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1.
Nature ; 615(7950): 134-142, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36470304

RESUMO

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Receptores Virais , Ácido Ursodesoxicólico , Animais , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/prevenção & controle , Receptores Virais/genética , Receptores Virais/metabolismo , Estudos Retrospectivos , SARS-CoV-2/metabolismo , Tratamento Farmacológico da COVID-19 , Cricetinae , Transcrição Gênica , Ácido Ursodesoxicólico/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Organoides/efeitos dos fármacos , Organoides/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Sistema de Registros , Reprodutibilidade dos Testes , Transplante de Fígado
2.
J Cell Physiol ; 236(6): 4614-4624, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33305372

RESUMO

Supraphysiological levels of the osteoblast-enriched mineralization regulator ectonucleotide pyrophosphatase or phosphodiesterase-1 (NPP1) is associated with type 2 diabetes mellitus. We determined the impact of osteoblast-specific Enpp1 ablation on skeletal structure and metabolic phenotype in mice. Female, but not male, 6-week-old mice lacking osteoblast NPP1 expression (osteoblast-specific knockout [KO]) exhibited increased femoral bone volume or total volume (17.50% vs. 11.67%; p < .01), and reduced trabecular spacing (0.187 vs. 0.157 mm; p < .01) compared with floxed (control) mice. Furthermore, an enhanced ability of isolated osteoblasts from the osteoblast-specific KO to calcify their matrix in vitro compared to fl/fl osteoblasts was observed (p < .05). Male osteoblast-specific KO and fl/fl mice showed comparable glucose and insulin tolerance despite increased levels of insulin-sensitizing under-carboxylated osteocalcin (195% increase; p < .05). However, following high-fat-diet challenge, osteoblast-specific KO mice showed impaired glucose and insulin tolerance compared with fl/fl mice. These data highlight a crucial local role for osteoblast NPP1 in skeletal development and a secondary metabolic impact that predominantly maintains insulin sensitivity.


Assuntos
Osso e Ossos/enzimologia , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Osteoblastos/enzimologia , Osteogênese , Diester Fosfórico Hidrolases/deficiência , Pirofosfatases/deficiência , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Osso e Ossos/patologia , Osso Esponjoso/enzimologia , Osso Esponjoso/patologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fêmur/enzimologia , Fêmur/patologia , Insulina/sangue , Masculino , Camundongos Knockout , Osteoblastos/patologia , Osteocalcina/sangue , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Fatores Sexuais , Crânio/enzimologia , Crânio/patologia , Tíbia/enzimologia , Tíbia/patologia
3.
BMC Musculoskelet Disord ; 20(1): 344, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31351471

RESUMO

BACKGROUND: Subchondral bone (SCB) thickening is one of the earliest detectable changes in osteoarthritic joints and is considered a potential trigger for subsequent articular cartilage degeneration. In this manuscript, we examine whether disruption to the SCB osteocyte network contributes to the initiation and pathogenesis of osteoarthritis. METHODS: We examined expression patterns of the glycoprotein E11/podoplanin by immunohistochemical labelling in murine, human and canine osteoarthritis models. We also examined the effects of twice-weekly administration of Bortezomib, a proteasome inhibitor which stabilises osteocyte E11 levels, to C57/BL6 wild-type male mice (1 mg/kg/day) for 8 weeks after surgical destabilisation of the medial meniscus. By inducing osteoarthritis-like changes in the right knee joint of 12-week-old male E11 hypomorphic mice (and corresponding controls) using a post-traumatic joint loading model, we also investigated whether a bone-specific E11 deletion in mice increases joint vulnerability to osteoarthritis. Articular cartilage degradation and osteophyte formation were assessed by histology and in line with the OARSI grading system. RESULTS: Our studies reveal increased E11 expression in osteocytes of human and canine osteoarthritic SCB. We found that Bortezomib administration had no effect on surgically-induced osteoarthritis, potentially due to a lack of the expected stabilisation of E11 in the SCB. We also found, in concordance with our previous work, wild-type mice exhibited significant load-induced articular cartilage lesions on the lateral femoral condyle (p < 0.01) and osteophyte formation. In contrast, E11 hypomorphic mice did not develop osteophytes or any corresponding articular lesions. CONCLUSIONS: Overall, these data suggest that an intact osteocyte network in the SCB contributes to the development of mechanically-driven osteoarthritis. Further, the data presented here indicate that the molecular pathways that preserve the osteocyte network, such as those driven by E11, may be targeted to limit osteoarthritis pathogenesis.


