Excessive growth hormone promotes joint degeneration and chondrocyte metabolic dysfunction in mice

YesMany patients with acromegaly, a hormonal disorder with excessive growth hormone (GH), report pain in joints. The objective of this study is to characterize the joint pathology of mice with over-expression of either bovine GH (bGH) or a GH receptor antagonist (GHa). We also investigate the effect of GH on regulation of chondrocyte cellular metabolism. Knee joints from mice over-expressing bGH or GHa and WT were histologically and μCT analyzed for OA pathologies. Additionally, cartilage from bGH mice was used for metabolomics. Mouse primary chondrocytes from WT or bGH mice with or without Pegvisomant (Peg) treatment were used for Q-PCR and Seahorse Respirometry analysis. Both male and female bGH mice at ~13 months had increased knee joint degeneration, which is characterized by loss of cartilage structure, expansion of hypertrophic chondrocytes, synovitis, and subchondral plate thinning. The joint pathologies were also demonstrated by significantly higher OARSI and Mankin scores in bGH compared with WT mice. Metabolomics revealed changes of a wide range of metabolic pathways in bGH mice including beta-alanine metabolism, tryptophan metabolism, lysine degradation, and ascorbate and aldarate metabolism. Also, bGH chondrocytes upregulated fatty acid oxidation (FAO) and increased expression of Col10a. Joints of GHa mice are remarkably protected from developing age-associated joint degeneration with smooth articular joint surface. These studies uncover that an excessive amount of GH promotes joint degeneration in mice, whereas antagonizing GH action through a GHa protects mice from OA development, which is associated with chondrocyte metabolic dysfunction and hypertrophic changes

<em>Tbx15</em> defines a glycolytic subpopulation and white adipocyte heterogeneity.

Tbx15 is a member of the T-box gene family of mesodermal developmental genes. We have recently shown that Tbx15 plays a critical role in the formation and metabolic programming of glycolytic myofibers in skeletal muscle. Tbx15 is also differentially expressed among white adipose tissue (WAT) in different body depots. In the current study, using three independent methods, we show that even within a single WAT depot, high Tbx15 expression is restricted to a subset of preadipocytes and mature white adipocytes. Gene expression and metabolic profiling demonstrate that the Tbx15(Hi) preadipocyte and adipocyte subpopulations of cells are highly glycolytic, whereas Tbx15(Low) preadipocytes and adipocytes in the same depot are more oxidative and less glycolytic. Likewise, in humans, expression of TBX15 in subcutaneous and visceral WAT is positively correlated with markers of glycolytic metabolism and inversely correlated with obesity. Furthermore, overexpression of Tbx15 is sufficient to reduce oxidative and increase glycolytic metabolism in cultured adipocytes. Thus, Tbx15 differentially regulates oxidative and glycolytic metabolism within subpopulations of white adipocytes and preadipocytes. This leads to a functional heterogeneity of cellular metabolism within WAT that has potential impact in the understanding of human metabolic diseases

Time Analysis of the Three Characteristic Behaviours of Dual-Porosity Media. I: Fluid Flow and Solute Transport

International audienceHomogenisation of consolidation and compressible fluid flow in dual-porosity media has highlighted the existence of three characteristic macroscopic behaviours. These three behaviours are, namely, a dual-porosity description which includes memory effects, a single-porosity description with which the micro-porosity is simply ignored, and an intermediate behaviour which we refer as behaviour with reservoir effect. With this latter, the whole dual-porosity medium is represented by an equivalent single-porosity medium. In contrast with a single-porosity behaviour, the porosity of the entire dual-porosity medium is accounted for. During solute transport in dual-porosity media, while memory effects are most often experimentally observed, the homogenised model obtained for the most general values of the involved parameters leads to a model with reservoir effect. Therefore, the observed memory effects are not reproduced by this model and a clear interpretation of the origins of these effects remains an unresolved issue. The work is presented in two complementary articles. The objective of the present paper is, firstly, to determine a physical interpretation of the existence of the three characteristic behaviours of dual-porosity media. This is performed by exploring the homogenised models and their domains of validity for the analogy of heat conduction in a dual-conductivity composite. This leads to the original result that consists to relate each type of behaviour to a specific relationship between two characteristic times. This is then used for interpreting the results obtained for compressible flow in dual-porosity media. Finally, it allows to elucidate the conditions under which memory effects may occur during solute transport in dual-porosity media