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[PMID]: 29279050 [Au] Autor: Madrigal A; Tan L; Zhao Y [Ad] Endereço: Biological Sciences Department, California State Polytechnic University at Pomona, 3801 W. Temple Ave., Pomona, CA, 91768, USA. [Ti] Título: Expression regulation and functional analysis of RGS2 and RGS4 in adipogenic and osteogenic differentiation of human mesenchymal stem cells. [So] Source: Biol Res;50(1):43, 2017 Dec 26. [Is] ISSN: 0717-6287 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Understanding the molecular basis underlying the formation of bone-forming osteocytes and lipid-storing adipocytes will help provide insights into the cause of disorders originating in stem/progenitor cells and develop therapeutic treatments for bone- or adipose-related diseases. In this study, the role of RGS2 and RGS4, two members of the regulators of G protein signaling (RGS) family, was investigated during adipogenenic and osteogenenic differentiation of human mesenchymal stem cells (hMSCs). RESULTS: Expression of RGS2 and RGS4 were found to be inversely regulated during adipogenesis induced by dexamethasone (DEX) and 3-isobutyl-methylxanthine, regardless if insulin was present, with RGS2 up-regulated and RGS4 down-regulated in response to adipogenic induction. RGS2 expression was also up-regulated during osteogenesis at a level similar to that induced by treatment of DEX alone, a shared component of adipogenic and osteogenic differentiation inducing media, but significantly lower than the level induced by adipogenic inducing media. RGS4 expression was down-regulated during the first 48 h of osteogenesis but up-regulated afterwards, in both cases at levels similar to that induced by DEX alone. Expression knock-down using small interfering RNA against RGS2 resulted in decreased differentiation efficiency during both adipogenesis and osteogenesis. On the other hand, expression knock-down of RGS4 also resulted in decreased adipogenic differentiation but increased osteogenic differentiation. CONCLUSIONS: RGS2 and RGS4 are differentially regulated during adipogenic and osteogenic differentiation of hMSCs. In addition, both RGS2 and RGS4 play positive roles during adipogenesis but opposing roles during osteogenesis, with RGS2 as a positive regulator and RGS4 as a negative regulator. These results imply that members of RGS proteins may play multifaceted roles during human adipogenesis and osteogenesis to balance or counterbalance each other's function during those processes. [Mh] Termos MeSH primário: Adipogenia/fisiologia Regulação da Expressão Gênica/fisiologia Células Mesenquimais Estromais/citologia Osteócitos/citologia Osteogênese/fisiologia Proteínas RGS/metabolismo [Mh] Termos MeSH secundário: Adipogenia/genética Regulação da Expressão Gênica/genética Seres Humanos Osteogênese/genética Proteínas RGS/genética Fatores de Tempo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (RGS Proteins); 175335-35-0 (RGS4 protein) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171228 [St] Status: MEDLINE [do] DOI: 10.1186/s40659-017-0148-1

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[PMID]: 27771736 [Au] Autor: Wang J; Ishimoto T; Nakano T [Ad] Endereço: School of Material Science and Engineering, Zhengzhou University, Zhengzhou, 450001, China. [Ti] Título: Unloading-Induced Degradation of the Anisotropic Arrangement of Collagen/Apatite in Rat Femurs. [So] Source: Calcif Tissue Int;100(1):87-94, 2017 Jan. [Is] ISSN: 1432-0827 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The specific orientation of collagen and biological apatite (BAp) is an anisotropic feature of bone micro-organization; it is an important determinant of bone mechanical function and performance under anisotropic stress. However, it is poorly understood how this microstructure orientation is altered when the mechanical environment changes. We hypothesized that the preferential orientation of collagen/BAp would change in response to changes in mechanical conditions, similar to the manner in which bone mass and bone shape change. In the present study, we investigated