ABSTRACT
El raquitismo hipofosfatémico hereditario es una condición genética asociada con una mineralización ósea alterada causada por la deficiencia de fosfato. Produce deformidad esquelética y retraso del crecimiento en la infancia. Se describen diferentes patrones de herencia según el locus involucrado. Dado el solapamiento de los fenotipos y la dificultad en analizar genealogías reducidas, los estudios moleculares son importantes para establecer la causa genética y realizar el abordaje familiar. La forma recesiva del raquitismo hipofosfatémico (ARHR, OMIM #241520) es una condición extremadamente poco frecuente reportada en familias de origen europeo y de Oriente Medio. Las mutaciones con pérdida de función del gen DMP1 (dentin matrix acidic phosphoprotein 1) se asocian al raquitismo hipofosfatémico hereditario tipo 1. En este artículo presentamos el primer reporte de una familia argentina con raquitismo hipofosfatémico hereditario por mutación en DMP1
Hereditary hypophosphatemic rickets is a genetic condition associated with impaired bone mineralization caused by phosphate deficiency. It results in skeletal deformity and growth retardation in early childhood. Different inheritance patterns have been described according to the locus involved. Given the phenotypic overlapping and the difficulty in analyzing reduced genealogies, molecular studies are important to establish the genetic cause and implement a family-centered approach. The autosomal recessive form of hypophosphatemic rickets (ARHR, OMIM 241520) is an extremely rare condition reported in families of European and Middle Eastern descent. Loss-of-function mutations in the DMP1 (dentin matrix acidic phosphoprotein 1) gene are associated with hereditary hypophosphatemic rickets type 1. In this article, we describe the first report of an Argentine family with hereditary hypophosphatemic rickets due to a mutation in the DMP1 gene.
Subject(s)
Humans , Male , Infant , Familial Hypophosphatemic Rickets/genetics , Argentina , Calcification, Physiologic , MutationABSTRACT
During bone remodeling, there is requirement of differentiation of osteoblastic cells. Previously, we identified proteins differentially expressed in soft tissue during bone healing. Of these proteins, we focused the effect of LTF on differentiation of osteoblast. In order to analyze the osteogenic ability of LTF, we treated conditioned media collected from human LTF-stably transfected HEK293T cells into osteoblastic MC3T3-E1. The results showed that the activity and expression of alkaline phosphatase were increased in MC3T3-E1 cells treated with conditioned media containing LTF in dose- and time-dependent manner. At the same time, we observed the significant increase of the expression of osteoblastic genes, such as ALP, BSP, COL1A1, and OCN, and along with matrix mineralization genes, such as DMP1 and DMP2, in LTF conditioned media-treated groups. Moreover, the result of treating recombinant human LTF directly into osteoblastic MC3T3-E1 showed the same pattern of treating conditioned media containing LTF. Our study demonstrated that LTF constitutively enhances osteoblastic differentiation via induction of osteoblastic genes and activation of matrix mineralization in MC3T3-E1 cells.
Subject(s)
Humans , Alkaline Phosphatase , Bone Remodeling , Culture Media, Conditioned , Lactoferrin , OsteoblastsABSTRACT
Dentin matrix protein 1 (DMP1) is an acidic phosphoprotein that plays an important role in mineralized tissue formation by initiation of nucleation and modulation of mineral phase morphology. The purpose of the present study was to examine the immunoexpression of DMP1 in tooth germs of 7 human fetuses at different gestational ages (14, 16, 19, 20, 21, 23 and 24 weeks) comparing with completed tooth formation erupted teeth. The results showed the presence of DMP1 in the dental lamina, as well as in the cells of the external epithelium, stellate reticulum and stratum intermedium of the enamel organ. However, in the internal dental epithelium, cervical loop region and dental papilla some cells have not labeled for DMP1. In the crown stage, DMP1 was expressed in the ameloblast and odontoblast layer, as well as in the dentinal tubules of coronal dentin near the odontoblast area. Erupted teeth with complete tooth formation exhibited immunolabeling for DMP1 only in the dentinal tubules mainly close to the dental pulp. No staining was observed in the enamel, predentin or dental pulp matrix. DMP1 is present in all developing dental structures (dental lamina, enamel organ, dental papilla) presenting few immunoexpression variations, with no staining in mineralized enamel and dentin.