Assuntos
Cartilagem Articular/patologia , Glicoproteínas de Membrana/metabolismo , Osteoartrite/patologia , Osteófito/patologia , Animais , Bortezomib/administração & dosagem , Modelos Animais de Doenças , Cães , Humanos , Masculino , Glicoproteínas de Membrana/genética , Meniscos Tibiais/patologia , Camundongos , Camundongos Knockout , Osteoartrite/tratamento farmacológico , Osteoartrite/etiologia , Osteócitos/efeitos dos fármacos , Osteócitos/patologia , Osteófito/tratamento farmacológico , Suporte de Carga
4.
J Bone Miner Res ; 38(5): 792-807, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36824055

RESUMO

Lipids play a crucial role in signaling and metabolism, regulating the development and maintenance of the skeleton. Membrane lipids have been hypothesized to act as intermediates upstream of orphan phosphatase 1 (PHOSPHO1), a major contributor to phosphate generation required for bone mineralization. Here, we spatially resolve the lipid atlas of the healthy mouse knee and demonstrate the effects of PHOSPHO1 ablation on the growth plate lipidome. Lipids spanning 17 subclasses were mapped across the knee joints of healthy juvenile and adult mice using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS), with annotation supported by shotgun lipidomics. Multivariate analysis identified 96 and 80 lipid ions with differential abundances across joint tissues in juvenile and adult mice, respectively. In both ages, marrow was enriched in phospholipid platelet activating factors (PAFs) and related metabolites, cortical bone had a low lipid content, whereas lysophospholipids were strikingly enriched in the growth plate, an active site of mineralization and PHOSPHO1 activity. Spatially-resolved profiling of PHOSPHO1-knockout (KO) mice across the resting, proliferating, and hypertrophic growth plate zones revealed 272, 306, and 296 significantly upregulated, and 155, 220, and 190 significantly downregulated features, respectively, relative to wild-type (WT) controls. Of note, phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, lysophosphatidylethanolamine, and phosphatidylethanolamine derived lipid ions were upregulated in PHOSPHO1-KO versus WT. Our imaging pipeline has established a spatially-resolved lipid signature of joint tissues and has demonstrated that PHOSPHO1 ablation significantly alters the growth plate lipidome, highlighting an essential role of the PHOSPHO1-mediated membrane phospholipid metabolism in lipid and bone homeostasis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Lipidômica , Monoéster Fosfórico Hidrolases , Camundongos , Animais , Monoéster Fosfórico Hidrolases/metabolismo , Lâmina de Crescimento/metabolismo , Camundongos Knockout , Homeostase , Fosfolipídeos
5.
J Endocrinol ; 253(2): 63-74, 2022 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-35191394

RESUMO

Short stature and osteoporosis are common in Duchenne muscular dystrophy (DMD) and its pathophysiology may include an abnormality of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which is further exacerbated by long-term glucocorticoid (GC) treatment. Hence, an agent that has anabolic properties and may improve linear growth would be beneficial in this setting and therefore requires further exploration. A 5-week-old x-linked muscular dystrophy (mdx) mice were used as a model of DMD. They were treated with prednisolone ± GH + IGF-1 for 4 weeks and then compared to control mdx mice to allow the study of both growth and skeletal structure. GC reduced cortical bone area, bone fraction, tissue area and volume and cortical bone volume, as assessed by micro computed tomography (CT) In addition, GC caused somatic and skeletal growth retardation but improved grip strength. The addition of GH + IGF-1 therapy rescued the somatic growth retardation and induced additional improvements in grip strength (16.9% increase, P < 0.05 compared to control). There was no improvement in bone microarchitecture (assessed by micro-CT and static histomorphometry) or biomechanical properties (assessed by three-point bending). Serum bone turnover markers (Serum procollagen 1 intact N-terminal propeptide (P1NP), alpha C-terminal telopeptide (αCTX)) also remained unaffected. Further work is needed to maximise these gains before proceeding to clinical trials in boys with DMD.


