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1.
J Struct Biol ; 212(3): 107627, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32950603

RESUMEN

Biglycan (Bgn) and Fibromodulin (Fmod) are small leucine rich proteoglycans (SLRPs) which are abundant in the extra-cellular matrix (ECM) of mineralized tissues. We have previously generated a Bgn/Fmod double knock-out (DKO) mouse model and found it has a 3-fold increase in osteoclastogenesis compared with Wild type (WT) controls, resulting in a markedly low bone mass (LBM) phenotype. To try and rescue/repair the LBM phenotype of Bgn/Fmod DKO mice by suppressing osteoclast formation and activity, 3- and 26-week-old Bgn/Fmod DKO mice and age/gender matched WT controls were treated with OPG-Fc for 6 weeks after which bone parameters were evaluated using DEXA, micro-computed tomography (µCT) and serum biomarkers analyses. In the appendicular skeleton, OPG-Fc treatment improved some morphometric and geometric parameters in both the trabecular and cortical compartments in Bgn/Fmod DKO female and male mice, especially in the repair module. For many of the skeletal parameters analyzed, the Bgn/Fmod DKO mice were more responsive to the treatment than their WT controls. In addition, we found that OPG-Fc treatment was not able to prevent or ameliorate the formation of ectopic ossification, which are common lesions seen in aged joints and are one of the phenotypical hallmarks of our Bgn/Fmod DKO model. Analysis of skull bones, specifically the occipital bone, showed the treatment recovered some parameters of LBM phenotype in the craniofacial skeleton, more so in the younger rescue module. Using OPG-Fc as treatment alleviated, yet did not completely restore, the severe osteopenia and mineralized tissue structural abnormalities that Bgn/Fmod DKO mice suffer from.


Asunto(s)
Biglicano/deficiencia , Huesos/efectos de los fármacos , Fibromodulina/deficiencia , Fragmentos Fc de Inmunoglobulinas/farmacología , Osteoprotegerina/farmacología , Proteínas Recombinantes de Fusión/farmacología , Esqueleto/efectos de los fármacos , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Huesos/metabolismo , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Fenotipo , Esqueleto/metabolismo
2.
PLoS One ; 12(8): e0182973, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28827814

RESUMEN

Tumor barrier function in carcinoma represents a major challenge to treatment and is therefore an attractive target for increasing drug delivery. Variables related to tumor barrier include aberrant blood vessels, high interstitial fluid pressure, and the composition and structure of the extracellular matrix. One of the proteins associated with dense extracellular matrices is fibromodulin, a collagen fibrillogenesis modulator expressed in tumor stroma but scarce in normal loose connective tissues. Here, we investigated the effects of fibromodulin on stroma ECM in a syngeneic murine colon carcinoma model. We show that fibromodulin deficiency decreased collagen fibril thickness but glycosaminoglycan content and composition were unchanged. Furthermore, vascular density, pericyte coverage and macrophage amount were unaffected. Fibromodulin can therefore be a unique effector of dense collagen matrix assembly in tumor stroma and, without affecting other major matrix components or the cellular composition, can function as a main agent in tumor barrier function.


Asunto(s)
Colágeno/metabolismo , Neoplasias del Colon/metabolismo , Modelos Animales de Enfermedad , Fibromodulina/deficiencia , Glicosaminoglicanos/metabolismo , Animales , Línea Celular Tumoral , Neoplasias del Colon/patología , Fibromodulina/genética , Ratones , Ratones Endogámicos C57BL
3.
Exp Dermatol ; 25(7): 558-61, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26997256

RESUMEN

Excessive production of collagen is the hallmark of fatal diseases of fibrosis such as systemic sclerosis. Overexpression of the proteoglycan fibromodulin (FMOD) has been associated with improved wound healing and scarless repair. In this study, we have investigated the consequences of FMOD deficiency on the development of experimental skin fibrosis. Using immunohistochemistry, we identified FMOD in both human and murine fibrotic skin. In the bleomycin model of skin fibrosis, FMOD(-/-) mice developed skin fibrosis to a similar degree compared to FMOD(+/+) mice. Analysis of skin ultrastructure using transmission electron microscopy revealed a significant reduction in collagen fibril diameter in FMOD(-/-) but not FMOD(+/+) mice following fibrosis. We conclude that the impact of FMOD deficiency on the development of experimental skin fibrosis is limited.


Asunto(s)
Fibromodulina/deficiencia , Esclerodermia Sistémica/metabolismo , Adolescente , Animales , Bleomicina , Estudios de Casos y Controles , Niño , Modelos Animales de Enfermedad , Fibrosis , Humanos , Ratones Endogámicos C57BL , Esclerodermia Sistémica/etiología , Piel/metabolismo , Piel/patología , Piel/ultraestructura
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