the effect of unloading (removal of anisotropic stress) on the preferential orientation of collagen/BAp using a rat sciatic neurectomy model. Bone tissue that formed under unloaded conditions showed a more disordered collagen/BAp orientation than bone tissue that formed under physiological conditions. Coincidentally, osteocytes in unloaded bone displayed spherical morphology and random alignment. To the best of our knowledge, this study is the first to demonstrate the degradation of preferential collagen/BAp orientation in response to unloading conditions. In summary, we identified alterations in bone material anisotropy as an important aspect of the bone's response to unloading, which had previously been examined with regard to bone loss only. [Mh] Termos MeSH primário: Apatitas/metabolismo Colágeno/metabolismo Fêmur/metabolismo Osteócitos/metabolismo [Mh] Termos MeSH secundário: Animais Anisotropia Densidade Óssea/fisiologia Doenças Ósseas Metabólicas/metabolismo Osso e Ossos/metabolismo Ratos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Apatites); 9007-34-5 (Collagen) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180201 [Lr] Data última revisão: 180201 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161025 [St] Status: MEDLINE [do] DOI: 10.1007/s00223-016-0200-0

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[PMID]: 28460416 [Au] Autor: Fairfield H; Falank C; Harris E; Demambro V; McDonald M; Pettitt JA; Mohanty ST; Croucher P; Kramer I; Kneissel M; Rosen CJ; Reagan MR [Ad] Endereço: Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, Maine. [Ti] Título: The skeletal cell-derived molecule sclerostin drives bone marrow adipogenesis. [So] Source: J Cell Physiol;233(2):1156-1167, 2018 Feb. [Is] ISSN: 1097-4652 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The bone marrow niche is a dynamic and complex microenvironment that can both regulate, and be regulated by the bone matrix. Within the bone marrow (BM), mesenchymal stromal cell (MSC) precursors reside in a multi-potent state and retain the capacity to differentiate down osteoblastic, adipogenic, or chondrogenic lineages in response to numerous biochemical cues. These signals can be altered in various pathological states including, but not limited to, osteoporotic-induced fracture, systemic adiposity, and the presence of bone-homing cancers. Herein we provide evidence that signals from the bone matrix (osteocytes) determine marrow adiposity by regulating adipogenesis in the bone marrow. Specifically, we found that physiologically relevant levels of Sclerostin (SOST), which is a Wnt-inhibitory molecule secreted from bone matrix-embedded osteocytes, can induce adipogenesis in 3T3-L1 cells, mouse ear- and BM-derived MSCs, and human BM-derived MSCs. We demonstrate that the mechanism of SOST induction of adipogenesis is through inhibition of Wnt signaling in pre-adipocytes. We also demonstrate that a decrease of sclerostin in vivo, via both genetic and pharmaceutical methods, significantly decreases bone marrow adipose tissue (BMAT) formation. Overall, this work demonstrates a direct role for SOST in regulating fate determination of BM-adipocyte progenitors. This provides a novel mechanism for which BMAT is governed by the local bone microenvironment, which may prove relevant in the pathogenesis of certain diseases involving marrow adipose. Importantly, with anti-sclerostin therapy at the forefront of osteoporosis treatment and a greater recognition of the role of BMAT in disease, these data are likely to have important clinical implications. [Mh] Termos MeSH primário: Adipócitos/metabolismo Adipogenia Tecido Adiposo/metabolismo Células da Medula Óssea/metabolismo Glicoproteínas/metabolismo Células Mesenquimais Estromais/metabolismo Osteócitos/metabolismo [Mh] Termos MeSH secundário: Células 3T3-L1 Tecido Adiposo/citologia Adiposidade Animais Meios de Cultivo Condicionados/metabolismo Glicoproteínas/deficiência Glicoproteínas/genética Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Comunicação Parácrina Fenótipo Nicho de Células-Tronco Via de Sinalização Wnt [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Culture Media, Conditioned); 0 (Glycoproteins); 0 (Sost protein, mouse) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 180124 [Lr] Data última revisão: 180124 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170502 [St] Status: MEDLINE [do] DOI: 10.1002/jcp.25976

