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1.
JCI Insight ; 7(3)2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-34990412

RESUMO

Short stature is a major skeletal phenotype in osteogenesis imperfecta (OI), a genetic disorder mainly caused by mutations in genes encoding type I collagen. However, the underlying mechanism is poorly understood, and no effective treatment is available. In OI mice that carry a G610C mutation in COL1A2, we previously found that mature hypertrophic chondrocytes (HCs) are exposed to cell stress due to accumulation of misfolded mutant type I procollagen in the endoplasmic reticulum (ER). By fate mapping analysis of HCs in G610C OI mice, we found that HCs stagnate in the growth plate, inhibiting translocation of HC descendants to the trabecular area and their differentiation to osteoblasts. Treatment with 4-phenylbutyric acid (4PBA), a chemical chaperone, restored HC ER structure and rescued this inhibition, resulting in enhanced longitudinal bone growth in G610C OI mice. Interestingly, the effects of 4PBA on ER dilation were limited in osteoblasts, and the bone fragility was not ameliorated. These results highlight the importance of targeting HCs to treat growth deficiency in OI. Our findings demonstrate that HC dysfunction induced by ER disruption plays a critical role in the pathogenesis of OI growth deficiency, which lays the foundation for developing new therapies for OI.


Assuntos
Condrócitos/metabolismo , Condrogênese/genética , Colágeno Tipo I/genética , Mutação , Osteogênese Imperfeita/tratamento farmacológico , Animais , Proliferação de Células , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Condrogênese/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo
2.
Curr Opin Cell Biol ; 61: 132-140, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31541943

RESUMO

Endochondral bone formation relies on a finely controlled sequence of chondrocyte proliferation, maturation and hypertrophy that establishes the growth plate which, combined with the deposition of bone upon the cartilage template, mediates longitudinal skeletal growth. Recent lineage studies support a chondrocyte-osteoblast differentiation continuum and the presence of skeletal stem cells within cartilage. The biological significance of the lineage extension and the mechanisms controlling the process are unclear. In this review, we describe recent work on the extended chondrocyte-osteoblast lineage and its contribution to the development, growth and repair of bone and to bone disorders that provides insight into the process and the molecular controls involved. The implications for skeletal homeostasis are discussed.


Assuntos
Desenvolvimento Ósseo/fisiologia , Osso e Ossos/embriologia , Cartilagem/citologia , Condrócitos/citologia , Osteoblastos/citologia , Animais , Doenças Ósseas/embriologia , Doenças Ósseas/genética , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Lâmina de Crescimento/embriologia , Homeostase
3.
Curr Opin Genet Dev ; 57: 84-90, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31470291

RESUMO

The emergence of multipotent and migratory neural crest (NC) cells defines a key evolutionary transition from invertebrates to vertebrates. Studies in vertebrates have identified a complex gene regulatory network that governs sequential stages of NC ontogeny. Comparative analysis has revealed extensive conservation of the overall architecture of the NC gene regulatory network between jawless and jawed vertebrates. Among invertebrates, urochordates express putative NC gene homologs in the neural plate border region, but these NC-like cells do not have migratory capacity, whereas cephalochordates contain no NC cells but its genome contains most homologs of vertebrate NC genes. Whether the absence of migratory NC cells in invertebrates is due to differences in enhancer elements or an intrinsic limitation in potency remains unclear. We provide a brief overview of mechanisms that might explain how ancestral NC-like cells acquired the multipotency and migratory capacity seen in vertebrates.


Assuntos
Evolução Biológica , Crista Neural/crescimento & desenvolvimento , Neurogênese/genética , Vertebrados/genética , Animais , Diferenciação Celular/genética , Movimento Celular/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Genoma/genética , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/metabolismo , Vertebrados/crescimento & desenvolvimento
4.
JCI Insight ; 3(2)2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29367466

