Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling

Transferrin receptor 2 (Tfr2) is mainly expressed in the liver and controls iron homeostasis. Here, we identify Tfr2 as a regulator of bone homeostasis that inhibits bone formation. Mice lacking Tfr2 display increased bone mass and mineralization independent of iron homeostasis and hepatic Tfr2. Bone marrow transplantation experiments and studies of cell-specific Tfr2 knockout mice demonstrate that Tfr2 impairs BMP-p38MAPK signaling and decreases expression of the Wnt inhibitor sclerostin specifically in osteoblasts. Reactivation of MAPK or overexpression of sclerostin rescues skeletal abnormalities in Tfr2 knockout mice. We further show that the extracellular domain of Tfr2 binds BMPs and inhibits BMP-2-induced heterotopic ossification by acting as a decoy receptor. These data indicate that Tfr2 limits bone formation by modulating BMP signaling, possibly through direct interaction with BMP either as a receptor or as a co-receptor in a complex with other BMP receptors. Finally, the Tfr2 extracellular domain may be effective in the treatment of conditions associated with pathological bone formation

Strain dependent differences in glucocorticoid-induced bone loss between C57BL/6J and CD-1 mice

We have investigated the effect of long-term glucocorticoid (GC) administration on bone turnover in two frequently used mouse strains; C57BL/6J and CD1, in order to assess the influence of their genetic background on GC-induced osteoporosis (GIO). GIO was induced in 12 weeks old female C57BL/6J and CD1 mice by subcutaneous insertion of long-term release prednisolone or placebo pellets. Biomechanical properties as assessed by three point bent testing revealed that femoral elasticity and strength significantly decreased in CD1 mice receiving GC, whereas C57BL/6J mice showed no differences between placebo and prednisolone treatment. Bone turnover assessed by microcomputer tomography revealed that contrary to C57BL/6J mice, prednisolone treated CD1 mice developed osteoporosis. In vitro experiments have underlined that, at a cellular level, C57BL/6J mice osteoclasts and osteoblasts were less responsive to GC treatment and tolerated higher doses than CD1 cells. Whilst administration of long-term release prednisolone pellets provided a robust GIO animal model in 12 weeks old CD1 mice, age matched C57BL/6J mice were not susceptible to the bone changes associated with GIO. This study indicates that for the induction of experimental GIO, the mouse strain choice together with other factors such as age should be carefully evaluated

Differentiation and Glucocorticoid Regulated Apopto-Phagocytic Gene Expression Patterns in Human Macrophages. Role of Mertk in Enhanced Phagocytosis

The daily clearance of physiologically dying cells is performed safely mainly by cells in the mononuclear phagocyte system. They can recognize and engulf dying cells utilizing several cooperative mechanisms. In our study we show that the expression of a broad range of apopto-phagocytic genes is strongly up-regulated during differentiation of human monocytes to macrophages with different donor variability. The glucocorticoid dexamethasone has a profound effect on this process by selectively up-regulating six genes and down-regulating several others. The key role of the up-regulated mer tyrosine kinase (Mertk) in dexamethasone induced enhancement of phagocytosis could be demonstrated in human monocyte derived macrophages by gene silencing as well as blocking antibodies, and also in a monocyte-macrophage like cell line. However, the additional role of other glucocorticoid induced elements must be also considered since the presence of autologous serum during phagocytosis could almost completely compensate for the blocked function of Mertk

Editorial: Glucocorticoid and bone: Friend or foe

Metabolic health: pathophysiological trajectories and therap

Editorial: Glucocorticoid and bone: Friend or foe

Metabolic health: pathophysiological trajectories and therap

When to Start and Stop Bone-Protecting Medication for Preventing Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) leads to fractures in up to 40% of patients with chronic glucocorticoid (GC) therapy when left untreated. GCs rapidly increase fracture risk, and thus many patients with anticipated chronic GC exposures should start anti-osteoporosis pharmacotherapy to prevent fractures. In addition to low awareness of the need for anti-osteoporosis therapy among clinicians treating patients with GCs, a major barrier to prevention of fractures from GIOP is a lack of clear guideline recommendations on when to start and stop anti-osteoporosis treatment in patients with GC use. The aim of this narrative review is to summarize current evidence and provide considerations for the duration of anti-osteoporosis treatment in patients taking GCs based on pre-clinical, clinical, epidemiologic, and pharmacologic evidence. We review the pathophysiology of GIOP, outline current guideline recommendations on initiating and stopping anti-osteoporosis therapy for GIOP, and present considerations for the duration of anti-osteoporosis treatment based on existing evidence. In each section, we illustrate major points through a patient case example. Finally, we conclude with proposed areas for future research and emerging areas of interest related to GIOP clinical management.Diabetes mellitus: pathophysiological changes and therap

