Hypoxia-inducible factor-1 (HIF-1) but not HIF-2 is essential for hypoxic induction of collagen prolyl 4-hydroxylases in primary newborn mouse epiphyseal growth plate chondrocytes

Hypoxia-inducible factors (HIFs) are the master regulators of hypoxia-responsive genes. They play a critical role in the survival, development, and differentiation of chondrocytes in the avascular hypoxic fetal growth plate, which is rich in extracellular matrix (ECM) and in its main component, collagens. Several genes involved in the synthesis, maintenance, and degradation of ECM are regulated by HIFs. Collagen prolyl 4-hydroxylases (C-P4Hs) are key enzymes in collagen synthesis because the resulting 4-hydroxyprolines are necessary for the stability of all collagen molecules. The vertebrate C-P4Hs are \u3b1(2)\u3b2(2) tetramers with three isoforms of the catalytic \u3b1 subunit, yielding C-P4Hs of types I-III. C-P4H-I is the main form in most cells, but C-P4H-II is the major form in chondrocytes. We postulated here that post-translational modification of collagens, particularly 4-hydroxylation of proline residues, could be one of the modalities by which HIF regulates the adaptive responses of chondrocytes in fetal growth plates. To address this hypothesis, we used primary epiphyseal growth plate chondrocytes isolated from newborn mice with conditionally inactivated genes for HIF-1\u3b1, HIF-2\u3b1, or the von Hippel-Lindau protein. The data obtained showed that C-P4H \u3b1(I) and \u3b1(II) mRNA levels were increased in hypoxic chondrocytes in a manner dependent on HIF-1 but not on HIF-2. Furthermore, the increases in the C-P4H mRNA levels were associated with both increased amounts of the C-P4H tetramers and augmented C-P4H activity in hypoxia. The hypoxia inducibility of the C-P4H isoenzymes is thus likely to ensure sufficient C-P4H activity for collagen synthesis occurring in chondrocytes in a hypoxic environment

Fuentes del derecho financiero Salvadoreño

Nos referimos al derecho financiero en esta época es algo corriente, no así hace un siglo en donde esta disciplina era desconocida. ¿Qué significa realmente esta rama del derecho y cual es su contenido? se justifica su existencia o estaban en lo correcto los juristas de hace una centuria cuando no hacían referencia a ellas

Use of knockout and transgenic mouse models in disc research

The intervertebral disc is a fibrocartilaginous structure that is located between two vertebral bodies; it transmits loads through the spine and allows bending, flexion, and torsion of the column. The intervertebral disc consists of an outer ring of fibrous cartilage called the annulus fibrosus and an inner gelatinous structure, the nucleus pulposus. The nucleus pulposus is a gelatinous structure mainly formed by sparse chondrocyte-like cells embedded in a highly hydrated aggrecan-containing gel (Raj 2008). For more details of the structure of the disc, see Chaps. 4 and 5. The annulus fibrosus is composed of an outer layer of collagen I and an inner region containing collagen II. The collagen fibers are arranged in parallel lamellae, and elastin fibers are interposed between the lamellae

Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitors

The hypoxia-inducible factor (Hif)-1\u3b1 (Hif-1\u3b1) and Hif-2\u3b1 (Epas1) have a critical role in both normal development and cancer. von Hippel Lindau (Vhl) protein, encoded by a tumor suppressor gene, is an E3 ubiquitin ligase that targets Hif-1\u3b1 and Epas1 to the proteasome for degradation. To better understand the role of Vhl in the biology of mesenchymal cells, we analyzed mutant mice lacking Vhl in mesenchymal progenitors that give rise to the soft tissues that form and surround synovial joints. Loss of Vhl in mesenchymal progenitors of the limb bud caused severe fibrosis of the synovial joints and formation of aggressive masses with histologic features of mesenchymal tumors. Hif-1\u3b1 and its downstream target connective tissue growth factor were necessary for the development of these tumors, which conversely still developed in the absence of Epas1, but at lower frequency. Human tumors of the soft tissue are a very complex and heterogeneous group of neoplasias. Our novel findings in genetically altered mice suggest that activation of the HIF signaling pathway could be an important pathogenetic event in the development and progression of at least a subset of these tumors