 and 48 h for MMP-1 and ADAMTS-4. Cyclooxygenase (COX)-1 gene expression was upregulated after 48 h. Tenocytes did not alter expression of scleraxis and tendon collagens, and expression of pro-inflammatory cytokines was not induced with BCP crystals. BCP crystals increased tenocyte release of prostaglandin E2 (PGE2) and MMP-1 protein after 24 h. However, neither COX-1 inhibition nor COX-2 inhibition led to consistent change in BCP crystal-induced tenocyte gene expression of extracellular matrix remodelling enzymes. BCP crystals had no effect on tenocyte viability. CONCLUSION: BCP crystals induce extracellular matrix remodelling enzymes, but not inflammatory cytokines, in tenocytes.
Asunto(s)
Metaloproteinasa 1 de la Matriz , Inhibidor Tisular de Metaloproteinasa-1 , Humanos , Tenocitos/metabolismo , Células Cultivadas , Matriz Extracelular/metabolismo , Fosfatos de Calcio/metabolismoRESUMEN
Bone and joint infections are a rare but serious problem worldwide. Lactoferrin's antimicrobial and antibiofilm activity coupled with its bone-regenerating effects may make it suitable for improving bone and joint infection treatment. However, free lactoferrin (LF) has highly variable oral bioavailability in humans due to potential for degradation in the stomach and small intestine. It also has a short half-life in blood plasma. Therefore, encapsulating LF in nanocarriers may slow degradation in the gastrointestinal tract and enhance LF absorption, stability, permeability and oral bioavailability. This review will summarize the literature on the encapsulation of LF into liposomes, solid lipid nanoparticles, nanostructured lipid carriers, polymeric micro and nanoparticles and hydroxyapatite nanocrystals. The fabrication, characterization, advantages, disadvantages and applications of each system will be discussed and compared.
Asunto(s)
Antiinfecciosos , Nanopartículas , Nanoestructuras , Humanos , Lactoferrina/farmacología , Lactoferrina/química , Antiinfecciosos/farmacología , Nanopartículas/química , Tracto Gastrointestinal , Biopelículas , Portadores de Fármacos/químicaRESUMEN
HYPOTHESIS AND BACKGROUND: Traumatic rotator cuff injuries can be a leading cause of prolonged shoulder pain and disability and contribute to significant morbidity and health care costs. Previous studies have shown evidence of sociodemographic disparities with these injuries. The purpose of this nationwide study was to better understand these disparities based on ethnicity, sex, and socioeconomic status, in order to inform future health care strategies. METHODS: Accident Compensation Corporation (ACC) is a no-fault comprehensive compensation scheme encompassing all of Aotearoa/New Zealand (population in 2018, 4.7 million). Using the ACC database, traumatic rotator cuff injuries were identified between January 2010 and December 2018. Injuries were categorized by sex, ethnicity, age, and socioeconomic deprivation index of the claimant. RESULTS: During the 9-year study period, there were 351,554 claims accepted for traumatic rotator cuff injury, which totaled more than NZ$960 million. The greatest proportion of costs was spent on vocational support (49.8%), then surgery (26.3%), rehabilitation (13.1%), radiology (8.1%), general practitioner (1.6%), and "Other" (1.1%). Asian, Maori (indigenous New Zealanders), and Pacific peoples were under-represented in the age-standardized proportion of total claims and had lower rates of surgery than Europeans. Maori had higher proportion of costs spent on vocational support and lower proportions spent on radiology, rehabilitation, and surgery than Europeans. Males had higher number and costs of claims and were more likely to have surgery than females. There were considerably fewer claims from areas of high socioeconomic deprivation. DISCUSSION AND CONCLUSION: This large nationwide study demonstrates the important and growing economic burden of rotator cuff injuries. Indirect costs, such as vocational supports, are a major contributor to the cost, suggesting improving treatment and rehabilitation protocols would have the greatest economic impact. This study has also identified sociodemographic disparities that need to be addressed in order to achieve equity in health outcomes.