Assuntos
Doenças Ósseas Metabólicas , Hormônio do Crescimento Humano , Distrofia Muscular de Duchenne , Animais , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/prevenção & controle , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/prevenção & controle , Hormônio do Crescimento/farmacologia , Humanos , Fator de Crescimento Insulin-Like I , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/tratamento farmacológico , Microtomografia por Raio-X
6.
J Endocrinol ; 254(3): 153-167, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35900032

RESUMO

Patients with advanced chronic kidney disease (CKD) often present with skeletal abnormalities, a condition known as renal osteodystrophy (ROD). While tissue non-specific alkaline phosphatase (TNAP) and PHOSPHO1 are critical for bone mineralization, their role in the etiology of ROD is unclear. To address this, ROD was induced in both WT and Phospho1 knockout (P1KO) mice through dietary adenine supplementation. The mice presented with hyperphosphatemia, hyperparathyroidism, and elevated levels of FGF23 and bone turnover markers. In particular, we noted that in CKD mice, bone mineral density (BMD) was increased in cortical bone (P < 0.05) but decreased in trabecular bone (P < 0.05). These changes were accompanied by decreased TNAP (P < 0.01) and increased PHOSPHO1 (P < 0.001) expression in WT CKD bones. In P1KO CKD mice, the cortical BMD phenotype was rescued, suggesting that the increased cortical BMD of CKD mice was driven by increased PHOSPHO1 expression. Other structural parameters were also improved in P1KO CKD mice. We further investigated the driver of the mineralization defects, by studying the effects of FGF23, PTH, and phosphate administration on PHOSPHO1 and TNAP expression by primary murine osteoblasts. We found both PHOSPHO1 and TNAP expressions to be downregulated in response to phosphate and PTH. The in vitro data suggest that the TNAP reduction in CKD-MBD is driven by the hyperphosphatemia and/or hyperparathyroidism noted in these mice, while the higher PHOSPHO1 expression may be a compensatory mechanism. Increased PHOSPHO1 expression in ROD may contribute to the disordered skeletal mineralization characteristic of this progressive disorder.


Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Hiperfosfatemia , Monoéster Fosfórico Hidrolases , Insuficiência Renal Crônica , Animais , Densidade Óssea/fisiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicações , Distúrbio Mineral e Ósseo na Doença Renal Crônica/genética , Hiperfosfatemia/complicações , Camundongos , Camundongos Knockout , Fosfatos , Monoéster Fosfórico Hidrolases/metabolismo , Insuficiência Renal Crônica/genética
7.
Cell Stem Cell ; 29(4): 528-544.e9, 2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-35276096

RESUMO

The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone. A neurotrophic dependency mediated through GDNF-family receptor-α2 (GFRα2) and its ligand, neurturin (NRTN), is established between sympathetic cholinergic fibers and bone-embedded osteocytes, which require cholinergic innervation for their survival and connectivity. Bone-lining osteoprogenitors amplify and propagate cholinergic signals in the bone marrow (BM). Moderate exercise augments trabecular bone partly through an IL-6-dependent expansion of sympathetic cholinergic nerve fibers. Consequently, loss of cholinergic skeletal innervation reduces osteocyte survival and function, causing osteopenia and impaired skeletal adaptation to moderate exercise. These results uncover a cholinergic neuro-osteocyte interface that regulates skeletogenesis and skeletal turnover through bone-anabolic effects.


Assuntos
Interleucina-6 , Osteogênese , Colinérgicos , Fibras Colinérgicas , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia
8.
JBMR Plus ; 5(2): e10439, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33615108

RESUMO

Biomineralization is a fundamental process key to the development of the skeleton. The phosphatase orphan phosphatase 1 (PHOSPHO1), which likely functions within extracellular matrix vesicles, has emerged as a critical regulator of biomineralization. However, the biochemical pathways that generate intravesicular PHOSPHO1 substrates are currently unknown. We hypothesized that the enzyme ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6) is an upstream source of the PHOSPHO1 substrate. To test this, we characterized skeletal phenotypes of mice homozygous for a targeted deletion of Enpp6 (Enpp6 -/- ). Micro-computed tomography of the trabecular compartment revealed transient hypomineralization in Enpp6 -/- tibias (p < 0.05) that normalized by 12 weeks of age. Whole-bone cortical analysis also revealed significantly hypomineralized proximal bone in 4- but not 12-week-old Enpp6 -/- mice (p < 0.05) compared with WT animals. Back-scattered SEM revealed a failure in 4-week-old trabecular bone of mineralization foci to propagate. Static histomorphometry revealed increased osteoid volume (p > 0.01) and osteoid surface (p < 0.05), which recovered by 12 weeks but was not accompanied by changes in osteoblast or osteoclast number. This study is the first to characterize the skeletal phenotype of Enpp6 -/- mice, revealing transient hypomineralization in young animals compared with WT controls. These data suggest that ENPP6 is important for bone mineralization and may function upstream of PHOSPHO1 as a novel means of generating its substrates inside matrix vesicles. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

