Differentiation dependent expression of urocortin’s mRNA and peptide in human osteoprogenitor cells: influence of BMP-2, TGF-beta-1 and dexamethasone

Urocortin-1 (UCN) a corticotropin releasing-factor (CRF) related peptide, has been found to be expressed in many different tissues like the central nervous system, the cardiovascular system, adipose tissue, and skeletal muscle. The effects of UCN are mediated via stimulation of CRF-receptors 1 and 2 (CRFR1 and 2, CRFR’s) with a high affinity for CRFR2. It has been shown that the CRF-related peptides and CRFR’s are involved in the regulation of stress-related endocrine, autonomic and behavioural responses. Using immunocytochemistry, immunohistochemistry and RT–PCR, we now can show the differentiation dependent expression of UCN mRNA and peptide in human mesenchymal progenitor cells (MSCs) directed to the osteoblastic phenotype for the first time. UCN expression was down regulated by TGF-beta and BMP-2 in the early proliferation phase of osteoblast development, whereas dexamethasone (dex) minimally induced UCN gene expression during matrix maturation after 24 h stimulation. Stimulation of MSCs for 28 days with ascorbate/beta-glycerophosphate (asc/bGp) induced UCN gene expression at day 14. This effect was prevented when using 1,25-vitamin D3 or dex in addition. There was no obvious correlation to osteocalcin (OCN) gene expression in these experiments. In MSCs from patients with metabolic bone disease (n = 9) UCN gene expression was significantly higher compared to MSCs from normal controls (n = 6). Human MSCs did not express any of the CRFR’s during differentiation to osteoblasts. Our results indicate that UCN is produced during the development of MSCs to osteoblasts and differentially regulated during culture as well as by differentiation factors. The expression is maximal between proliferation and matrix maturation phase. However, UCN does not seem to act on the osteoblast itself as shown by the missing CRFR’s. Our results suggest new perspectives on the role of urocortin in human skeletal tissue in health and disease

PD-L1 status and Immune checkpoint inhibitors in kidney cancer: ignorance, lack of knowledge or both

<jats:title>Abstract</jats:title><jats:p>The East African margin between the Somali Basin in the north and the Natal Basin in the south formed as a result of the Jurassic/Cretaceous dispersal of Gondwana. While the initial movements between East and West Gondwana left (oblique) rifted margins behind, the subsequent southward drift of East Gondwana from 157 Ma onwards created a major shear zone, the Davie Fracture Zone (DFZ), along East Africa. To document the structural variability of the DFZ, several deep seismic lines were acquired off northern Mozambique. The profiles clearly indicate the structural changes along the shear zone from an elevated continental block in the south (14°–20°S) to non-elevated basement covered by up to 6-km-thick sediments in the north (9°–13°S). Here, we compile the geological/geophysical knowledge of five profiles along East Africa and interpret them in the context of one of the latest kinematic reconstructions. A pre-rift position of the detached continental sliver of the Davie Ridge between Tanzania/Kenya and southeastern Madagascar fits to this kinematic reconstruction without general changes of the rotation poles.</jats:p&gt