Asunto(s)
Lesiones del Manguito de los Rotadores , Masculino , Femenino , Humanos , Lesiones del Manguito de los Rotadores/cirugía , Nueva Zelanda/epidemiología , Disparidades Socioeconómicas en Salud , Resultado del Tratamiento , Dolor de Hombro/etiologíaRESUMEN
Research in heart valve biology is a growing field that has yet to elucidate the fundamentals of valve disease. Human valvular interstitial cells (hVICs) are the best option for studying the cellular mechanisms behind valvular pathologies. However, there is a wide range of isolation procedures for these cells published in the literature. To what extent various isolation methods, patient pathologies, and seeding densities influence the behaviour of hVICs remains unclear. Here, we present an optimised method of hVIC isolation from diseased human valves donated at the time of surgery. We show that two rounds of 1000 U/mL collagenase digestion for not >2 h results in a phenotypically stable cell culture with a near complete absence of endothelial cell contamination. We also suggest that cells should be seeded at 10,000 cells/cm2 for experimentation. We found that patient pathology does not affect the success of the isolation procedure, and that instead, successful cultures are predicted by ensuring >500 mg valve tissue as starting material.
Asunto(s)
Estenosis de la Válvula Aórtica , Calcinosis , Humanos , Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/patología , Calcinosis/patología , Células Cultivadas , Técnicas de Cultivo de CélulaRESUMEN
PURPOSE: The hamstring tendon is the most commonly used autograft material in reconstructive surgeries of anterior cruciate ligament (ACL) tears. Younger patients have worse surgical outcomes, with a higher risk of re-rupture. We hypothesized that age-related changes in hamstring tendon properties affect the tendon's propensity to rupture when used as an autograft in ACL reconstructions. The purpose of this study was to compare hamstring tendon samples obtained from people aged 20 years or younger to samples obtained from older people. METHODS: Superfluous hamstring tendon material was collected from 13 young donors (aged 16-20 years) and 17 older donors undergoing ACL reconstructive surgery. Sections of the tendon samples were used for biomechanical testing, structural analysis of collagen fibrils by electron microscopy, and global analysis of gene expression by microarrays. RESULTS: We found that tendon samples from the older group had lower Young's modulus than the younger group (P = 0.015), whereas the stress to failure was similar in the two groups. We found no difference in the average diameter of collagen fibrils between the two groups. Microarray analysis identified 162 differentially expressed genes (fold change ≥ 1.5, P < 0.05), with overrepresentation of several biological processes, including regulation of adhesion, migration, inflammation, and differentiation (fold enrichment > 2.0, false discovery rate P < 0.05). CONCLUSION: The hamstring tendon from younger people has higher stiffness than tendon from older people, and the profile of gene expression in tendon varies with age. These differences may negatively affect the performance of the hamstring tendon in ACL reconstructions in younger people.
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Lesiones del Ligamento Cruzado Anterior , Reconstrucción del Ligamento Cruzado Anterior , Tendones Isquiotibiales , Anciano , Ligamento Cruzado Anterior/cirugía , Lesiones del Ligamento Cruzado Anterior/etiología , Lesiones del Ligamento Cruzado Anterior/cirugía , Reconstrucción del Ligamento Cruzado Anterior/efectos adversos , Autoinjertos/cirugía , Colágeno , Tendones Isquiotibiales/trasplante , Humanos , Rotura/cirugía , Trasplante Autólogo/efectos adversosRESUMEN
BACKGROUND: Tendinopathy is a major complication of diet-induced obesity. However, the effects of a high-fat diet (HFD) on tendon have not been well characterised. We aimed to determine: [1] the impact of a HFD on tendon properties and gene expression; and [2] whether dietary transition to a control diet (CD) could restore normal tendon health. METHODS: Sprague-Dawley rats were randomised into three groups from weaning and fed either a: CD, HFD or HFD for 12 weeks and then CD thereafter (HF-CD). Biomechanical, histological and structural evaluation of the Achilles tendon was performed at 17 and 27 weeks of age. Tail tenocytes were isolated with growth rate and collagen production determined. Tenocytes and activated THP-1 cells were exposed to conditioned media (CM) of visceral adipose tissue explants, and gene expression was analysed. RESULTS: There were no differences in the biomechanical, histological or structural tendon properties between groups. However, tenocyte growth and collagen production were increased in the HFD group at 27 weeks. There was lower SOX-9 expression in the HFD and HF-CD groups at 17 weeks and higher expression of collagen-Iα1 and matrix metalloproteinase-13 in the HFD group at 27 weeks. THP-1 cells exposed to adipose tissue CM from animals fed a HFD or HF-CD had lower expression of Il-10 and higher expression of Il-1ß. CONCLUSIONS: In this rodent model, a HFD negatively altered tendon cell characteristics. Dietary intervention restored some gene expression changes; however, adipose tissue secretions from the HF-CD group promoted an increased inflammatory state in macrophages. These changes may predispose tendon to injury and adverse events later in life.
