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Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. PURPOSE: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. METHODS: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. RESULTS: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. CONCLUSION: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.
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The vast majority of transcribed RNAs are noncoding RNAs. Among noncoding RNAs, long noncoding RNAs (lncRNAs), which contain hundreds to thousands of bases, have received attention in many fields. The vast majority of the constituent cells in bone tissue are osteocytes, but their regulatory mechanisms are incompletely understood. Considering the wide range of potential contributions of lncRNAs to physiological processes and pathological conditions, we hypothesized that lncRNAs in osteocytes, which have not been reported, could be involved in bone metabolism. Here, we first isolated osteocytes from femurs of mice with osteocyte-specific GFP expression. Then, through RNA-sequencing, we identified osteocyte-specific lncRNAs and focused on a novel lncRNA, 9530026P05Rik (lncRNA953Rik), which strongly suppressed osteogenic differentiation. In the IDG-SW3 osteocyte line with lncRNA953Rik overexpression, the expression of Osterix and its downstream genes was reduced. RNA pull-down and subsequent LC-MS/MS analysis revealed that lncRNA953Rik bound the nuclear protein CCAR2. We demonstrated that CCAR2 promoted Wnt/ß-catenin signaling and that lncRNA953Rik inhibited this pathway. lncRNA953Rik sequestered CCAR2 from HDAC1, leading to deacetylation of H3K27 in the Osterix promoter and consequent transcriptional downregulation of Osterix. This research is the first to clarify the role of a lncRNA in osteocytes. Our findings can pave the way for novel therapeutic options targeting lncRNAs in osteocytes to treat bone metabolic diseases such as osteoporosis.
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Osteocitos , Osteogénesis , ARN Largo no Codificante , Animales , Ratones , Cromatografía Liquida , Osteogénesis/genética , ARN Largo no Codificante/genética , Espectrometría de Masas en Tándem , Vía de Señalización WntRESUMEN
Bone is one of the largest organ systems in humans and is considered to regulate whole-body homeostasis in cooperation with other organs. We have previously reported that a sympathetic or sensory nervous system inside bone regulates bone homeostasis. However, the detailed regulatory mechanism, including the distribution of nerves inside bone, remains unknown. Although a two-dimensional histological analysis has been widely used to evaluate the structure of nerves or blood vessels, the actual structure is more complex, suggesting that it should be evaluated three-dimensionally. Here, we established a novel bone tissue clearing technique (Osteo-DISCO) for murine bones which enabled us to visualize the detailed distribution of nerves or blood vessels inside bone. Interestingly, we found that there is a specific nerve entry site in each long bone and that surgical ablation of the specific nerve fibers entering bone tissue led to decreased bone formation and impaired bone regeneration. Furthermore, we revealed that the administration of calcitonin gene-related peptide (CGRP), which is primarily released from sensory nerves, suppressed the bone loss caused by surgical nerve ablation. An in vitro study also indicated that CGRP directly promotes osteoblast activity, suggesting that sensory nerves inside bone can regulate osteogenesis via the secretion of CGRP.
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Péptido Relacionado con Gen de Calcitonina , Imagenología Tridimensional , Ratones , Humanos , Animales , Huesos/diagnóstico por imagen , Remodelación Ósea , Redes Neurales de la ComputaciónRESUMEN
In bone marrow, special microenvironments, known as niches, are essential for the maintenance of hematopoietic stem cells (HSCs). A population of mesenchymal stem cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells or leptin receptor-expressing cells are the major cellular component of HSC niches. The molecular regulation of HSC niche properties is not fully understood. The role of Runx transcription factors, Runx1 and Runx2 in HSC cellular niches remains unclear. Here we show that Runx1 is predominantly expressed in CAR cells and that mice lacking both Runx1 and Runx2 in CAR cells display an increase in fibrosis and bone formation with markedly reduced hematopoietic stem and progenitor cells in bone marrow. In vitro, Runx1 is induced by the transcription factor Foxc1 and decreases fibrotic gene expression in CAR cells. Thus, HSC cellular niches require Runx1 or Runx2 to prevent their fibrotic conversion and maintain HSCs and hematopoiesis in adults.