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[PMID]: 29244883 [Au] Autor: Uto Y; Kuroshima S; Nakano T; Ishimoto T; Inaba N; Uchida Y; Sawase T [Ad] Endereço: Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. [Ti] Título: Effects of mechanical repetitive load on bone quality around implants in rat maxillae. [So] Source: PLoS One;12(12):e0189893, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Greater understanding and acceptance of the new concept "bone quality", which was proposed by the National Institutes of Health and is based on bone cells and collagen fibers, are required. The novel protein Semaphorin3A (Sema3A) is associated with osteoprotection by regulating bone cells. The aims of this study were to investigate the effects of mechanical loads on Sema3A production and bone quality based on bone cells and collagen fibers around implants in rat maxillae. Grade IV-titanium threaded implants were placed at 4 weeks post-extraction in maxillary first molars. Implants received mechanical loads (10 N, 3 Hz for 1800 cycles, 2 days/week) for 5 weeks from 3 weeks post-implant placement to minimize the effects of wound healing processes by implant placement. Bone structures, bone mineral density (BMD), Sema3A production and bone quality based on bone cells and collagen fibers were analyzed using microcomputed tomography, histomorphometry, immunohistomorphometry, polarized light microscopy and birefringence measurement system inside of the first and second thread (designated as thread A and B, respectively), as mechanical stresses are concentrated and differently distributed on the first two threads from the implant neck. Mechanical load significantly increased BMD, but not bone volume around implants. Inside thread B, but not thread A, mechanical load significantly accelerated Sema3A production with increased number of osteoblasts and osteocytes, and enhanced production of both type I and III collagen. Moreover, mechanical load also significantly induced preferential alignment of collagen fibers in the lower flank of thread B. These data demonstrate that mechanical load has different effects on Sema3A production and bone quality based on bone cells and collagen fibers between the inside threads of A and B. Mechanical load-induced Sema3A production may be differentially regulated by the type of bone structure or distinct stress distribution, resulting in control of bone quality around implants in jaw bones. [Mh] Termos MeSH primário: Osso e Ossos/metabolismo Implantes Dentários Semaforina-3A/metabolismo Titânio/uso terapêutico [Mh] Termos MeSH secundário: Animais Densidade Óssea Osso e Ossos/patologia Implantação Dentária Endo-Óssea/métodos Planejamento de Prótese Dentária Análise do Estresse Dentário Análise de Elementos Finitos Seres Humanos Mandíbula/cirurgia Maxila/cirurgia Osseointegração/fisiologia Osteócitos/metabolismo Ratos Estresse Mecânico Titânio/química Microtomografia por Raio-X [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Dental Implants); 0 (Sema3a protein, rat); 0 (Semaphorin-3A); D1JT611TNE (Titanium) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180102 [Lr] Data última revisão: 180102 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171216 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0189893