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Tendón Calcáneo , Dieta Alta en Grasa , Animales , Ratas , Tendón Calcáneo/patología , Colágeno , Dieta Alta en Grasa/efectos adversos , Obesidad/complicaciones , Ratas Sprague-DawleyRESUMEN
INTRODUCTION: Gluteus medius tendon tears often occur in the context of chronic tendinopathy and remain a difficult clinical problem. Surgical repair is challenging as it is often delayed and performed in degenerative tendons. No animal model currently exists to mimic the delayed repair of tendinopathic gluteus medius tears. The aims of this study were to develop a chronic model of gluteus medius tendinopathy and tear and then compare this model to an acute gluteus medius tear and repair. MATERIALS AND METHODS: Six gluteus medius muscles were dissected and examined in mature sheep to confirm anatomical similarity to the human counterpart. Ten separate adult sheep underwent tendon detachment, followed by relook and histological sampling at 6 and 16 weeks to assess the extent of tendon degeneration. Six adult sheep underwent tendon repair at 6 weeks and were later assessed for healing of the tendon and compared to a further four adult sheep who underwent an acute tendon detachment and repair procedure. RESULTS: The sheep gluteus medius muscle consisted of three compartments, the anterior, middle and posterior. All compartments inserted via the common tendon on the superolateral aspect of the greater trochanter. At both 6 and 16 weeks, there was significant tendinopathic changes on histology compared to controls as assessed by modified Movin's score (p = 0.018, p = 0.047) but no difference between the 6- and 16-week groups (p = 0.25). There were significant differences between delayed and acute repair in both histological appearance (p = 0.025) and biomechanical properties (p = 0.019), with acute repair superior in both. CONCLUSIONS: Tendon detachment for 6 weeks is sufficient to produce histological changes similar to chronic tendinopathy and repair of this degenerative tendon results in significantly poorer healing when compared to an acute repair model. Animal models for gluteus medius tears should use a delayed repair model to improve clinical validity.
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Tendinopatía , Tendones , Animales , Nalgas , Modelos Animales de Enfermedad , Músculo Esquelético , Ovinos , Tendinopatía/cirugía , Tendones/cirugíaRESUMEN
Physiological loading is essential for the maintenance of articular cartilage through the regulation of tissue remodeling. To correctly understand the behavior of chondrocytes in their native environment, cell stimulating devices and bioreactors have been developed to examine the effect of mechanical stimuli on chondrocytes. This study describes the design and validation of a novel system for analyzing chondrocyte deformation patterns. This involves an in vitro mechanical device for a controlled application of multi-axial-loading regimes to chondrocyte-seeded agarose constructs and in silico models for analyzing chondrocyte deformation patterns. The computer-controlled device precisely applies compressive, tensile, and shear strains to hydrogel constructs using a customizable macro-based program. The synchronization of the displacements is shown to be accurate with a 1.2% error and is highly reproducible. The device design allows housing for up to eight novel designed free-swelling three-dimensional hydrogel constructs. Constructs include mesh ends and are optimized to withstand the application of up to 7% mechanical tensile and 15% shear strains. Constructs were characterized through mapping the strain within as mechanical load was applied and was validated using light microscopy methods, chondrocyte viability using live/dead imaging, and cell deformation strains. Images were then analyzed to determine the complex deformation strain patterns of chondrocytes under a range of dynamic mechanical stimulations. This is one of the first systems that have characterized construct strains to cellular strains. The features in this device make the system ideally suited for a systematic approach for the investigation of the response of chondrocytes to a complex physiologically relevant deformation profile.