A proteína da matriz dentinária 1 (DMP1) é uma fosfoproteína ácida que tem sido relacionada diretamente ao processo de mineralização dos tecidos em formação sendo iniciadora do processo de nucleação e modulação da fase mineral. O objetivo desse trabalho foi avaliar a imunoexpressão da DMP1 em germes dentários em diferentes fases da odontogênese, obtidos de 7 fetos humanos em diversos estágios gestacionais (14, 16, 19, 20, 21, 23 e 24 semanas), comparando-se com dentes com rizogênese completa. Os resultados mostraram que a DMP1 esteve expressa na lâmina dentária, bem como, nas células do epitélio externo, retículo estrelado e estrato intermediário do órgão do esmalte. Diferentemente, no epitélio interno do órgão do esmalte, alça cervical e papila dentária algumas células não apresentaram a DMP1. Nas fases de coroa, os ameloblastos e odontoblastos apresentaram marcação positiva para a DMP1, bem como os túbulos dentinários da dentina coronária próximos à região odontoblástica. Os dentes com rizogênese completa exibiram marcação para a DMP1 apenas nos túbulos dentinários principalmente próximos à polpa dentária. Nenhuma marcação foi observada na matriz de esmalte ou pré-dentina, nem na polpa dentária. Concluímos que a DMP1 está presente em todas as fases da odontogênese, tanto na lâmina dentária, órgão do esmalte, bem como na papila dentária, com pequenas variações de nuances de expressão, estando ausente na dentina e esmalte mineralizados.
Subject(s)
Humans , Extracellular Matrix Proteins/biosynthesis , Phosphoproteins/biosynthesis , Tooth Germ/metabolism , Extracellular Matrix Proteins/genetics , Extracellular Matrix/metabolism , Fetal Development , Gene Expression , Immunohistochemistry , Odontoblasts/metabolism , Odontogenesis/physiology , Phosphoproteins/geneticsABSTRACT
El eje hueso-riñón ha sido pensado como un mecanismo por el cual el esqueleto se comunica con el riñón para coordinar la mineralización de la matriz extracelular ósea con el manejo renal del fosfato. Osteoblastos /osteocitos están bien preparados para coordinar las homeostasis sistémica de fósforo y la mineralización ósea, ya que ellos expresan todos los componentes implicados en un posible eje hueso-riñón, incluyendo al PHEX, FGF-23, MEPE, y DMP1. Los efectos autocrinos de proteínas de la familia SIBLING como MEPE y DMP1 sobre los osteoblastos podrían regular la producción de proteínas de matriz extracelular que intervienen en la mineralización. El riñón provee uno de los efectores de este eje que regula el balance de fosfato a través de la expresión apical de los cotransportadores sodio/fosfato NaPi-IIa y NaPi-IIc en el túbulo proximal. Central en este eje es el FGF-23, producido por los osteoblastos que tiene acciones fosfatúricas sobre el riñón. Cuando se descubrió que el FGF23, la primera fosfatonina era de origen osteoblástico/osteocitico, quedó establecido el eje hueso-riñón. Probar definitivamente la existencia de este eje hueso-riñón y definir exactamente su rol fisiológico requerirá de investigaciones adicionales
The bone-kidney axis has been thought as a mechanism for the skeleton to communicate with the kidney to coordinate the mineralization of extracelular matrix with the renal handling of phosphate. Osteoblasts / osteocytes are well suited for coordinating systemic phosphate homeostasis and mineralization, since they express all of the implicated components of a possible bone-kidney axis, including PHEX, FGF-23, MEPE, and DMP1. In addition, autocrine effects of SIBLING proteins as MEPE and DMP1 on osteoblasts could regulate the production of ECM proteins that regulate mineralization. The kidney provides one of the effectors of the axis that regulates phosphate balance through the apical expression of NaPi-IIa and NaPi-IIc in proximal tubules. Central in this axis is FGF-23, produced by osteoblasts that has phosphaturic actions on the kidney. When FGF23, the first phosphatonin, was discovered to be of osteoblastic/osteocyte origin, the bone kidney axis was established. Proving the existence of this bone-kidney axis and defining its physiological role will require additional investigations