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1.
J Physiol Biochem ; 74(1): 3-8, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29019082

RESUMEN

The taste receptor type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors participates in monitoring energy and nutrient status. TAS1R member 3 (TAS1R3) is a bi-functional protein that recognizes amino acids such as L-glycine and L-glutamate or sweet molecules such as sucrose and fructose when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively. It was recently reported that deletion of TAS1R3 expression in Tas1R3 mutant mice leads to increased cortical bone mass but the underlying cellular mechanism leading to this phenotype remains unclear. Here, we independently corroborate the increased thickness of cortical bone in femurs of 20-week-old male Tas1R3 mutant mice and confirm that Tas1R3 is expressed in the bone environment. Tas1R3 is expressed in undifferentiated bone marrow stromal cells (BMSCs) in vitro and its expression is maintained during BMP2-induced osteogenic differentiation. However, levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) are unchanged in the serum of 20-week-old Tas1R3 mutant mice as compared to controls. In contrast, levels of the bone resorption marker collagen type I C-telopeptide are reduced greater than 60% in Tas1R3 mutant mice. Consistent with this, Tas1R3 and its putative signaling partner Tas1R2 are expressed in primary osteoclasts and their expression levels positively correlate with differentiation status. Collectively, these findings suggest that high bone mass in Tas1R3 mutant mice is due to uncoupled bone remodeling with reduced osteoclast function and provide rationale for future experiments examining the cell-type-dependent role for TAS1R family members in nutrient sensing in postnatal bone remodeling.


Asunto(s)
Resorción Ósea/metabolismo , Hueso Cortical/metabolismo , Regulación del Desarrollo de la Expresión Génica , Células Madre Mesenquimatosas/metabolismo , Osteoclastos/metabolismo , Osteogénesis , Receptores Acoplados a Proteínas G/metabolismo , Animales , Biomarcadores/metabolismo , Resorción Ósea/inmunología , Resorción Ósea/patología , Catepsina K/genética , Catepsina K/metabolismo , Línea Celular , Células Cultivadas , Hueso Cortical/citología , Hueso Cortical/inmunología , Hueso Cortical/patología , Mutación con Pérdida de Función , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Células Madre Mesenquimatosas/citología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Mutantes , Osteoblastos/citología , Osteoblastos/metabolismo , Osteoblastos/patología , Osteoclastos/citología , Osteoclastos/patología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Acoplados a Proteínas G/genética
2.
Am J Physiol Endocrinol Metab ; 310(9): E762-73, 2016 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-26956187

RESUMEN

ApoE-null (ApoE-KO) mice fed a high-fat diet (HFD) develop atherosclerosis, due in part to activation of vascular inflammation by oxidized low-density lipoprotein. Since bone loss also occurs in these mice, we used them to investigate the impact of oxidized lipids on bone homeostasis and to search for underlying pathogenic pathways. Four-month-old female ApoE-KO mice fed a HFD for three months exhibited increased levels of oxidized lipids in bone, as well as decreased femoral and vertebral trabecular and cortical bone mass, compared with ApoE-KO mice on normal diet. Despite HFD-induced increase in expression of Alox15, a lipoxygenase that oxidizes LDL and promotes atherogenesis, global deletion of this gene failed to ameliorate the skeletal impact of HFD. Osteoblast number and function were dramatically reduced in trabecular and cortical bone of HFD-fed mice, whereas osteoclast number was modestly reduced only in trabecular bone, indicating that an imbalance in favor of osteoclasts was responsible for HFD-induced bone loss. These changes were associated with decreased osteoblast progenitors and increased monocyte/macrophages in the bone marrow as well as increased expression of IL-1ß, IL-6, and TNF. HFD also attenuated Wnt signaling as evidenced by reduced expression of Wnt target genes, and it decreased expression of pro-osteoblastogenic Wnt ligands. These results suggest that oxidized lipids decrease bone mass by increasing anti-osteoblastogenic inflammatory cytokines and decreasing pro-osteoblastogenic Wnt ligands.


Asunto(s)
Aorta/patología , Apolipoproteínas E/genética , Aterosclerosis/genética , Enfermedades Óseas Metabólicas/genética , Huesos/inmunología , Osteogénesis , Proteínas Wnt/genética , Absorciometría de Fotón , Animales , Araquidonato 12-Lipooxigenasa/genética , Araquidonato 15-Lipooxigenasa/genética , Aterosclerosis/inmunología , Aterosclerosis/patología , Western Blotting , Densidad Ósea , Enfermedades Óseas Metabólicas/diagnóstico por imagen , Enfermedades Óseas Metabólicas/inmunología , Enfermedades Óseas Metabólicas/patología , Huesos/diagnóstico por imagen , Huesos/metabolismo , Huesos/patología , Hueso Esponjoso/diagnóstico por imagen , Hueso Esponjoso/inmunología , Hueso Esponjoso/metabolismo , Hueso Esponjoso/patología , Recuento de Células , Hueso Cortical/efectos de los fármacos , Hueso Cortical/inmunología , Hueso Cortical/metabolismo , Hueso Cortical/patología , Dieta Alta en Grasa , Femenino , Fémur/diagnóstico por imagen , Fémur/inmunología , Fémur/metabolismo , Fémur/patología , Citometría de Flujo , Separación Inmunomagnética , Inflamación , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Lipoproteínas LDL/metabolismo , Macrófagos/inmunología , Ratones , Ratones Noqueados , Monocitos/inmunología , Osteoblastos/citología , Osteoclastos/citología , Porosidad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/inmunología , Columna Vertebral/metabolismo , Columna Vertebral/patología , Factor de Necrosis Tumoral alfa/genética
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