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Células Madre Hematopoyéticas , Nicho de Células Madre , Animales , Médula Ósea/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Fibrosis , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , RatonesRESUMEN
Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, eventually leading to joint destruction. However, the epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here, we showed that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is a central epigenetic regulator that orchestrates multiple pathogeneses in RA in a suppressive manner. UHRF1 expression was remarkably upregulated in synovial fibroblasts (SFs) from arthritis model mice and patients with RA. Mice with SF-specific Uhrf1 conditional knockout showed more severe arthritic phenotypes than littermate controls. Uhrf1-deficient SFs also exhibited enhanced apoptosis resistance and upregulated expression of several cytokines, including Ccl20. In patients with RA, DAS28, CRP, and Th17 accumulation and apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, Ryuvidine administration stabilized UHRF1 ameliorated arthritis pathogeneses in a mouse model of RA. This study demonstrated that UHRF1 expressed in RA SFs can contribute to negative feedback mechanisms that suppress multiple pathogenic events in arthritis, suggesting that targeting UHRF1 could be one of the therapeutic strategies for RA.
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Artritis Reumatoide , Proteínas Potenciadoras de Unión a CCAAT , Epigénesis Genética , Ubiquitina-Proteína Ligasas , Animales , Artritis Reumatoide/patología , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Fibroblastos/metabolismo , Expresión Génica , Humanos , Inflamación/patología , Ratones , Membrana Sinovial/patología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Mechanical stimuli including loading after birth promote bone growth. However, little is known about how mechanical force triggers biochemical signals to regulate bone growth. Here, we identified a periosteal-osteoblast-derived secretory peptide, Osteocrin (OSTN), as a mechanotransducer involved in load-induced long bone growth. OSTN produced by periosteal osteoblasts regulates growth plate growth by enhancing C-type natriuretic peptide (CNP)-dependent proliferation and maturation of chondrocytes, leading to elongation of long bones. Additionally, OSTN cooperates with CNP to regulate bone formation. CNP stimulates osteogenic differentiation of periosteal osteoprogenitors to induce bone formation. OSTN binds to natriuretic peptide receptor 3 (NPR3) in periosteal osteoprogenitors, thereby preventing NPR3-mediated clearance of CNP and consequently facilitating CNP-signal-mediated bone growth. Importantly, physiological loading induces Ostn expression in periosteal osteoblasts by suppressing Forkhead box protein O1 (FoxO1) transcription factor. Thus, this study reveals a crucial role of OSTN as a mechanotransducer converting mechanical loading to CNP-dependent bone formation.
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Desarrollo Óseo , Proteínas Musculares/metabolismo , Periostio/crecimiento & desarrollo , Periostio/metabolismo , Estrés Mecánico , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Ratones Noqueados , Péptido Natriurético Tipo-C/metabolismo , Osteoblastos/metabolismo , Osteogénesis , Receptores del Factor Natriurético Atrial/metabolismo , Transducción de Señal , Soporte de PesoRESUMEN
Considering that stress condition associated with osteoporosis, the hypothalamic-pituitary-adrenal (HPA) axis, which is essential for central stress response system, is implicated in regulating bone mass accrual. Melanocortin 2 receptor (MC2R), the receptor of adrenocorticotropic hormone is expressed in both adrenal gland cells and bone cells. To elucidate the role of HPA axis in bone metabolism, we assessed the skeletal phenotype of MC2R deficient mice (MC2R -/- mice). We first examined bone mineral density and cortical thickness of femur using dual x-ray absorptiometry and micro-computed tomography. We then conducted histomorphometric analysis to calculate the static and dynamic parameters of vertebrae in MC2R -/- mice. The levels of osteoblastic marker genes were examined by quantitative PCR in primary osteoblasts derived from MC2R -/- mice. Based on these observations, bone mineral density of femur in MC2R -/- mice was increasing relative to litter controls. Meanwhile, the thickness of cortical bone of femur in MC2R -/- mice was remarkably elevated. Moreover, serum osteocalcin level was drastically raised in MC2R -/- mice. However, bone histomorphometry revealed that static and dynamic parameters reflecting bone formation and resorption were unchanged in vertebrae of MC2R -/- mice compared to the control, indicating that MC2R function may be specific to appendicular bone than axis bone. Taken together, the HPA axis due to deletion of MC2R is involved in bone metabolism.