Asunto(s)
CondrocitosRESUMEN
PURPOSE: Intra-articular administration of tranexamic acid (TXA) in orthopaedic arthroplasty and arthroscopic procedures has become increasingly common over the past decade. However, several recent reports have shown that TXA has the potential to be cytotoxic to cartilage, tendon and synovium. Our aim was to review the literature for evidence of toxic effects from TXA exposure to intra-articular tissue. METHODS: A scoping review methodology was used to search for studies assessing the toxic effects of TXA exposure to intra-articular tissues. MEDLINE, EMBASE, SCOPUS and The Cochrane Library were searched. Relevant information was extracted and synthesis of the retrieved data followed a basic content analytical approach. RESULTS: A total of 15 laboratory studies were retrieved. No clinical studies reporting a toxic effect of TXA on intra-articular tissue were identified in our search. Studies were analysed according to species of origin, tissue of origin and study setting (in vitro, ex vivo, or in vivo). There was increasing cytotoxicity to chondrocytes, tenocytes, synoviocytes and periosteum-derived cells with TXA concentrations beyond 20 mg/ml. Monolayer cell cultures appear more susceptible to TXA exposure, than three-dimensional and explant culture models. In vivo studies have not demonstrated a major toxic effect. CONCLUSIONS: Current evidence suggests a dose-dependent toxic effect on cartilage, tendon, and synovial tissue. Concentrations of 20 mg/ml or less are expected to be safe. There is a significant body of evidence to suggest the need for caution with intraarticular administration of TXA. There is a need for further human clinical trials in order to clarify the long-term safety of TXA topical application.
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Antifibrinolíticos/efectos adversos , Artroscopía , Condrocitos/efectos de los fármacos , Sinoviocitos/efectos de los fármacos , Tenocitos/efectos de los fármacos , Ácido Tranexámico/efectos adversos , Antifibrinolíticos/administración & dosificación , Humanos , Inyecciones Intraarticulares , Periostio/efectos de los fármacos , Ácido Tranexámico/administración & dosificaciónRESUMEN
BACKGROUND: The hip abductors are crucial in maintaining pelvic stability. Tears in these tendons are common and often debilitating. There is uncertainty regarding both the histological and macroscopic features of hip abductor tears. This study aims to clarify both the macroscopic and microscopic features of the tendon and enthesis in hip abductor tendon tears. METHODS: Thirty-six cadavers with an average age of 81 were dissected, and the hip abductor mechanisms removed en-bloc. The presence, location and size of the tears were recorded and analysed. The samples were processed into histological blocks and viewed using both transmitted and polarised light. Tendon histology was graded using the modified Movin's score in three sections (deep, middle and superficial layers) and the enthesis graded separately using 5-point criteria. Analysis of variance was used to confirm histological features associated with tears. RESULTS: Tears were found in 24 of 36 samples (67%). The most common finding was an isolated tear in the gluteus minimus (46%), followed by concurrent gluteus medius and gluteus minimus tears (33%). Histology revealed significantly more degeneration in both the tendon (p = 0.0005) and enthesis (p = 0.0011) when tears were present. Furthermore, these changes were concentrated in the deeper layers of the tendon (p = 0.0002) and enthesis (p = 0.003). CONCLUSION: This study demonstrated degeneration as the primary pathology underlying hip abductor tendon tears. Degenerative changes occur in both the tendon and enthesis, with the deeper layers predominantly affected. These findings are important for guiding surgical repair techniques and to aid the development of novel materials and biologics.