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[PMID]: 29240821 [Au] Autor: Kim JH; Kim AR; Choi YH; Jang S; Woo GH; Cha JH; Bak EJ; Yoo YJ [Ad] Endereço: Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Republic of Korea. [Ti] Título: Tumor necrosis factor-α antagonist diminishes osteocytic RANKL and sclerostin expression in diabetes rats with periodontitis. [So] Source: PLoS One;12(12):e0189702, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Type 1 diabetes with periodontitis shows elevated TNF-α expression. Tumor necrosis factor (TNF)-α stimulates the expression of receptor activator of nuclear factor-κB ligand (RANKL) and sclerostin. The objective of this study was to determine the effect of TNF-α expression of osteocytic RANKL and sclerostin in type 1 diabetes rats with periodontitis using infliximab (IFX), a TNF-α antagonist. Rats were divided into two timepoint groups: day 3 and day 20. Each timepoint group was then divided into four subgroups: 1) control (C, n = 6 for each time point); 2) periodontitis (P, n = 6 for each time point); 3) diabetes with periodontitis (DP, n = 8 for each time point); and 4) diabetes with periodontitis treated with IFX (DP+IFX, n = 8 for each time point). To induce type 1 diabetes, rats were injected with streptozotocin (50 mg/kg dissolved in 0.1 M citrate buffer). Periodontitis was then induced by ligature of the mandibular first molars at day 7 after STZ injection (day 0). IFX was administered once for the 3 day group (on day 0) and twice for the 20 day group (on days 7 and 14). The DP group showed greater alveolar bone loss than the P group on day 20 (P = 0.020). On day 3, higher osteoclast formation and RANKL-positive osteocytes in P group (P = 0.000 and P = 0.011, respectively) and DP group (P = 0.006 and P = 0.017, respectively) than those in C group were observed. However, there was no significant difference in osteoclast formation or RANKL-positive osteocytes between P and DP groups. The DP+IFX group exhibited lower alveolar bone loss (P = 0.041), osteoclast formation (P = 0.019), and RANKL-positive osteocytes (P = 0.009) than that of the DP group. On day 20, DP group showed a lower osteoid area (P = 0.001) and more sclerostin-positive osteocytes (P = 0.000) than P group. On days 3 and 20, the DP+IFX group showed more osteoid area (P = 0.048 and 0.040, respectively) but lower sclerostin-positive osteocytes (both P = 0.000) than DP group. Taken together, these results suggest that TNF-α antagonist can diminish osteocytic RANKL/sclerostin expression and osteoclast formation, eventually recovering osteoid formation. Therefore, TNF-α might mediate alveolar bone loss via inducing expression of osteocytic RANKL and sclerostin in type 1 diabetes rats with periodontitis. [Mh] Termos MeSH primário: Proteínas Morfogenéticas Ósseas/metabolismo Diabetes Mellitus Experimental/metabolismo Infliximab/farmacologia Osteócitos/efeitos dos fármacos Periodontite/metabolismo Ligante RANK/metabolismo Fator de Necrose Tumoral alfa/antagonistas & inibidores [Mh] Termos MeSH secundário: Perda do Osso Alveolar Animais Diabetes Mellitus Experimental/complicações Marcadores Genéticos Imuno-Histoquímica Masculino Osteócitos/metabolismo Periodontite/complicações Ratos Ratos Endogâmicos F344 [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Bone Morphogenetic Proteins); 0 (Genetic Markers); 0 (RANK Ligand); 0 (Sost protein, rat); 0 (Tumor Necrosis Factor-alpha); B72HH48FLU (Infliximab) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171229 [Lr] Data última revisão: 171229 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171215 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0189702

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[PMID]: 28465350 [Au] Autor: Qin Y; Peng Y; Zhao W; Pan J; Ksiezak-Reding H; Cardozo C; Wu Y; Divieti Pajevic P; Bonewald LF; Bauman WA; Qin W [Ad] Endereço: From the National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters Veterans Affairs Medical Center, Bronx, New York 10468. [Ti] Título: Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: A novel mechanism in muscle-bone communication. [So] Source: J Biol Chem;292(26):11021-11033, 2017 06 30. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Muscle and bone are closely associated in both anatomy and function, but the mechanisms that coordinate their synergistic action remain poorly defined. Myostatin, a myokine secreted by muscles, has been shown to inhibit muscle growth, and the disruption of the myostatin gene has been reported to cause muscle hypertrophy and increase bone mass. Extracellular vesicle-exosomes that carry microRNA (miRNA), mRNA, and proteins are known to perform an important role in cell-cell communication. We hypothesized that myostatin may play a crucial role in muscle-bone interactions and may promote direct effects on osteocytes and on osteocyte-derived exosomal miRNAs, thereby indirectly influencing the function of other bone cells. We report herein that myostatin promotes expression of several bone regulators such as sclerostin (SOST), DKK1, and RANKL in cultured osteocytic (Ocy454) cells, concomitant with the suppression of miR-218 in both parent Ocy454 cells and derived exosomes. Exosomes produced by Ocy454 cells that had been pretreated with myostatin could be taken up by osteoblastic MC3T3 cells, resulting in a marked reduction of Runx2, a key regulator of osteoblastic differentiation, and in decreased osteoblastic differentiation via the down-regulation of the Wnt signaling pathway. Importantly, the inhibitory effect of myostatin-modified osteocytic exosomes on osteoblast differentiation is completely reversed by expression of exogenous miR-218, through a mechanism involving miR-218-mediated inhibition of SOST. Together, our findings indicate that myostatin directly influences osteocyte function and thereby inhibits osteoblastic differentiation, at least in part, through the suppression of osteocyte-derived exosomal miR-218, suggesting a novel mechanism in muscle-bone communication. [Mh] Termos MeSH primário: Diferenciação Celular Exossomos/metabolismo MicroRNAs/metabolismo Músculo Esquelético/metabolismo Miostatina/metabolismo Osteócitos/metabolismo Via de Sinalização Wnt/fisiologia [Mh] Termos MeSH secundário: Animais Linhagem Celular Exossomos/genética Glicoproteínas/genética Glicoproteínas/metabolismo Peptídeos e Proteínas de Sinalização Intercelular/genética Peptídeos e Proteínas de Sinalização Intercelular/metabolismo Camundongos MicroRNAs/genética Miostatina/genética Ligante RANK/genética Ligante RANK/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, N.I.H., EXTRAMURAL [Nm] Nome de substância: 0 (Dkk1 protein, mouse); 0 (Glycoproteins); 0 (Intercellular Signaling Peptides and Proteins); 0 (MIRN218 microRNA, mouse); 0 (MicroRNAs); 0 (Mstn protein, mouse); 0 (Myostatin); 0 (RANK Ligand); 0 (Sost protein, mouse); 0 (Tnfsf11 protein, mouse) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 171229 [Lr] Data última revisão: 171229 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170504 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M116.770941

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[PMID]: 29065178 [Au] Autor: Tokarz D; Cisek R; Wein MN; Turcotte R; Haase C; Yeh SA; Bharadwaj S; Raphael AP; Paudel H; Alt C; Liu TM; Kronenberg HM; Lin CP [Ad] Endereço: Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. [Ti] Título: Intravital imaging of osteocytes in mouse calvaria using third harmonic generation microscopy. [So] Source: PLoS One;12(10):e0186846, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Osteocytes are the most abundant cell in the bone, and have multiple functions including mechanosensing and regulation of bone remodeling activities. Since osteocytes are embedded in the bone matrix, their inaccessibility makes in vivo studies problematic. Therefore, a non-invasive technique with high spatial resolution is desired. The purpose of this study is to investigate the use of third harmonic generation (THG) microscopy as a noninvasive technique for high-resolution imaging of the lacunar-canalicular network (LCN) in live mice. By performing THG imaging in combination with two- and three-photon fluorescence microscopy, we show that THG signal is produced from the bone-interstitial fluid boundary of the lacuna, while the interstitial fluid-osteocyte cell boundary shows a weaker THG signal. Canaliculi are also readily visualized by THG imaging, with canaliculi oriented at small angles relative to the optical axis exhibiting stronger signal intensity compared to those oriented perpendicular to the optical axis (parallel to the image plane). By measuring forward- versus epi-detected