RESUMO

Incomplete penetrance of congenital heart defects (CHDs) was observed in a mouse model. We hypothesized that the contribution of a major genetic locus modulates the manifestation of the CHDs. After genome-wide linkage mapping, fine mapping, and high-throughput targeted sequencing, a recessive frameshift mutation of the heterogeneous nuclear ribonucleoprotein A1 (Hnrnpa1) gene was confirmed (Hnrnpa1ct). Hnrnpa1 was expressed in both the first heart field (FHF) and second heart field (SHF) at the cardiac crescent stage but was only maintained in SHF progenitors after heart tube formation. Hnrnpa1ct/ct homozygous mutants displayed complete CHD penetrance, including truncated and incomplete looped heart tube at E9.5, ventricular septal defect (VSD) and persistent truncus arteriosus (PTA) at E13.5, and VSD and double outlet right ventricle at P0. Impaired development of the dorsal mesocardium and sinoatrial node progenitors was also observed. Loss of Hnrnpa1 expression leads to dysregulation of cardiac transcription networks and multiple signaling pathways, including BMP, FGF, and Notch in the SHF. Finally, two rare heterozygous mutations of HNRNPA1 were detected in human CHDs. These findings suggest a role of Hnrnpa1 in embryonic heart development in mice and humans.


Assuntos
Cardiopatias Congênitas/genética , Coração/embriologia , Ribonucleoproteína Nuclear Heterogênea A1/genética , Animais , Análise Mutacional de DNA , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Mutação da Fase de Leitura , Técnicas de Inativação de Genes , Cardiopatias Congênitas/patologia , Homozigoto , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , Miócitos Cardíacos , Organogênese/genética , Transdução de Sinais/genética
5.
J Bone Miner Res ; 27(11): 2399-412, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22692895

RESUMO

Numerous biochemical studies have pointed to an essential role of annexin A5 (AnxA5), annexin A6 (AnxA6), and collagen X in matrix vesicle-mediated biomineralization during endochondral ossification and in osteoarthritis. By binding to the extracellular matrix protein collagen X and matrix vesicles, annexins were proposed to anchor matrix vesicles in the extracellular space of hypertrophic chondrocytes to initiate the calcification of cartilage. However, mineralization appears to be normal in mice lacking AnxA5 and AnxA6, whereas collagen X-deficient mice show only subtle alterations in the growth plate organization. We hypothesized that the simultaneous lack of AnxA5, AnxA6, and collagen X in vivo induces more pronounced changes in the growth plate development and the initiation of mineralization. In this study, we generated and analyzed mice deficient for AnxA5, AnxA6, and collagen X. Surprisingly, mice were viable, fertile, and showed no obvious abnormalities. Assessment of growth plate development indicated that the hypertrophic zone was expanded in Col10a1(-/-) and AnxA5(-/-) AnxA6(-/-) Col10a1(-/-) newborns, whereas endochondral ossification and mineralization were not affected in 13-day- and 1-month-old mutants. In peripheral quantitative computed tomography, no changes in the degree of biomineralization were found in femora of 1-month- and 1-year-old mutants even though the diaphyseal circumference was reduced in Col10a1(-/-) and AnxA5(-/-) AnxA6(-/-) Col10a1(-/-) mice. The percentage of naive immature IgM(+) /IgM(+) B cells and peripheral T-helper cells were increased in Col10a1(-/-) and AnxA5(-/-) AnxA6(-/-) Col10a1(-/-) mutants, and activated splenic T cells isolated from Col10a1(-/-) mice secreted elevated levels of IL-4 and GM-CSF. Hence, collagen X is needed for hematopoiesis during endochondral ossification and for the immune response, but the interaction of annexin A5, annexin A6, and collagen X is not essential for physiological calcification of growth plate cartilage. Therefore, annexins and collagen X may rather fulfill functions in growth plate cartilage not directly linked to the mineralization process.


Assuntos
Anexina A5/deficiência , Anexina A6/deficiência , Calcificação Fisiológica , Colágeno Tipo X/deficiência , Matriz Extracelular/metabolismo , Hematopoese , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Animais Recém-Nascidos , Anexina A5/metabolismo , Anexina A6/metabolismo , Osso e Ossos/patologia , Colágeno Tipo X/metabolismo , Cruzamentos Genéticos , Feminino , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/patologia , Hipertrofia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Mutantes , Células Th1/imunologia , Células Th2/imunologia
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