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Pericytes are mesenchymal cells that surround the endothelial cells of small vessels in various organs. These cells express several markers, such as NG2, CD146, and PDGFRß, and play an important role in the stabilization and maturation of blood vessels. It was also recently revealed that like mesenchymal stem cells (MSCs), pericytes possess multilineage differentiation capacity, especially myogenic, adipogenic, and fibrogenic differentiation capacities. Although some previous studies have reported that pericytes also have osteogenic potential, the osteogenesis of pericytes can still be further elucidated. In the present study, we established novel methods for isolating and culturing primary murine pericytes. An immortalized pericyte line was also established. Multilineage induction of the pericyte line induced osteogenesis, adipogenesis, and chondrogenesis of the cells in vitro. In addition, pericytes that were injected into the fracture site of a bone fracture mouse model contributed to callus formation. Furthermore, in vivo pericyte-lineage-tracing studies demonstrated that endogenous pericytes also differentiate into osteoblasts and osteocytes and contribute to bone fracture healing as a cellular source of osteogenic cells. Pericytes can be a promising therapeutic candidate for treating bone fractures with a delayed union or nonunion as well as bone diseases causing bone defects.
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Condrogénesis , Curación de Fractura , Osteogénesis , Pericitos/citología , Cultivo Primario de Células/métodos , Animales , Diferenciación Celular , Línea Celular , Células Cultivadas , Condrocitos/citología , Trasplante de Células Madre Mesenquimatosas/métodos , Ratones , Ratones Endogámicos BALB C , Osteoblastos/citología , Pericitos/trasplanteRESUMEN
Bone is one of common metastasis sites for many types of cancer. In bone metastatic microenvironment, tumor-bone interactions play a significant role in the regulation of osteolytic or osteoblastic bone metastasis. In order to investigate the direct interaction between tumor cells and bone tissue, it is essential to generate appropriate animal models that mimic the behavior of tumor cells in bone metastatic lesions. Calvarial implantation model (bone invasion model) is a newly-established animal model that accurately recapitulates the behavior of tumor cells in the tumor-bone microenvironment. The surgical technique for tumor cell implantation is simpler than intracardiac, intra-arterial, or intraosseous injection techniques. This model can be useful for the identification of key factors driving tumor-induced osteolytic or osteoblastic changes.
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SP7/Osterix (OSX) is a master regulatory transcription factor that activates a variety of genes during differentiation of osteoblasts. However, the influence of post-translational modifications on the regulation of its transactivation activity is largely unknown. Here, we report that sirtuins, which are NAD(+)-dependent deacylases, regulate lysine deacylation-mediated transactivation of OSX. Germline Sirt7 knockout mice develop severe osteopenia characterized by decreased bone formation and an increase of osteoclasts. Similarly, osteoblast-specific Sirt7 knockout mice showed attenuated bone formation. Interaction of SIRT7 with OSX leads to the activation of transactivation by OSX without altering its protein expression. Deacylation of lysine (K) 368 in the C-terminal region of OSX by SIRT7 promote its N-terminal transactivation activity. In addition, SIRT7-mediated deacylation of K368 also facilitates depropionylation of OSX by SIRT1, thereby increasing OSX transactivation activity. In conclusion, our findings suggest that SIRT7 has a critical role in bone formation by regulating acylation of OSX.
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Enfermedades Óseas Metabólicas/genética , Lisina/metabolismo , Osteoblastos/metabolismo , Sirtuinas/genética , Factor de Transcripción Sp7/genética , Activación Transcripcional , Acilación , Animales , Densidad Ósea , Enfermedades Óseas Metabólicas/metabolismo , Enfermedades Óseas Metabólicas/patología , Diferenciación Celular , Línea Celular , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoblastos/patología , Osteoclastos/metabolismo , Osteoclastos/patología , Osteogénesis/genética , Transducción de Señal , Sirtuinas/deficiencia , Factor de Transcripción Sp7/metabolismoRESUMEN
Recent advances demonstrated that osteoporosis is one of the major complications in diabetes. In Diabetic conditions, both bone material properties and bone microarchitecture are impaired, resulting in the decline in bone strength. Furthermore, bone-derived osteocalcin stimulates insulin secretion, thereby regulates the whole body glucose metabolism. Thus, it was revealed that bone metabolism and glucose metabolism are intimately involved.
