Fragile X Messenger Ribonucleoprotein 1 (FMR1), a novel inhibitor of osteoblast/osteocyte differentiation, regulates bone formation, mass, and strength in young and aged male and female mice.

Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene mutations lead to fragile X syndrome, cognitive disorders, and, in some individuals, scoliosis and craniofacial abnormalities. Four-month-old (mo) male mice with deletion of the FMR1 gene exhibit a mild increase in cortical and cancellous femoral bone mass. However, consequences of absence of FMR1 in bone of young/aged male/female mice and the cellular basis of the skeletal phenotype remain unknown. We found that absence of FMR1 results in improved bone properties with higher bone mineral density in both sexes and in 2- and 9-mo mice. The cancellous bone mass is higher only in females, whereas, cortical bone mass is higher in 2- and 9-mo males, but higher in 2- and lower in 9-mo female FMR1-knockout mice. Furthermore, male bones show higher biomechanical properties at 2mo, and females at both ages. Absence of FMR1 increases osteoblast/mineralization/bone formation and osteocyte dendricity/gene expression in vivo/ex vivo/in vitro, without affecting osteoclasts in vivo/ex vivo. Thus, FMR1 is a novel osteoblast/osteocyte differentiation inhibitor, and its absence leads to age-, site- and sex-dependent higher bone mass/strength.

3D Interrelationship between Osteocyte Network and Forming Mineral during Human Bone Remodeling.

During bone remodeling, osteoblasts are known to deposit unmineralized collagenous tissue (osteoid), which mineralizes after some time lag. Some of the osteoblasts differentiate into osteocytes, forming a cell network within the lacunocanalicular network (LCN) of bone. To get more insight into the potential role of osteocytes in the mineralization process of osteoid, sites of bone formation are three-dimensionally imaged in nine forming human osteons using focused ion beam-scanning electron microscopy (FIB-SEM). In agreement with previous observations, the mineral concentration is found to gradually increase from the central Haversian canal toward pre-existing mineralized bone. Most interestingly, a similar feature is discovered on a length scale more than 100-times smaller, whereby mineral concentration increases from the LCN, leaving around the canaliculi a zone virtually free of mineral, the size of which decreases with progressing mineralization. This suggests that the LCN controls mineral formation but not just by diffusion of mineralization precursors, which would lead to a continuous decrease of mineral concentration from the LCN. The observation is, however, compatible with the codiffusion and reaction of precursors and inhibitors from the LCN into the bone matrix.

Biochemical mechanisms of dose-dependent cytotoxicity and ROS-mediated apoptosis induced by lead sulfide/graphene oxide quantum dots for potential bioimaging applications.

Colloidal quantum dots (CQD) have attracted considerable attention for biomedical diagnosis and imaging as well as biochemical analysis and stem cell tracking. In this study, quasi core/shell lead sulfide/reduced graphene oxide CQD with near infrared emission (1100 nm) were prepared for potential bioimaging applications. The nanocrystals had an average diameter of ~4 nm, a hydrodynamic size of ~8 nm, and a high quantum efficiency of 28%. Toxicity assay of the hybrid CQD in the cultured human mononuclear blood cells does not show cytotoxicity up to 200 µg/ml. At high concentrations, damage to mitochondrial activity and mitochondrial membrane potential (MMP) due to the formation of uncontrollable amounts of intracellular oxygen radicals (ROS) was observed. Cell membrane and Lysosome damage or a transition in mitochondrial permeability were also noticed. Understanding of cell-nanoparticle interaction at the molecular level is useful for the development of new fluorophores for biomedical imaging.