THG signals in thinned versus thick bone samples ex vivo, we found that the epi-collected THG from the LCN of intact bone contains a superposition of backward-directed and backscattered forward-THG. As an example of a biological application, THG was used as a label-free imaging technique to study structural variations in the LCN of live mice deficient in both histone deacetylase 4 and 5 (HDAC4, HDAC5). Three-dimensional analyses were performed and revealed statistically significant differences between the HDAC4/5 double knockout and wild type mice in the number of osteocytes per volume and the number of canaliculi per lacunar surface area. These changes in osteocyte density and dendritic projections occurred without differences in lacunar size. This study demonstrates that THG microscopy imaging of the LCN in live mice enables quantitative analysis of osteocytes in animal models without the use of dyes or physical sectioning. [Mh] Termos MeSH primário: Microscopia Intravital/métodos Osteócitos/metabolismo Crânio/citologia [Mh] Termos MeSH secundário: Animais Histona Desacetilases/genética Camundongos Camundongos Knockout [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 3.5.1.98 (Hdac5 protein, mouse); EC 3.5.1.98 (Histone Deacetylases) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171113 [Lr] Data última revisão: 171113 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171025 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0186846

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[PMID]: 29045447 [Au] Autor: Ye T; Cao P; Qi J; Zhou Q; Rao DS; Qiu S [Ad] Endereço: Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. [Ti] Título: Protective effect of low-dose risedronate against osteocyte apoptosis and bone loss in ovariectomized rats. [So] Source: PLoS One;12(10):e0186012, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Osteocyte apoptosis is the first reaction to estrogen depletion, thereby stimulating osteoclastic bone resorption resulting in bone loss. We investigated the effects of two different risedronate (RIS) doses (high and low) on osteocyte apoptosis, osteoclast activity and bone loss in ovariectomized rats. Forty rats with ovariectomy (OVX) and sham ovariectomy (SHAM) were divided into 4 groups: 1) SHAM rats treated with saline (SHAM); 2) OVX rats treated with saline (OVX); 3) OVX rats treated with low-dose RIS (OVX-LR, 0.08 µg/kg/day); 4) OVX rats treated with high-dose RIS (OVX-HR, 0.8 µg/kg/day). All animals were sacrificed 90 days after surgery for the examinations of osteocyte apoptosis by caspase-3 staining, osteoclast activity by TRAP staining and bone volume by micro-CT scanning in lumbar vertebral cancellous bone. Both low and high dose RIS significantly reduced caspase-3 positive osteocytes, empty lacunae and TRAP positive osteoclasts in OVX rats. Although the difference in caspase-3 positive osteocytes was not significant between the OVX-LR and OVX-HR groups, numerically these cells were significantly more prevalent in OVX-HR (not OVX-LR) group than in SHAM group. TRAP positive osteoclasts were significantly higher in OVX-LR group than in SHAM or OVX-HR group. There was no significant difference in bone volume among the OVX-LR, OVX-HR and SHAM groups, but lower in OVX group alone. However, significant increase in trabecular thickness only occurred in OVX-LR group. We conclude that both low and high dose RIS significantly inhibit osteocyte apoptosis and osteoclast activity in OVX rats, but the low-dose RIS has weaker effect on osteoclast activity. However, low-dose RIS preserves cancellous bone mass and microarchitecture as well as high-dose RIS after estrogen depletion. [Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos Reabsorção Óssea/tratamento farmacológico Reabsorção Óssea/patologia Osteócitos/patologia Ovariectomia Substâncias Protetoras/uso terapêutico Risedronato Sódico/uso terapêutico [Mh] Termos MeSH secundário: Animais Osso Esponjoso/diagnóstico por imagem Osso Esponjoso/efeitos dos fármacos Osso Esponjoso/patologia Relação Dose-Resposta a Droga Feminino Osteoclastos/efeitos dos fármacos Osteoclastos/patologia Osteócitos/efeitos dos fármacos Substâncias Protetoras/farmacologia Ratos Sprague-Dawley Risedronato Sódico/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Protective Agents); OFG5EXG60L (Risedronate Sodium) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171031 [Lr] Data última revisão: 171031 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171019 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0186012