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Peso Corporal , Huesos , Calcio , Glucosa , Humanos , Insulina , OsteocalcinaRESUMEN
Bone metastatic lesions are classified as osteoblastic or osteolytic lesions. Prostate and breast cancer patients frequently exhibit osteoblastic-type and osteolytic-type bone metastasis, respectively. In metastatic lesions, tumor cells interact with many different cell types, including osteoblasts, osteoclasts, and mesenchymal stem cells, resulting in an osteoblastic or osteolytic phenotype. However, the mechanisms responsible for the modification of bone remodeling have not been fully elucidated. MicroRNAs (miRNAs) are transferred between cells via exosomes and serve as intercellular communication tools, and numerous studies have demonstrated that cancer-secreted miRNAs are capable of modifying the tumor microenvironment. Thus, cancer-secreted miRNAs can induce an osteoblastic or osteolytic phenotype in the bone metastatic microenvironment. In this study, we performed a comprehensive expression analysis of exosomal miRNAs secreted by several human cancer cell lines and identified eight types of human miRNAs that were highly expressed in exosomes from osteoblastic phenotype-inducing prostate cancer cell lines. One of these miRNAs, hsa-miR-940, significantly promoted the osteogenic differentiation of human mesenchymal stem cells in vitro by targeting ARHGAP1 and FAM134A Interestingly, although MDA-MB-231 breast cancer cells are commonly known as an osteolytic phenotype-inducing cancer cell line, the implantation of miR-940-overexpressing MDA-MB-231 cells induced extensive osteoblastic lesions in the resulting tumors by facilitating the osteogenic differentiation of host mesenchymal cells. Our results suggest that the phenotypes of bone metastases can be induced by miRNAs secreted by cancer cells in the bone microenvironment.
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Neoplasias Óseas/metabolismo , Neoplasias de la Mama/patología , Proteínas Activadoras de GTPasa/metabolismo , Proteínas de la Membrana/metabolismo , MicroARNs/metabolismo , Neoplasias de la Próstata/metabolismo , Adenocarcinoma/metabolismo , Animales , Neoplasias Óseas/secundario , Sustitutos de Huesos , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Femenino , Proteínas Activadoras de GTPasa/genética , Humanos , Masculino , Proteínas de la Membrana/genética , Células Madre Mesenquimatosas , Ratones , MicroARNs/genética , Neoplasias Experimentales/metabolismoRESUMEN
Long-term antiretroviral therapy is associated with increased fracture risk, but the mechanism remains elusive. We measured serum undercarboxylated osteocalcin and pentosidine (markers of poor bone quality) in human immunodeficiency virus-infected patients treated with protease inhibitors (PIs) or an integrase strand transfer inhibitor-containing regimen. The results demonstrated significantly higher undercarboxylated osteocalcin and pentosidine in PI-treated patients. Switching to integrase strand transfer inhibitor significant decreased these markers. We also showed impaired bone mechanical properties with higher undercarboxylated osteocalcin level in PI-treated mice and inhibited osteoblast differentiation in PI-treated osteogenic cells. The results confirmed the adverse effects of PIs on bone quality and osteoblast differentiation.
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Terapia Antirretroviral Altamente Activa/efectos adversos , Densidad Ósea/efectos de los fármacos , Inhibidores de Proteasas/efectos adversos , Animales , Arginina/análogos & derivados , Arginina/sangre , Biomarcadores/sangre , Femenino , VIH-1/efectos de los fármacos , Humanos , Inhibidores de Integrasa , Lisina/análogos & derivados , Lisina/sangre , Masculino , Ratones , Osteocalcina/sangre , Estudios Retrospectivos , Inhibidores de la Transcriptasa InversaRESUMEN
The with-no-lysine kinase (WNK) 4 gene is a causative gene in pseudohypoaldosteronism type II. Although WNKs are widely expressed in the body, neither their metabolic functions nor their extrarenal role is clear. In this study, we found that WNK4 was expressed in mouse adipose tissue and 3T3-L1 adipocytes. In mouse primary preadipocytes and in 3T3-L1 adipocytes, WNK4 was markedly induced in the early phase of adipocyte differentiation. WNK4 expression preceded the expression of key transcriptional factors PPARγ and C/EBPα. WNK4-siRNA-transfected 3T3-L1 cells and human mesenchymal stem cells showed reduced expression of PPARγ and C/EBPα and lipid accumulation. WNK4 protein affected the DNA-binding ability of C/EBPß and thereby reduced PPARγ expression. In the WNK4-/- mice, PPARγ and C/EBPα expression were decreased in adipose tissues, and the mice exhibited partial resistance to high-fat diet-induced adiposity. These data suggest that WNK4 may be a proadipogenic factor, and offer insights into the relationship between WNKs and energy metabolism.