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Traumatismos de los Tendones , Anciano de 80 o más Años , Nalgas , Cadáver , Humanos , Imagen por Resonancia Magnética , Músculo Esquelético , TendonesRESUMEN
Bisphosphonates are used in treating patients with breast cancer. In vitro studies have shown that bisphosphonates act directly on tumour cells, inhibiting cell proliferation and inducing apoptosis. In most such studies, drugs were added to culture media exposing cells to high bisphosphonate concentrations in solution. However, since bisphosphonates bind to bone hydroxyapatite with high affinity and remain bound for very long periods of time, these experimental systems are not an optimal model for the action of the drugs in vivo. The aim of this study was to determine whether bone-bound zoledronate has direct effects on adjacent breast cancer cells. Bone slices were pre-incubated with bisphosphonate solutions, washed, and seeded with cells of the breast cancer cell lines, MCF7 or MDA-MB-231. Proliferation was assessed by cell counts and thymidine incorporation for up to 72 h. Inhibition of the mevalonate pathway was tested by measuring the levels of unprenylated Rap1A, and apoptosis was examined by the presence of cleaved caspase-8 on western blots. The proliferation rate of breast cancer cells on zoledronate-treated bone was significantly lower compared to cells on control bone. Other bisphosphonates showed a similar inhibitory effect, with an order of potency similar to their clinical potencies. Unprenylated Rap1A accumulated in MCF7 cells on zoledronate-treated bone, suggesting zoledronate acted through the inhibition of the mevalonate pathway. Accumulation of cleaved caspase-8 in MDA-MB-231 cells on bisphosphonate-treated bone indicated increased apoptosis in the cells. In conclusion, bone-bound zoledronate inhibits breast cancer cell proliferation, an activity that may contribute to its clinical anti-tumour effects.
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Conservadores de la Densidad Ósea/farmacología , Huesos/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Ácido Zoledrónico/farmacología , Animales , Huesos/efectos de los fármacos , Bovinos , Línea Celular Tumoral , Difosfonatos/farmacología , HumanosRESUMEN
Chondrocytes in osteoarthritis undergo a phenotype shift leading to increased production of cartilage-degrading enzymes. There are similarities between the phenotype of osteoarthritic chondrocytes and those of growth plate chondrocytes. Hydroxyapatite can promote chondrocyte differentiation in the growth plate. Basic calcium phosphate (BCP) crystals (which consist of hydroxyapatite, octacalcium apatite and tricalcium phosphate) are frequently found in osteoarthritic joints. The objective of this study was to determine whether BCP crystals induce disease-associated changes in phenotypic marker expression in chondrocytes. Primary human chondrocytes isolated from macroscopically normal cartilage were treated with BCP for up to 48 h. Expression of indian hedgehog (IHH), matrix metalloproteinase 13 (MMP13), interleukin-6 (IL-6) and type X collagen (COLX) were higher, and expression of sry-box 9 (SOX9) lower, in BCP-treated chondrocytes (50 µg/mL) compared to untreated controls. COLX protein was also present in BCP-treated chondrocytes. Intracellular calcium and levels of phosphorylated and total calcium/calmodulin kinase 2 (CaMK2) were elevated following BCP treatment due to BCP-induced release of calcium from intracellular stores. CaMK2 inhibition or knockdown ameliorated the BCP-induced changes in SOX9, IHH, COLX, IL-6 and MMP13 expression. BCP crystals induce osteoarthritis-associated changes in phenotypic marker expression in chondrocytes by calcium-mediated activation of CaMK2. The presence of BCP crystals in osteoarthritic joints may contribute to disease progression.
