Thermal stress induces glycolytic beige fat formation via a myogenic state.

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of β-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival

TGF-β Inducible Early Gene 1 Regulates Osteoclast Differentiation and Survival by Mediating the NFATc1, AKT, and MEK/ERK Signaling Pathways

TGF-β Inducible Early Gene-1 (TIEG1) is a Krüppel-like transcription factor (KLF10) that was originally cloned from human osteoblasts as an early response gene to TGF-β treatment. As reported previously, TIEG1−/− mice have decreased cortical bone thickness and vertebral bone volume and have increased spacing between the trabeculae in the femoral head relative to wildtype controls. Here, we have investigated the role of TIEG1 in osteoclasts to further determine their potential role in mediating this phenotype. We have found that TIEG1−/− osteoclast precursors differentiated more slowly compared to wildtype precursors in vitro and high RANKL doses are able to overcome this defect. We also discovered that TIEG1−/− precursors exhibit defective RANKL-induced phosphorylation and accumulation of NFATc1 and the NFATc1 target gene DC-STAMP. Higher RANKL concentrations reversed defective NFATc1 signaling and restored differentiation. After differentiation, wildtype osteoclasts underwent apoptosis more quickly than TIEG1−/− osteoclasts. We observed increased AKT and MEK/ERK signaling pathway activation in TIEG1−/− osteoclasts, consistent with the roles of these kinases in promoting osteoclast survival. Adenoviral delivery of TIEG1 (AdTIEG1) to TIEG1−/− cells reversed the RANKL-induced NFATc1 signaling defect in TIEG1−/− precursors and eliminated the differentiation and apoptosis defects. Suppression of TIEG1 with siRNA in wildtype cells reduced differentiation and NFATc1 activation. Together, these data provide evidence that TIEG1 controls osteoclast differentiation by reducing NFATc1 pathway activation and reduces osteoclast survival by suppressing AKT and MEK/ERK signaling

Application of disease system analysis to osteoporosis: From temporal to spatio-temporal assessment of disease progression and intervention

Osteoporosis (OP) is a progressive bone disorder regarded as an important worldwide health issue. OP is characterised by a slow reduction of the bone matrix and changes in the bone matrix properties. Novel drug treatments are continuously developed to reduce the risk of bone fractures. Assessing the effects of novel and existing treatments on OP can be challenging. This is due to the difficulties of establishing the effects of the drug on the disease progression as reflected in the slowly changing bone mineral density (BMD). In recent years, our understanding of the pathophysiology of OP has considerably improved. Biomarkers reflecting bone physiology have been identified at the cellular, tissue and organ levels. Cellular biomarkers reflect the dynamics of bone remodelling (i.e., bone formation and resorption) on a short time scale. On the other hand, tissue and organ scale biomarkers show changes of BMD and bone structural arrangements on a larger time scale. Biomarkers can be used to characterise bone remodelling and to quantify the effect of the drug on OP. Recently, the concept of disease system analysis (DSA) has been proposed as a novel approach to quantitatively characterise drug effects on disease progression. This approach integrates physiology, disease progression and drug treatment in a comprehensive mechanism-based modelling framework using a large amount of complementary biomarker data. This chapter will provide an overview of the use of DSA to characterise drug effects on OP. We will review classical (i.e., non-mechanistic) pharmacokinetic-pharmacodynamic (PK/PD) models used to study drug dose-effect responses. Latest mechanistic bone remodelling models will be presented together with the study of the effect of the drug denosumab on disease progression in postmenopausal osteoporosis (PMO). Finally, we will provide an outlook on how to extend the temporal mechanistic model towards a spatio-temporal description. We conclude that the development of fully mechanistic disease system models of OP has great potential to adequately predict the long-term effects of drug treatments on clinical outcomes. This may provide a means for patient-specific estimation of bone fracture risk

Interstitial fluid flow in canaliculi as a mechanical stimulus for cancellous bone remodeling: in silico validation

Cancellous bone has a dynamic 3-dimensional architecture of trabeculae, the arrangement of which is continually reorganized via bone remodeling to adapt to the mechanical environment. Osteocytes are currently believed to be the major mechanosensory cells and to regulate osteoclastic bone resorption and osteoblastic bone formation in response to mechanical stimuli. We previously developed a mathematical model of trabecular bone remodeling incorporating the possible mechanisms of cellular mechanosensing and intercellular communication in which we assumed that interstitial fluid flow activates the osteocytes to regulate bone remodeling. While the proposed model has been validated by the simulation of remodeling of a single trabecula, it remains unclear whether it can successfully represent in silico the functional adaptation of cancellous bone with its multiple trabeculae. In the present study, we demonstrated the response of cancellous bone morphology to uniaxial or bending loads using a combination of our remodeling model with the voxel finite element method. In this simulation, cancellous bone with randomly arranged trabeculae remodeled to form a well-organized architecture oriented parallel to the direction of loading, in agreement with the previous simulation results and experimental findings. These results suggested that our mathematical model for trabecular bone remodeling enables us to predict the reorganization of cancellous bone architecture from cellular activities. Furthermore, our remodeling model can represent the phenomenological law of bone transformation toward a locally uniform state of stress or strain at the trabecular level