9.
J Endocrinol ; 245(2): R11-R22, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32130201

RESUMO

The physiological mineralisation of skeletal tissues, as well as the pathological mineralisation of soft tissues involves a fine balance between regulators that either promote or inhibit the process. In recent years, several studies have advocated a non-skeletal role for some of these mineralisation regulators in a range of human diseases, including diabetes, cardiovascular disease, obesity and neurodegenerative disease. This is an emerging area of interest and the functional roles and mechanisms of action of these various endocrine factors, phosphatases and phosphodiesterase's in important pathologies are the focus of this review. Mechanistic insight of the pathways through which these acknowledged regulators of skeletal mineralisation act beyond the skeleton has the potential to identify druggable targets for commonly experienced morbidities, notably those related to metabolism and metabolic syndrome.


Assuntos
Biomineralização/fisiologia , Diester Fosfórico Hidrolases/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Humanos , Doenças Metabólicas/metabolismo
10.
Dis Model Mech ; 13(2)2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31754018

RESUMO

The muscular dystrophy X-linked (mdx) mouse is commonly used as a mouse model of Duchenne muscular dystrophy (DMD). Its phenotype is, however, mild, and other mouse models have been explored. The mdx:Cmah-/- mouse carries a human-like mutation in the Cmah gene and has a severe muscle phenotype, but its growth and bone development are unknown. In this study, we compared male mdx, mdx:Utrn+/-, mdx:Cmah-/- and wild-type (WT) mice at 3, 5 and 7 weeks of age to determine the suitability of the mdx:Cmah-/- mouse as a model for assessing growth and skeletal development in DMD. The mdx:Cmah-/- mice were lighter than WT mice at 3 weeks, but heavier at 7 weeks, and showed an increased growth rate at 5 weeks. Cortical bone fraction as assessed by micro-computed tomography was greater in both mdx and mdx:Cmah-/- mice versus WT mice at 7 weeks. Tissue mineral density was also higher in mdx:Cmah-/- mice at 3 and 7 weeks. Gene profiling of mdx:Cmah-/- bone identified increased expression of Igf1, Igf1r and Vegfa Both the mdx and mdx:Cmah-/- mice showed an increased proportion of regulated bone marrow adipose tissue (BMAT) but a reduction in constitutive BMAT. The mdx:Cmah-/- mice show evidence of catch-up growth and more rapid bone development. This pattern does not mimic the typical DMD growth trajectory and therefore the utility of the mdx:Cmah-/- mouse for studying growth and skeletal development in DMD is limited. Further studies of this model may, however, shed light on the phenomenon of catch-up growth.This article has an associated First Person interview with the first author of the paper.


Assuntos
Desenvolvimento Ósseo , Osso e Ossos/patologia , Utrofina/metabolismo , Adiposidade , Animais , Fenômenos Biomecânicos , Medula Óssea/patologia , Osso e Ossos/diagnóstico por imagem , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/patologia , Osso Esponjoso/fisiopatologia , Osso Cortical/diagnóstico por imagem , Osso Cortical/patologia , Osso Cortical/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Lâmina de Crescimento/diagnóstico por imagem , Lâmina de Crescimento/patologia , Lâmina de Crescimento/fisiopatologia , Força da Mão , Inflamação/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/diagnóstico por imagem , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tíbia/diagnóstico por imagem , Tíbia/patologia , Tíbia/fisiopatologia , Microtomografia por Raio-X
11.
Biosci Rep ; 40(1)2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31894854