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Biomarcadores/metabolismo , Fosfatos de Calcio/farmacología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Calcio/metabolismo , Condrocitos/efectos de los fármacos , Osteoartritis/metabolismo , Fosfatos de Calcio/química , Cartílago Articular/metabolismo , Cartílago Articular/patología , Células Cultivadas , Condrocitos/citología , Condrocitos/metabolismo , Cristalización , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Osteoartritis/genética , Osteoartritis/patología , Fenotipo , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Augmenting repairs with extracellular matrix-based scaffolds is a common option for rotator cuff tears. In this study, a new collagen scaffold was assessed for its efficacy in augmenting rotator cuff repair. METHODS: The collagen scaffold was assessed in vitro for cytocompatibility and retention of tenocyte phenotype using alamarBlue assays, fluorescent imaging, and real-time polymerase chain reaction. Immunogenicity was assessed in vitro by the activation of human monocytes. In vivo, by use of a modified rat rotator cuff defect model, supraspinatus tendon repairs were carried out in 40 animals. Overlay augmentation with the collagen scaffold was compared with unaugmented repairs. At 6 and 12 weeks postoperatively, the repairs were tested biomechanically to evaluate repair strength, as well as histologically to assess quality of healing. RESULTS: The collagen scaffold supported human tendon-derived cell growth in vitro, with cells demonstrating proliferation and appearing morphologically tenocytic over the experimental period. No immunogenic responses were provoked compared with suture material control. In vivo, augmentation with the scaffold improved the histologic scores at 12 weeks (8.4 of 15 vs 6.4 of 15, P = .032). However, no significant difference was detected with mechanical testing. CONCLUSION: The new collagen scaffold was supportive of cell growth in vitro and generated a minimal acute inflammatory response. In vivo, we observed an improvement in the histologic appearance of the repair at 12 weeks. However, a meaningful increase in biomechanical strength was not achieved. Further modification and improvement of the scaffold are required prior to consideration for clinical use.
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Colágeno , Matriz Extracelular , Lesiones del Manguito de los Rotadores/cirugía , Andamios del Tejido , Animales , Fenómenos Biomecánicos , Modelos Animales de Enfermedad , Ratas , Ratas Sprague-Dawley , Cicatrización de Heridas/fisiologíaRESUMEN
INTRODUCTION: Numerous observational studies have reported that serum urate concentration positively correlates with bone density and reduced risk of fractures. The aim of this study was to examine whether soluble urate directly influences bone remodelling. METHODS: In laboratory studies, the in vitro effects of soluble urate were examined in osteoclast, osteoblast and osteocyte assays at a range of urate concentrations consistent with those typically observed in humans (up to 0.70 mmol/L). The clinical relevance of the in vitro assay findings was assessed using serial procollagen-1 N-terminal propeptide (P1NP) and Month 12 bone density data from a randomised controlled trial of allopurinol dose escalation in people with gout. RESULTS: Addition of urate in the RAW264.7 cell osteoclastogenesis assay led to small increases in osteoclast formation (ANOVA p = 0.018), but no significant difference in bone resorption. No significant effects on osteoclast number or activity were observed in primary cell osteoclastogenesis or resorption assays. Addition of urate did not alter viability or function in MC3T3-E1 pre-osteoblast, primary human osteoblast, or MLO-Y4 osteocyte assays. In the clinical trial analysis, reducing serum urate over a 12 month period by allopurinol dose escalation did not lead to significant changes in P1NP or differences in bone mineral density. CONCLUSION: Addition of soluble urate at physiological concentrations does not influence bone remodelling in vitro. These data, together with clinical trial data showing no effect of urate-lowering on P1NP or bone density, do not support a direct role for urate in influencing bone remodelling.
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Remodelación Ósea/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Osteocitos/efectos de los fármacos , Ácido Úrico/farmacología , Remodelación Ósea/fisiología , Resorción Ósea/metabolismo , Huesos/efectos de los fármacos , Huesos/metabolismo , Diferenciación Celular/efectos de los fármacos , Humanos , Osteoclastos/metabolismo , Osteocitos/metabolismo , Osteogénesis/efectos de los fármacosRESUMEN
PURPOSE OF REVIEW: The goal of this review is to gain a better understanding of marrow adipocyte development, its regulation of energy, and its characterization responsible for bone homeostasis. RECENT FINDINGS: Despite major advances in uncovering the complex association of bone-fat in the marrow, the underlying basic biological process of adipose tissue development, as well as its interaction with bone homeostasis in pathophysiological conditions, is still not well understood. This review identifies many pro- and anti-osteogenic factors secreted by adipocytes to play a role in the manipulating the fate of mesenchymal stem cells as well as the osteoblastic activity during bone remodeling. It also addresses the function of adipose tissue capable of negative regulation of the hematopoietic microenvironment to influence the bone quantity and the nature of bone homeostasis.
