Development of osteoporosis severely complicates long-term glucocorticoid (GC) therapy. Using a Cre-transgenic mouse line, we now demonstrate that GCs are unable to repress bone formation in the absence of glucocorticoid receptor (GR) expression in osteoblasts as they become refractory to hormone-induced apoptosis, inhibition of proliferation, and differentiation. In contrast, GC treatment still reduces bone formation in mice carrying a mutation that only disrupts GR dimerization, resulting in bone loss in vivo, enhanced apoptosis, and suppressed differentiation in vitro. The inhibitory GC effects on osteoblasts can be explained by a mechanism involving suppression of cytokines, such as interleukin 11, via interaction of the monomeric GR with AP-1, but not NF-kappaB. Thus, GCs inhibit cytokines independent of GR dimerization and thereby attenuate osteoblast differentiation, which accounts, in part, for bone loss during GC therapy.

Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.

ECV measurement with CMR reflects myocardial collagen content in DCM. Therefore, CMR-based assessment of ECV may have the potential to serve as a non-invasive tool for the quantification of diffuse MF in order to monitor therapy response and aid risk stratification in different stages of DCM.

Almost 20 years after the invention of tissue engineering, autogenous bone grafting has remained the favored strategy for the treatment of bone defects. As an alternative, a vast variety of bone substitutes has been developed and is available for clinical use. The ongoing search for bone substitutes, however, reflects the limitations imposed to both autogenous and allogenous bone grafts as well as to bone substitute materials. The concept of tissue engineering holds great promise for the future treatment of osseous defects. Research in this interdisciplinary field is carried out to find a way of producing biologic substitutes as functional tissue replacement. For this, functionally active cells are applied on supporting scaffolds under controlled stimulation with growth factors. Scaffolds are temporary matrices for bone growth and provide a specific environment and architecture for tissue development. Ideally, scaffolds favor cellular attachment, growth and differentiation in vitro and in vivo. Especially ceramics and biodegradable polymers are widely used and have been tested in various animal studies. Yet, to allow for precise production of specific custom-made scaffolds, rapid prototyping (RP) techniques have recently drawn a lot of attention. Using these methods scaffolds with a predefined, well-controlled internal and external architecture mimicking the structure of natural bone can be generated. Although biocompatibility of the materials used in the process and the structural resolution that can be technically achieved so far limit the range of use, rapid manufacturing techniques do offer great opportunities to generate suitable scaffolds for bone tissue engineering in the near future.

Mast cells, important sensor and effector cells of the immune system, may influence bone metabolism as their number is increased in osteoporotic patients. They are also present during bone fracture healing with currently unknown functions. Using a novel c-Kit-independent mouse model of mast cell deficiency, we demonstrated that mast cells did not affect physiological bone turnover. However, they triggered local and systemic inflammation after fracture by inducing release of inflammatory mediators and the recruitment of innate immune cells. In later healing stages, mast cells accumulated and regulated osteoclast activity to remodel the bony fracture callus. Furthermore, they were essential to induce osteoclast formation after ovariectomy. Additional in vitro studies revealed that they promote osteoclastogenesis via granular mediators, mainly histamine. In conclusion, mast cells are redundant in physiologic bone turnover but exert crucial functions after challenging the system, implicating mast cells as a potential target for treating inflammatory bone disorders. © 2017 American Society for Bone and Mineral Research.

These results indicate that estrogen seems to be an important factor in all stages of fracture healing. The application of estrogens enhances fracture healing of long bones at least in mice.

BackgroundClock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype.Methodology/Principal FindingsWe found that Per2Brdm1 mutant mice as well as mice lacking Cry2−/− displayed significantly increased bone volume at 12 weeks of age, when bone turnover is high. Per2Brdm1 mutant mice showed alterations in parameters specific for osteoblasts whereas mice lacking Cry2−/− displayed changes in osteoclast specific parameters. Interestingly, inactivation of both Per2 and Cry2 genes leads to normal bone volume as observed in wild type animals. Importantly, osteoclast parameters affected due to the lack of Cry2, remained at the level seen in the Cry2−/− mutants despite the simultaneous inactivation of Per2.Conclusions/SignificanceThis indicates that Cry2 and Per2 affect distinct pathways in the regulation of bone volume with Cry2 influencing mostly the osteoclastic cellular component of bone and Per2 acting on osteoblast parameters.

Taken together, our data provide the first complete histomorphometric analysis from NF1 patients. Moreover, they suggest that low vitamin D levels significantly contribute to the skeletal defects associated with the disease.