Selektive UV-fotometrische Messverfahren fuer SO_2 und NO Abschlussbericht

The results of the project work show that with suitable designs of XeBr* and KrCl* excimer UV radiation sources it is possible to achieve the required power supply data so that these sources can be used in measuring instruments. As information from the literature about the UV spectra of the gaseous components of interest is incomplete, a radiation measuring rig was built for spectral measurements in the range between 210 nm and 400 nm. It could be shown that selective SO_2 measurement is possible. However, at wavelengths below 230 nm, absorption of several relevant waste gas components occurs (SO-2, NO, NO_2, CO). The project work carried out in order to make the sources fit for use in measuring instruments solved the following problems encountered: Suppression of ozone formation during operation of the radiation source; optimisation of electrode arrangement; optimisation of electrode materials. Further details to be observed in the operation of the radiation source are explained. The final conclusion drawn is that the objectives of the project could be achieved only to some part, as only selective SO_2 measurement with excimer UV radiation sources could be proven, experiments for selective NO measurement failed. (orig./CB)Die Arbeiten haben gezeigt, dass XeBr*- und KrCl*-Excimer-UV-Strahler so aufgebaut werden koennen, dass die erforderlichen Stromversorgungsdaten einen Einsatz in Messgeraeten ermoeglichen. Da nur eingeschraenkte Literaturangaben zu den UV-Spektren interessierender Gaskomponenten vorhanden sind, wurde ein Strahlungsmessplatz zur Spektrenaufnahme in Bereich von 210 nm bis 400 nm aufgebaut. Es wurde nachgewiesen, dass eine selektive SO_2-Messung moeglich ist. Im Gegensatz dazu treten bei Wellenlaengen kleiner 230 nm Absorptionen mehrere relevanter Abgaskomponenten (SO_2, NO, NO_2, CO) auf. Bei der Anpassung der Strahler an die Bedingungen eines Messgeraetes wurden die folgenden Probleme geloest: - Unterdrueckung der Ozonbildung im Betrieb der Strahlungsquelle -Optimierung der Elektrodenanordnung - Optimierung des Elektrodenmaterials. Bei der Ansteuerung der Strahler muss beruecksichtigt werden, dass - die Versorgungsspannung eines Excimerstrahlers eine Wechselspannung mit einer Amplitude von ca. 2000 V und einer Frequenz groesser 100 kHz ist, - die Zuendspannung erheblich hoeher liegt als die Brennspannung im Dauerbetrieb, -der Arbeitspunkt der Brennspannung nach Betriebspausen an den aktuellen Lampenzustand angepasst werden muss. Dazu wurden eine Treiberschaltung sowie ein Verfahren und eine Schaltung zur automatischen Arbeitspunkteinstellung der Strahleransteuerung entwickelt. Das Ziel des Vorhabens bezueglich der SO_2-Messung wurde erreicht. Eine NO-Messung ist mit Excimer-UV-Strahlern nicht moeglich. Damit wurde das Vorhabensziel teilweise erreicht. (orig.)SIGLEAvailable from TIB Hannover: F99B42 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekArbeitsgemeinschaft Industrieller Forschungsvereinigungen e.V., Koeln (Germany); Bundesministerium fuer Wirtschaft, Bonn (Germany)DEGerman

Effects of rigosertib on the osteo-hematopoietic niche in myelodysplastic syndromes

Rigosertib is a novel multi-kinase inhibitor, which has clinical activity towards leukemic progenitor cells of patients with high-risk myelodysplastic syndromes (MDS) after failure or progression on hypomethylating agents. Since the bone marrow microenvironment plays an important role in MDS pathogenesis, we investigated the impact of rigosertib on cellular compartments within the osteo-hematopoietic niche. Healthy C57BL/6J mice treated with rigosertib for 3 weeks showed a mild suppression of hematopoiesis (hemoglobin and red blood cells, both - 16%, p < 0.01; white blood cells, - 34%, p < 0.05; platelets, - 38%, p < 0.05), whereas there was no difference in the number of hematopoietic stem cells in the bone marrow. Trabecular bone mass of the spine was reduced by rigosertib (- 16%, p = 0.05). This was accompanied by a lower trabecular number and thickness (- 6% and - 10%, respectively, p < 0.05), partly explained by the increase in osteoclast number and surface (p < 0.01). Milder effects of rigosertib on bone mass were detected in an MDS mouse model system (NHD13). However, rigosertib did not further aggravate MDS-associated cytopenia in NHD13 mice. Finally, we tested the effects of rigosertib on human mesenchymal stromal cells (MSC) in vitro and demonstrated reduced cell viability at nanomolar concentrations. Deterioration of the hematopoietic supportive capacity of MDS-MSC after rigosertib pretreatment demonstrated by decreased number of colony-forming units, especially in the monocytic lineage, further supports the idea of disturbed crosstalk within the osteo-hematopoietic niche mediated by rigosertib. Thus, rigosertib exerts inhibitory effects on the stromal components of the osteo-hematopoietic niche which may explain the dissociation between anti-leukemic activity and the absence of hematological improvement