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Dieta Alta en Grasa , Obesidad/etiología , Proteínas Serina-Treonina Quinasas/metabolismo , Células 3T3-L1 , Adipocitos/citología , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Glucemia/análisis , Proteína alfa Potenciadora de Unión a CCAAT/genética , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Células Cultivadas , Humanos , Insulina/sangre , Leptina/sangre , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Obesidad/patología , Obesidad/prevención & control , PPAR gamma/genética , PPAR gamma/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
We have previously shown that endochondral ossification is finely regulated by the Clock system expressed in chondrocytes during postnatal skeletogenesis. Here we show a sophisticated modulation of bone resorption and bone mass by the Clock system through its expression in bone-forming osteoblasts. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) and Period1 (Per1) were expressed with oscillatory rhythmicity in the bone in vivo, and circadian rhythm was also observed in cultured osteoblasts of Per1::luciferase transgenic mice. Global deletion of murine Bmal1, a core component of the Clock system, led to a low bone mass, associated with increased bone resorption. This phenotype was recapitulated by the deletion of Bmal1 in osteoblasts alone. Co-culture experiments revealed that Bmal1-deficient osteoblasts have a higher ability to support osteoclastogenesis. Moreover, 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ]-induced receptor activator of nuclear factor κB ligand (Rankl) expression was more strongly enhanced in both Bmal1-deficient bone and cultured osteoblasts, whereas overexpression of Bmal1/Clock conversely inhibited it in osteoblasts. These results suggest that bone resorption and bone mass are regulated at a sophisticated level by osteoblastic Clock system through a mechanism relevant to the modulation of 1,25(OH)2 D3 -induced Rankl expression in osteoblasts. © 2017 American Society for Bone and Mineral Research.
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Factores de Transcripción ARNTL/metabolismo , Resorción Ósea/metabolismo , Proteínas CLOCK/metabolismo , Osteoblastos/metabolismo , Proteínas Circadianas Period/metabolismo , Ligando RANK/metabolismo , Factores de Transcripción ARNTL/genética , Animales , Resorción Ósea/genética , Proteínas CLOCK/genética , Células Cultivadas , Ratones , Ratones Noqueados , Proteínas Circadianas Period/genética , Ligando RANK/genéticaRESUMEN
Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of PPP3CA, a catalytic subunit of calcineurin, was high in advanced patients. Panobinostat degraded PPP3CA, a degradation that should have been induced by inhibition of the chaperone function of heat shock protein 90 (HSP90). Cotreatment with HDAC inhibitors and FK506 led to an enhanced antimyeloma effect with a greater PPP3CA reduction compared with HDAC inhibitors alone both in vitro and in vivo. In addition, this combination treatment efficiently blocked osteoclast formation, which results in osteolytic lesions. The poor response and short PFS duration observed in the bortezomib-containing therapies of patients with high PPP3CA suggested its relevance to bortezomib resistance. Moreover, bortezomib and HDAC inhibitors synergistically suppressed MM cell viability through PPP3CA inhibition. Our findings underscore the usefulness of calcineurin-targeted therapy in MM patients, including patients who are resistant to bortezomib.
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Calcineurina/metabolismo , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Indoles/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Animales , Línea Celular Tumoral , Femenino , Humanos , Ratones Endogámicos NOD , Ratones SCID , Panobinostat , Tacrolimus/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The cell of origin for most mesenchymal tumors is unclear. One cell type that contributes to this lineages is the pericyte, a cell expressing Ng2/Cspg4. Using lineage tracing, we demonstrated that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc, can derive from cells expressing Ng2/Cspg4. Deletion of the Trp53 tumor suppressor gene in these cells resulted in the bone and soft tissue sarcomas that closely resemble human sarcomas, while stabilizing ß-catenin in this same cell type caused desmoid tumors. Comparing expression between Ng2/Cspg4-expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53 showed inhibition of ß-catenin signaling in the sarcomas. Activation of ß-catenin inhibited the formation and growth of sarcomas. Thus, pericytes can be a cell of origin for mesenchymal tumors, and ß-catenin dysregulation plays an important role in the neoplastic phenotype.
