Actinide(IV) Deposits on Bone: Potential Role of the Osteopontin–Thorium Complex

Abstract

In case of a nuclear event, contamination (broad or limited) of the population or of specific workers might occur. In such a senario, the fate of actinide contaminants may be of first concern, in particular with regard to human target organs like the skeleton. To improve our understanding of the toxicological processes that might take place, a mechanistic approach is necessary. For instance, ∼50% of Pu(IV) is known from biokinetic data to accumulate in bone, but the underlining mechanisms are almost unknown. In this context, and to obtain a better description of the toxicological mechanisms associated with actinides(IV), we have undertaken the investigation, on a molecular scale, of the interaction of thorium(IV) with osteopontin (OPN) a hyperphosphorylated protein involved in bone turnover. Thorium is taken here as a simple model for actinide(IV) chemistry. In addition, we have selected a phosphorylated hexapeptide (His-pSer-Asp-Glu-pSer-Asp-Glu-Val) that is representative of the peptidic sequence involved in the bone interaction. For both the protein and the biomimetic peptide, we have determined the local environment of Th(IV) within the bioactinidic complex, combining isothermal titration calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, theoretical calculations with density functional theory, and extended X-ray absorption fine structure spectroscopy at the Th LIII edge. The results demonstrate a predominance of interaction of metal with the phosphate groups and confirmed the previous physiological studies that have highlighted a high affinity of Th(IV) for the bone matrix. Data are further compared with those of the uranyl case, representing the actinyl(V) and actinyl(VI) species. Last, our approach shows the importance of developing simplified systems [Th(IV)-peptide] that can serve as models for more biologically relevant systems.

TGF‑β1 promotes the osteoinduction of human osteoblasts via the PI3K/AKT/mTOR/S6K1 signalling pathway

“…It has been reported that the Runx2 gene activates the transcription and expression of OCN, OPN, bone sialoprotein and type I collagen by binding to the cis-acting elements of osteoblasts (50). OPN serves an important role in the mineralisation and absorption of bone matrix (51). OCN is an important component of the extracellular matrix and is regarded as a specific marker of the bone turnover process (52); when OCN is in an inactive state, it directly affects the formation, absorption and mineralisation of bone (53).…”

Revisiting binding of plutonium to transferrin by CE-ICP-MS

“…The binding of metals to a protein can be monitored by several techniques, such as fluorescence spectroscopy, isothermal titration calorimetry (ITC), time-resolved laser spectroscopy (TRLS), capillary electrophoresis coupled with an inductively coupled plasma mass spectrometer (CE-ICP-MS), and a binding constant expressed as K d , K, or pK d can be determined. [17][18][19][20] This overall constant reflects the protein's affinity for the metal whatever the number of metal binding sites. A small K d or a high K means that the protein's affinity for the metal is strong.…”

How Do Actinyls Interact with Hyperphosphorylated Yolk Protein Phosvitin?

“…On the other hand, there is no visible change associated with the symmetric stretching frequency of the carboxylate groups at about 1402 cm À1 .D enticity of the carboxylicg roups with the oxocation has been reportedly found, withadifference betweena symmetrica nd symmetric stretching frequencies. [7] Thisisn ot visible here. In addition, we could not find ar eproducible methodo fc reatingt he difference absorption spectra, owing to the strong amide II band.…”

“…On the other hand, there is no visible change associated with the symmetric stretching frequency of the carboxylate groups at about 1402 cm −1 . Denticity of the carboxylic groups with the oxocation has been reportedly found, with a difference between asymmetric and symmetric stretching frequencies . This is not visible here.…”

“…Laser fluorescence spectroscopy studies of U VI -phosvitin complexation TRLFS spectra were measured at af ixed uranyl concentration of 5.10 À6 m and in 5.10 À3 m TRIS + 15.10 À3 m NaCl as the sample medium. Fluorescence samples were prepared by using purified phosvitin under three different conditions:1 )asafunction of the incubation time (P/U ratio of 10:1 at pH 6.5);2 )varying ratio of phosphoryl/uranium content (30:1-1:1) at fixed pH (6.5 AE 0.1);a nd 3) varying pH values (3)(4)(5)(6)(7)(8) at af ixed ratio of phosphoryl/uranium content (10:1) after an equilibration time of 16 h. The required pH in the samples was achieved by using ap He lectrode and standard solution of HClO 4 or NaOH. Samples were frozen with liquid nitrogen at the end of the equilibration time for later measurement.…”