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Adipocitos/metabolismo , Remodelación Ósea , Huesos/metabolismo , Metabolismo Energético , Homeostasis , Osteogénesis , Adipocitos/fisiología , Adipogénesis , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Médula Ósea/metabolismo , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/fisiología , Diferenciación Celular , Humanos , Células Madre Mesenquimatosas , OsteoblastosRESUMEN
The adipokine adiponectin affects multiple target tissues and plays important roles in glucose metabolism and whole-body energy homeostasis. Circulating adiponectin levels in obese people are lower than in non-obese, and increased serum adiponectin is associated with weight loss. Numerous clinical studies have established that fat mass is positively related to bone mass, a relationship that is maintained by communication between the two tissues through hormones and cytokines. Since adiponectin levels inversely correspond to fat mass, its bone effects and its potential contribution to the relationship between fat and bone have been investigated. In clinical observational studies, adiponectin was found to be negatively associated with bone mineral density, suggesting it might be a negative regulator of bone metabolism. In order to identify the mechanisms that underlie the activity of adiponectin in bone, a large number of laboratory studies in vitro and in animal models of mice over-expressing or deficient of adiponectin have been carried out. Results of these studies are not entirely congruent, partly due to variation among experimental systems and partly due to the complex nature of adiponectin signaling, which involves a combination of multiple direct and indirect mechanisms.
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Adiponectina/metabolismo , Huesos/metabolismo , Animales , HumanosRESUMEN
Peptide based hydrogels have received much attention due to their potential biomedical applications. The majority of the gel forming peptides present a ß-sheet motif that is composed of alternating hydrophobic/hydrophilic amino acids. Furthermore, structural characterization of the assembly of these ß-sheet peptides has been refined recently. However, the relationship between peptide residue composition, molecular structure and the mechanical properties of the resulting hydrogel is not entirely understood. In this review, an analysis of the structural features of different ß-sheet peptide hydrogels and their mechanical properties is discussed, in order to provide further insight on the molecular features that are relevant for the design of effective ß-peptide hydrogels.
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Hidrogel de Polietilenoglicol-Dimetacrilato/química , Péptidos/química , Conformación Proteica en Lámina beta , Fenómenos Mecánicos , Modelos MolecularesRESUMEN
Loss of bone occurs in the age-related skeletal disorder, osteoporosis, leading to bone fragility and increased incidence of fractures, which are associated with enormous costs and substantial morbidity and mortality. Recent data indicate that osteoporotic fractures are more common than other diseases, which usually attract public attention (e.g., heart attack and breast cancer). The prevention and treatment of this skeletal disorder are therefore of paramount importance. Majority of osteoporosis medications restore skeletal balance by reducing osteoclastic activity, thereby reducing bone resorption. These agents, however, do not regenerate damaged bone tissue, leaving limited options for patients once bone loss has occurred. Recently, attention has turned to bone-anabolic agents. Such agents have the ability to increase bone mass and strength, potentially reversing structural damage. To date, only one bone-anabolic drug is available in the market. The discovery of more novel, cost-effective bone anabolic agents is therefore a priority to treat those suffering from this disabling condition. Short peptides offer an important alternative for the development of novel bone-anabolic agents given their high target binding specificity, which translates into potent activity with limited side effects. This review summarizes attempts in the identification of bone-anabolic peptides, and their development for promoting bone growth.
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Anabolizantes/farmacología , Desarrollo Óseo/efectos de los fármacos , Anabolizantes/uso terapéutico , Animales , Desarrollo Óseo/fisiología , Humanos , Osteoporosis/tratamiento farmacológicoRESUMEN
The cyclohexapeptide natural product dianthin G promotes osteoblast (bone-forming cell) proliferation in vitro at nanomolar concentrations, and is therefore considered a promising candidate for the treatment of osteoporosis. An N(α)-methyl amide bond scan of dianthin G was performed to probe the effect of modifying amide bonds on osteoblast proliferation. In addition, to provide greater structural diversity, a series of dicarba dianthin G analogues was synthesised using ring closing metathesis. Dianthin G and one novel dicarba analogue increased the number of human osteoblasts and importantly they did not increase osteoclast (bone-resorbing cell) differentiation in bone marrow cells.