RESUMO

E11/Podoplanin (Pdpn) is implicated in early osteocytogenesis and the formation of osteocyte dendrites. This dendritic network is critical for bone modelling/remodelling, through the production of receptor activator of nuclear factor κ B (RANK)-ligand (RANKL). Despite this, the role of Pdpn in the control of bone remodelling is yet to be established in vivo. Here we utilised bone-specific Pdpn conditional knockout mice (cKO) to examine the role of Pdpn in the bone loss associated with ovariectomy (OVX). MicroCT revealed that Pdpn deletion had no significant effect on OVX-induced changes in trabecular microarchitecture. Significant differences between genotypes were observed in the trabecular pattern factor (P<0.01) and structure model index (P<0.01). Phalloidin staining of F-actin revealed OVX to induce alterations in osteocyte morphology in both wild-type (WT) and cKO mice. Histological analysis revealed an expected significant increase in osteoclast number in WT mice (P<0.01, compared with sham). However, cKO mice were protected against such increases in osteoclast number. Consistent with this, serum levels of the bone resorption marker Ctx were significantly increased in WT mice following OVX (P<0.05), but were unmodified by OVX in cKO mice. Gene expression of the bone remodelling markers Rank, Rankl, Opg and Sost were unaffected by Pdpn deletion. Together, our data suggest that an intact osteocyte dendritic network is required for sustaining osteoclast formation and activity in the oestrogen-depleted state, through mechanisms potentially independent of RANKL expression. This work will enable a greater understanding of the role of osteocytes in bone loss induced by oestrogen deprivation.


Assuntos
Remodelação Óssea , Fêmur/metabolismo , Glicoproteínas de Membrana/deficiência , Osteoclastos/metabolismo , Osteogênese , Osteoporose Pós-Menopausa/prevenção & controle , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Feminino , Fêmur/patologia , Humanos , Glicoproteínas de Membrana/genética , Camundongos Knockout , Osteoclastos/patologia , Osteoporose Pós-Menopausa/genética , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/patologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ovariectomia , Peptídeos/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo
12.
JBMR Plus ; 3(7): e10202, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31372594

RESUMO

Since its characterization two decades ago, the phosphatase PHOSPHO1 has been the subject of an increasing focus of research. This work has elucidated PHOSPHO1's central role in the biomineralization of bone and other hard tissues, but has also implicated the enzyme in other biological processes in health and disease. During mineralization PHOSPHO1 liberates inorganic phosphate (Pi) to be incorporated into the mineral phase through hydrolysis of its substrates phosphocholine (PCho) and phosphoethanolamine (PEA). Localization of PHOSPHO1 within matrix vesicles allows accumulation of Pi within a protected environment where mineral crystals may nucleate and subsequently invade the organic collagenous scaffold. Here, we examine the evidence for this process, first discussing the discovery and characterization of PHOSPHO1, before considering experimental evidence for its canonical role in matrix vesicle-mediated biomineralization. We also contemplate roles for PHOSPHO1 in disorders of dysregulated mineralization such as vascular calcification, along with emerging evidence of its activity in other systems including choline synthesis and homeostasis, and energy metabolism. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

13.
J Forensic Sci ; 61(2): 402-408, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26478136

RESUMO

Many histological methods in forensic anthropology utilize combinations of traditional histomorphometric parameters which may not accurately describe the morphology of microstructural features. Here, we report the novel application of a geometric morphometric method suitable when considering structures without anatomically homologous landmarks for the quantification of complete secondary osteon size and morphology. The method is tested for its suitability in the measurement of intact secondary osteons using osteons digitized from transverse femoral diaphyseal sections prepared from two human individuals. The results of methodological testing demonstrate the efficacy of the technique when applied to intact secondary osteons. In providing accurate characterization of micromorphology within the robust mathematical framework of geometric morphometrics, this method may surpass traditional histomorphometric variables currently employed in forensic research and practice. A preliminary study of the intersectional histomorphometric variation within the femoral diaphysis is made using this geometric histomorphometric method to demonstrate its potential.


Assuntos
Diáfises/ultraestrutura , Fêmur/ultraestrutura , Ósteon/anatomia & histologia , Conceitos Matemáticos , Idoso de 80 Anos ou mais , Pontos de Referência Anatômicos , Remodelação Óssea , Feminino , Antropologia Forense , Análise de Fourier , Humanos , Processamento de Imagem Assistida por Computador , Microscopia
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