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1.
Stem Cell Reports ; 13(4): 713-729, 2019 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-31522976

RESUMEN

The synovial joint forms from a pool of progenitor cells in the future region of the joint, the interzone. Expression of Gdf5 and Wnt9a has been used to mark the earliest cellular processes in the formation of the interzone and the progenitor cells. However, lineage specification and progression toward the different tissues of the joint are not well understood. Here, by lineage-tracing studies we identify a population of Lgr5+ interzone cells that contribute to the formation of cruciate ligaments, synovial membrane, and articular chondrocytes of the joint. This finding is supported by single-cell transcriptome analyses. We show that Col22a1, a marker of early articular chondrocytes, is co-expressed with Lgr5+ cells prior to cavitation as an important lineage marker specifying the progression toward articular chondrocytes. Lgr5+ cells contribute to the repair of a joint defect with the re-establishment of a Col22a1-expressing superficial layer.


Asunto(s)
Linaje de la Célula , Condrocitos/metabolismo , Colágeno/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Madre/metabolismo , Animales , Biomarcadores , Cartílago Articular/citología , Linaje de la Célula/genética , Condrocitos/citología , Colágeno/genética , Técnica del Anticuerpo Fluorescente , Expresión Génica , Inmunohistoquímica , Ratones , Modelos Biológicos , Imagen Molecular , Receptores Acoplados a Proteínas G/genética , Células Madre/citología , Membrana Sinovial/citología
2.
Hum Mol Genet ; 26(23): 4572-4587, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-28973168

RESUMEN

Bone remodeling is a balanced process between bone synthesis and degradation, maintaining homeostasis and a constant bone mass in adult life. Imbalance will lead to conditions such as osteoporosis or hyperostosis. Osteoblasts build bone, becoming embedded in bone matrix as mature osteocytes. Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling. Excessive mechanical load can lead to activation of cellular stress responses altering cell behavior and differentiation. The unfolded protein response (UPR) is a shared pathway utilized by cells to cope with stress stimuli. We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis. A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA). As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion. Thus, therapeutic agents ameliorating protein folding or the UPR can be considered as a potential therapeutic treatment.


Asunto(s)
Anomalías Craneofaciales/metabolismo , Hiperostosis/metabolismo , Osteocondrodisplasias/metabolismo , Osteocitos/metabolismo , Respuesta de Proteína Desplegada , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Remodelación Ósea/fisiología , Huesos/metabolismo , Colágeno Tipo X/genética , Colágeno Tipo X/metabolismo , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Marcadores Genéticos/genética , Humanos , Hiperostosis/genética , Hiperostosis/patología , Ratones , Ratones Transgénicos , Osteoblastos/metabolismo , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Osteocitos/patología , Osteogénesis/fisiología , Fenilbutiratos/farmacología , Estrés Mecánico , Vía de Señalización Wnt
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