👤 A W Vogl

The association between metabolic syndrome (MetS) and osteoarthritis (OA) development has become increasingly recognized. In this context, the exact role of cholesterol and cholesterol-lowering therapies in OA development has remained elusive. Recently, we did not observe beneficial effects of intensive cholesterol-lowering treatments on spontaneous OA development in E3L.CETP mice. We postulated that in the presence of local inflammation caused by a joint lesion, cholesterol-lowering therapies may ameliorate OA pathology. Female ApoE3∗Leiden.CETP mice were fed a cholesterol-supplemented Western type diet. After 3 weeks, half of the mice received intensive cholesterol-lowering treatment consisting of atorvastatin and the anti-PCSK9 antibody alirocumab. Three weeks after the start of the treatment, OA was induced via intra-articular injections of collagenase. Serum levels of cholesterol and triglycerides were monitored throughout the study. Knee joints were analyzed for synovial inflammation, cartilage degeneration, subchondral bone sclerosis and ectopic bone formation using histology. Inflammatory cytokines were determined in serum and synovial washouts. Cholesterol-lowering treatment strongly reduced serum cholesterol and triglyceride levels. Mice receiving cholesterol-lowering treatment showed a significant reduction in synovial inflammation (P = 0.008, WTD: 95% CI: 1.4- 2.3; WTD + AA: 95% CI: 0.8- 1.5) and synovial lining thickness (WTD: 95% CI: 3.0-4.6, WTD + AA: 95% CI: 2.1-3.2) during early-stage collagenase-induced OA. Serum levels of S100A8/A9, MCP-1 and KC were significantly reduced after cholesterol-lowering treatment (P = 0.0005, 95% CI: -46.0 to -12.0; P = 2.8 × 10 This study shows that intensive cholesterol-lowering treatment reduces joint inflammation after induction of collagenase-induced OA, but this did not reduce end stage pathology in female mice. Show less

Enteroendocrine cells relay energy-derived signals to immune cells to signal states of nutrient abundance and control immunometabolism. Emerging data suggest that the gut-derived nutrient-induced incretin glucose-dependent insulinotropic polypeptide (GIP) operates at the interface of metabolism and inflammation. Here we show that high-fat diet (HFD)-fed mice with immune cell-targeted GIP receptor (GIPR) deficiency exhibit greater weight gain, insulin resistance, hepatic steatosis and significant myelopoiesis concomitantly with impaired energy expenditure and inguinal white adipose tissue (WAT) beiging. Expression of the S100 calcium-binding protein S100A8 was increased in the WAT of mice with immune cell-targeted GIPR deficiency and co-deletion of GIPR and the heterodimer S100A8/A9 in immune cells ameliorated the aggravated metabolic and inflammatory phenotype following a HFD. Specific GIPR deletion in myeloid cells identified this lineage as the target of GIP effects. Furthermore, GIP directly downregulated S100A8 expression in adipose tissue macrophages. Collectively, our results identify a myeloid-GIPR-S100A8/A9 signalling axis coupling nutrient signals to the control of inflammation and adaptive thermogenesis. Show less

Study of Sertoli cells of the ground squirrel provides a unique opportunity to examine cell structure and function. The cells are large, have an elaborate cytoskeleton, and undergo dramatic changes in organization during spermatogenesis. Microtubules (MTs) are prominent elements of the cytoskeleton and appear to be associated structurally with many of the events that occur during sperm production. To investigate the function of MTs, animals were injected subcutaneously with colchicine, and their seminiferous epithelia examined by light and electron microscopy. Some animals were injected with 30--80 mg of the drug per kg body weight and sacrificed 3 to 5 hr later. Others were given 0.3 mg/kg/day for 6 days and processed on day 7. Virtually no MTs were seen in Sertoli cells after short-term treatments, and their numbers were greatly reduced after the long-term injections. Intermediate filaments were very evident throughout the cytoplasm of treated cells, particularly in the short-term studies. Moreover, a close association of some of these filaments with centrioles was observed. In all cases, elongate spermatids which normally move apically did not do so. Indeed, some spermatids appear to have been pulled to a basal position after having moved apically prior to treatment. Also, smooth endoplasmic reticulum (SER) accumulated basally in the Sertoli cell, unlike controls, and the acrosomes of late spermatids developed abnormally or did not complete their shape changes. Cell junctions appeared normal and sperm release was observed. In conclusion, our data suggest that Sertoli cell MTs are necessary for the normal development and translocation of spermatids in the seminiferous epithelium and are involved with positional changes in Sertoli cell SER. They do not appear essential for the maintenance of cell junctions. Show less

Sertoli cells of the ground squirrel (Spermophilus lateralis), a seasonal breeder, were examined by light and electron microscopy and their structure, particularly the organization of the cytoskeleton, was related to events that occur in the seminiferous epithelium during spermatogenesis. Among the events considered and described are the apical movement of elongate spermatids, withdrawal of residual cytoplasm from germ cells, transport of smooth endoplasmic reticulum (SER) between the base and apex of the Sertoli cells, and sperm release. These events are dramatically evident in this species because the seminiferous epithelium is thin, i.e., there are few germ cells, and both the germ cells and Sertoli cells are large. Sertoli cells of the ground squirrel have a remarkably well developed cytoskeleton. Microfilaments occur throughout the cell but are most evident in ectoplasmic specializations associated with junctions. Intermediate filaments occur around the nucleus, as a layer at the base of the cell, and adjacent to desmosome-like junctions with germ cells. Intermediate filaments, together with microtubules, are also abundant in regions of the cell involved with the transport of SER, in cytoplasm associated with elongate spermatids, and in processes that extend into the residual cytoplasm of germ cells. Our observations of ultrastructure are consistent with the hypothesis that Sertoli cell microtubules are involved with the movement of germ cells within the seminiferous epithelium, and further implicate these structures as possibly playing a role in the retraction of residual cytoplasm from germ cells and the intracellular transport of SER. The abundance and organization of intermediate filaments suggest that these cytoskeletal elements may also be involved with events that occur during spermatogenesis. Show less