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[PMID]: 28869591 [Au] Autor: Kemp JP; Morris JA; Medina-Gomez C; Forgetta V; Warrington NM; Youlten SE; Zheng J; Gregson CL; Grundberg E; Trajanoska K; Logan JG; Pollard AS; Sparkes PC; Ghirardello EJ; Allen R; Leitch VD; Butterfield NC; Komla-Ebri D; Adoum AT; Curry KF; White JK; Kussy F; Greenlaw KM; Xu C; Harvey NC; Cooper C; Adams DJ; Greenwood CMT; Maurano MT; Kaptoge S; Rivadeneira F; Tobias JH; Croucher PI; Ackert-Bicknell CL; Bassett JHD; Williams GR; Richards JB; Evans DM [Ad] Endereço: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. [Ti] Título: Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. [So] Source: Nat Genet;49(10):1468-1475, 2017 Oct. [Is] ISSN: 1546-1718 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes. [Mh] Termos MeSH primário: Densidade Óssea/genética Calcâneo/patologia Estudo de Associação Genômica Ampla Osteoporose/genética Polimorfismo de Nucleotídeo Único [Mh] Termos MeSH secundário: Animais Modelos Animais de Doenças Feminino Fêmur/química Perfilação da Expressão Gênica Glipicanas/deficiência Glipicanas/genética Glipicanas/fisiologia Transtornos do Crescimento/genética Seres Humanos Masculino Camundongos Camundongos Knockout Anotação de Sequência Molecular Osteoblastos/metabolismo Osteocondrodisplasias/congênito Osteocondrodisplasias/genética Osteoclastos/metabolismo Osteócitos/metabolismo Osteoporose/patologia Fenótipo [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Glypicans); 0 (glypican 6 protein, mouse) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171028 [Lr] Data última revisão: 171028 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170905 [St] Status: MEDLINE [do] DOI: 10.1038/ng.3949

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MEDLINE

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[PMID]: 28825716 [Au] Autor: Farr JN; Xu M; Weivoda MM; Monroe DG; Fraser DG; Onken JL; Negley BA; Sfeir JG; Ogrodnik MB; Hachfeld CM; LeBrasseur NK; Drake MT; Pignolo RJ; Pirtskhalava T; Tchkonia T; Oursler MJ; Kirkland JL; Khosla S [Ad] Endereço: Robert and Arlene Kogod Center on Aging and Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. [Ti] Título: Targeting cellular senescence prevents age-related bone loss in mice. [So] Source: Nat Med;23(9):1072-1079, 2017 Sep. [Is] ISSN: 1546-170X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities. [Mh] Termos MeSH primário: Osso e Ossos/efeitos dos fármacos Senescência Celular/efeitos dos fármacos Janus Quinases/antagonistas & inibidores Osteoblastos/efeitos dos fármacos Osteoclastos/efeitos dos fármacos Osteócitos/efeitos dos fármacos Osteoporose/metabolismo Pirazóis/farmacologia [Mh] Termos MeSH secundário: Absorciometria de Fóton Animais Apoptose/genética Osso e Ossos/metabolismo Osso Esponjoso/efeitos dos fármacos Osso Esponjoso/metabolismo Caspase 8/genética Diferenciação Celular Senescência Celular/genética Osso Cortical/efeitos dos fármacos Osso Cortical/metabolismo Meios de Cultivo Condicionados Citometria de Fluxo Perfilação da Expressão Gênica Técnicas In Vitro Camundongos Camundongos Transgênicos Osteoblastos/citologia Osteoclastos/citologia Osteoporose/genética Reação em Cadeia da Polimerase em Tempo Real Suporte de Carga beta-Galactosidase [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Culture Media, Conditioned); 0 (INCB018424); 0 (Pyrazoles); EC 2.7.10.2 (Janus Kinases); EC 3.2.1.23 (beta-Galactosidase); EC 3.4.22.- (Casp8 protein, mouse); EC 3.4.22.- (Caspase 8) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170822 [St] Status: MEDLINE [do] DOI: 10.1038/nm.4385

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