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Antígenos/metabolismo , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Mesodermo/metabolismo , Neoplasias/metabolismo , Pericitos/metabolismo , Proteoglicanos/metabolismo , beta Catenina/metabolismo , Animales , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Línea Celular Tumoral , Linaje de la Célula/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Masculino , Mesodermo/patología , Ratones , Ratones Noqueados , Mutación/fisiología , Neoplasias/patología , Fenotipo , Sarcoma/metabolismo , Sarcoma/patología , Transducción de Señal/fisiología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Activating transcription factor 3 (Atf3) has been implicated in the pathogenesis of various diseases, including cancer and inflammation, as well as in the regulation of cell proliferation and differentiation. However, the involvement of Atf3 in developmental skeletogenesis and joint disease has not been well studied to date. Here, we show that Atf3 is a critical mediator of osteoarthritis (OA) development through its expression in chondrocytes. ATF3 expression was markedly up-regulated in the OA cartilage of both mice and humans. Conditional deletion of Atf3 in chondrocytes did not result in skeletal abnormalities or affect the chondrogenesis, but alleviated the development of OA generated by surgically inducing knee joint instability in mice. Inflammatory cytokines significantly up-regulated Atf3 expression through the nuclear factor-kB (NF-kB) pathway, while cytokine-induced interleukin-6 (Il6) expression was repressed, in ATF3-deleted murine and human chondrocytes. Mechanistically, Atf3 deficiency decreased cytokine-induced Il6 transcription in chondrocytes through repressing NF-kB signalling by the attenuation of the phosphorylation status of IkB and p65. These findings suggest that Atf3 is implicated in the pathogenesis of OA through modulation of inflammatory cytokine expression in chondrocytes, and the feed-forward loop of inflammatory cytokines/NF-kB/Atf3 in chondrocytes may be a novel therapeutic target for the treatment for OA. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Factor de Transcripción Activador 3/genética , Cartílago Articular/metabolismo , Condrocitos/metabolismo , Osteoartritis/metabolismo , Factor de Transcripción Activador 3/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Células Cultivadas , Condrocitos/efectos de los fármacos , Condrocitos/patología , Femenino , Humanos , Interleucina-1beta/farmacología , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Transgénicos , Osteoartritis/genética , Osteoartritis/patología , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
It has been recently demonstrated that osteocalcin, which is secreted from osteoblasts, plays a significant role in glucose metabolism, fat metabolism, mail fertility, and brain functions. It has been also revealed that fibroblast growth factor 23 (FGF23), which is secreted from osteocytes, has an important role in phosphate metabolism or calcium homeostasis. These findings suggest that bone is not only a target organ of hormones but also involved in regulating other organs as an endocrine organ. Bone forms regulatory network with various organs to maintain the whole body homeostasis. This review introduces the regulation of various organs by osteoblasts.
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Huesos/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Homeostasis/fisiología , Osteoblastos/citología , Osteocitos/citología , Animales , Huesos/patología , Factor-23 de Crecimiento de Fibroblastos , Humanos , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteocitos/metabolismoRESUMEN
BACKGROUND: Osteocytes, which comprise over 90% of all bone cells, communicate with osteoblasts and osteoclasts to regulate each other's physiological function via dendrites, suggesting that dendrite elongation plays a vital role for bone regeneration. We examined the effect of semaphorin 3A (SEMA3A) on dendritic processes of an osteocyte cell line, since in previous work we found it to be essential for promoting osteoblast differentiation. MATERIALS AND METHODS: Dendrite length was analyzed by Cellomics Array Scan VTI quantitatively in osteocyte-like cell line, MLO-Y4 cells. We performed cell proliferation assay. Gene and protein expression was examined by real-time reverse-transcriptase polymerase chain reaction and western blotting, respectively. RESULTS: Both total and average dendrite length were significantly increased in MLO-Y4 cells stimulated with SEMA3A compared to control. E11 protein was up-regulated upon SEMA3A stimulation. Moreover, cyclin-dependent kinase 6 (CDK6) was down-regulated in a time-dependent manner. Taken together, these results suggest that SEMA3A regulates dendrites of osteocytes in association with down-regulation of CDK6. SEMA3A may be a promising drug to apply for bone tissue engineering.