Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat

The African naked mole-rat’s ($\textit{Heterocephalus glaber}$) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.Work was supported aEuropean Research Council (294678), the Deutsche Forschungsgemeinschaft SFB 665 and Go865/9-1, NSF (grant #0744979 ), NIH (grants HL71626 and HL606

Hypoxia activates the PTHrP-MEF2C pathway to attenuate hypertrophy in mesenchymal stem cell derived cartilage

Articular cartilage lacks an intrinsic repair capacity and due to the ability of mesenchymal stem cells (MSCs) to differentiate into chondrocytes, MSCs have been touted as a cellular source to regenerate damaged cartilage. However, a number of prevailing concerns for such a treatment remain. Generally, administration of MSCs into a cartilage defect results in poor regeneration of the damaged cartilage with the repaired cartilage consisting primarily of fibro-cartilage rather than hyaline cartilage. Methods that improve the chondrogenic potential of transplanted MSCs in vivo may be advantageous. In addition, the proclivity of MSC-derived cartilage to undergo hypertrophic differentiation or form bone in vivo also remains a clinical concern. If MSC-derived cartilage was to undergo hypertrophic differentiation in vivo, this would be deleterious in a clinical setting. This study focuses on establishing a mechanism of action by which hypoxia or low oxygen tension can be used to both enhance chondrogenesis and attenuate hypertrophic differentiation of both MSC and ATDC5 derived chondrocytes. Having elucidated a novel mechanism of action, the subsequent goals of this study were to develop an in vitro culture regime to mimic the beneficial effects of physiological low oxygen tension in a normoxic environment.Science Foundation Ireland (SFI 09/SRC/B1794) and FP7 Health (223298).peer-reviewe

INJURY TO THE GLENOHUMERAL CAPSULE DURING ANTERIOR DISLOCATION RESULTS IN DAMAGE TO THE ANTEROINFERIOR CAPSULE SBC2011-53840

INTRODUCTION The glenohumeral joint is the most frequently dislocated major joint in the body with about 2% of the population dislocating their shoulders between the ages of 18 and 70 MATERIALS AND METHODS Six fresh-frozen cadaveric shoulders were dissected down to the glenohumeral capsule. The scapula and humerus were potted in epoxy putty, and a 7x11 grid of strain markers was adhered to the anteroinferior capsule using cyanoacrylate. The markers were positioned on the glenohumeral capsule as previously described The joint was placed at 60° of external rotation (and 60° glenohumeral abduction) and an anterior dislocation was simulated by translating the humerus at least half of the largest anterior-posterior width of the glenoid in the anterior direction using a robotic/universal force-moment sensor testing system. The joint was allowed to translate in 3 degrees of freedom during this motion, but its orientation was fixed. The positions of the markers at dislocation were recorded. After a 30 minute recovery period, the specimen was returned to the reference strain configuration and the positions of the markers were recorded again (non-recoverable strain state). The positions of the markers for the reference strain state, at dislocation and in the nonrecoverable strain state were then input to a finite element analysis package (ABAQUS, Abaqus, Inc.) to calculate the maximum principle strains in all 60 elements of the glenohumeral capsule. A previous study determined the repeatability of the entire testing procedure to be ±3.5% for maximum principle strains The elements of the glenohumeral capsule were then divided into four sub-regions: anterior band glenoid side, anterior band humeral side, axillary pouch glenoid side, and axillary pouch humeral side. The average strains were determined for each sub-region at dislocation and in the non-recoverable strain state. A paired t-test was used to compare the average strain in the glenoid and humeral sub-regions in both the anterior band and axillary pouch. Significance was set at α = 0.05. RESULTS In general, the glenoid side of the capsule experienced higher strains at dislocation than the humeral side ( INJURY TO THE GLENOHUMERAL CAPSULE DURING ANTERIOR DISLOCATION RESULTS IN DAMAGE TO THE ANTEROINFERIOR CAPSULE DISCUSSION In this study, we have determined the strain distribution in the glenohumeral capsule during anterior dislocation of the glenohumeral joint, as well as the non-recoverable strain. Greater strains were found on the glenoid side of the capsule compared to the humeral side in both regions. The amount of non-recoverable strain was not significantly different between the glenoid and humeral sides. Thus, the magnitude of injury throughout the anteroinferior capsule due to anterior dislocation is similar, and is not localized to any specific subregion. Therefore, surgeons should consider plicating the entire anteroinferior capsule when performing repair procedures following anterior dislocation. Malicky and coworkers found similar magnitudes of nonrecoverable strain, even though they only subluxed the glenohumeral joint [3]. Therefore, the magnitude of translation required for subluxation was probably close to our definition of dislocation, and this experimental injury model is reasonable for producing injury to the capsule. The definition of dislocation used in the current study moved the humeral head out of the glenoid, but did not push it over the rim, thus allowing the robotic/universal force-moment sensor testing system to repeat this motion without damaging other structures. During the experimental protocol, only the strains in the midsubstance of the capsule were measured. Therefore, higher strains could have occurred near the insertion sites. In addition, injury to the capsule may have occurred during dislocation in regions outside our strain marker grid. Future studies will determine the mechanical properties of the injured capsule from this study and compare them to the normal capsule. ACKNOWLEDGMENT

Hypoxia activates the PTHrP-MEF2C pathway to attenuate hypertrophy in mesenchymal stem cell derived cartilage

Articular cartilage lacks an intrinsic repair capacity and due to the ability of mesenchymal stem cells (MSCs) to differentiate into chondrocytes, MSCs have been touted as a cellular source to regenerate damaged cartilage. However, a number of prevailing concerns for such a treatment remain. Generally, administration of MSCs into a cartilage defect results in poor regeneration of the damaged cartilage with the repaired cartilage consisting primarily of fibro-cartilage rather than hyaline cartilage. Methods that improve the chondrogenic potential of transplanted MSCs in vivo may be advantageous. In addition, the proclivity of MSC-derived cartilage to undergo hypertrophic differentiation or form bone in vivo also remains a clinical concern. If MSC-derived cartilage was to undergo hypertrophic differentiation in vivo, this would be deleterious in a clinical setting. This study focuses on establishing a mechanism of action by which hypoxia or low oxygen tension can be used to both enhance chondrogenesis and attenuate hypertrophic differentiation of both MSC and ATDC5 derived chondrocytes. Having elucidated a novel mechanism of action, the subsequent goals of this study were to develop an in vitro culture regime to mimic the beneficial effects of physiological low oxygen tension in a normoxic environment.Science Foundation Ireland (SFI 09/SRC/B1794) and FP7 Health (223298)

3D bioprinting spatiotemporally defined patterns of growth factors to tightly control tissue regeneration

Contains fulltext : 229012.pdf (publisher's version ) (Open Access)Therapeutic growth factor delivery typically requires supraphysiological dosages, which can cause undesirable off-target effects. The aim of this study was to 3D bioprint implants containing spatiotemporally defined patterns of growth factors optimized for coupled angiogenesis and osteogenesis. Using nanoparticle functionalized bioinks, it was possible to print implants with distinct growth factor patterns and release profiles spanning from days to weeks. The extent of angiogenesis in vivo depended on the spatial presentation of vascular endothelial growth factor (VEGF). Higher levels of vessel invasion were observed in implants containing a spatial gradient of VEGF compared to those homogenously loaded with the same total amount of protein. Printed implants containing a gradient of VEGF, coupled with spatially defined BMP-2 localization and release kinetics, accelerated large bone defect healing with little heterotopic bone formation. This demonstrates the potential of growth factor printing, a putative point of care therapy, for tightly controlled tissue regeneration