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Introduction Synthetic glucocorticoids (GCs), acting as antiinflammatory and immunomodulatory agents, are the mainstays in the treatment of immune-related disorders (e.g., rheumatoid arthritis and Graves' disease). GCs are also prescribed to [...], Elevated bone resorption and diminished bone formation have been recognized as the primary features of glucocorticoid-associated skeletal disorders. However, the direct effects of excess glucocorticoids on bone turnover remain unclear. Here, we explored the outcomes of exogenous glucocorticoid treatment on bone loss and delayed fracture healing in mice and found that reduced bone turnover was a dominant feature, resulting in a net loss of bone mass. The primary effect of glucocorticoids on osteogenic differentiation was not inhibitory; instead, they cooperated with macrophages to facilitate osteogenesis. Impaired local nutrient status--notably, obstructed fatty acid transportation--was a key factor contributing to glucocorticoid-induced impairment of bone turnover in vivo. Furthermore, fatty acid oxidation in macrophages fueled the ability of glucocorticoid-liganded receptors to enter the nucleus and then promoted the expression of BMP2, a key cytokine that facilitates osteogenesis. Metabolic reprogramming by localized fatty acid delivery partly rescued glucocorticoid-induced pathology by restoring a healthier immune-metabolic milieu. These data provide insights into the multifactorial metabolic mechanisms by which glucocorticoids generate skeletal disorders, thus suggesting possible therapeutic avenues.

In the ancient Chinese recipe for composite mortar used in the construction of ground layers for architectural painting, the mixture of porcine blood and lime water is one of the constituent materials. Herein, according to the traditional recipe, the interaction between porcine blood and lime water was systematically and deeply investigated. The experimental investigation demonstrated that porcine blood mixed with lime water at the ratio found in the recipe can form a hydrogel with a hydrophobic surface. During air-drying, the lime water in porcine blood hydrogel can react with CO2 to form calcium carbonate. The crystal morphology of the formed calcium carbonate depends on the surrounding micro-environment of calcium ions in the porcine blood hydrogel. The formed morphology of calcium carbonate includes small calcite crystallites, small graininess calcite crystals with round features, calcite aggregates with layered ladder-like structures, and amorphous calcium carbonate (ACC). Interestingly, the calcium carbonate formed in the inner part of the porcine blood hydrogel exhibits lamellar distribution due to a Liesegang pattern formation. Based on the findings that the porcine blood hydrogel has surface hydrophobicity and brittleness, it can be predicted that in the preparation process of composite mortar for ancient building color painting base course, porcine blood used in the form of a hydrogel is not only easier to be dispersed in hydrophobic tung oil than in liquid porcine blood but also the affinity between porcine blood gel and tung oil is enhanced. As constituent material dispersed in the composite mortar, the layered distribution of calcium carbonate in the porcine blood hydrogel may presumably be beneficial to reduce the internal stress of the composite mortar material. [ABSTRACT FROM AUTHOR]

Author(s): Yifeng Zhang [1]; Jiankun Xu [1]; Ye Chun Ruan [2]; Mei Kuen Yu [2]; Micheal O'Laughlin [1]; Helen Wise [3]; Di Chen [4]; Li Tian [1]; Dufang Shi [1]; [...], Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-[alpha] (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.

Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in [...]