Osteoarthritis is one of the most common forms of musculoskeletal disease and the most prominent type of arthritis encountered in all countries. Although great efforts have been made to investigate cartilage biology and osteoarthritis pathology, the treatment has lagged behind that of other arthritides, as there is a lack of effective disease-modifying therapies. Numerous approaches for dealing with cartilage degradation have been tried, but enjoyed very little success to develop approved OA treatments with not only symptomatic improvement but also structure-modifying effect. In this review we discuss the most recent findings regarding the regulation of cartilage biology and pathology and highlight their potential therapeutic values.
Unraveling the mechanisms involved in chemotactic navigation of immune cells is of particular interest for the development of new immunoregulatory therapies. It is generally agreed upon that members of the classical transient receptor potential channel family (TRPC) are involved in chemotaxis. However, the regulatory role of TRPC channels in chemoattractant receptor-mediated signaling has not yet been clarified in detail. In this study, we demonstrate that the TRPC6 channels play a pronounced role in CXCR2-mediated intermediary chemotaxis, whereas N-formyl-methionine-leucine-phenylalanine receptor–mediated end-target chemotaxis is TRPC6 independent. The knockout of TRPC6 channels in murine neutrophils led to a strongly impaired intermediary chemotaxis after CXCR2 activation which is not further reinforced by CXCR2, PI3K, or p38 MAPK inhibition. Furthermore, CXCR2-mediated Ca2+ influx but not Ca2+ store release was attenuated in TRPC6−/− neutrophils. We demonstrate that the TRPC6 deficiency affected phosphorylation of AKT and MAPK downstream of CXCR2 receptor activation and led to altered remodeling of actin. The relevance of this TRPC6-depending defect in neutrophil chemotaxis is underscored by our in vivo findings. A nonseptic peritoneal inflammation revealed an attenuated recruitment of neutrophils in the peritoneal cavity of TRPC6−/− mice. In summary, this paper defines a specific role of TRPC6 channels in CXCR2-induced intermediary chemotaxis. In particular, TRPC6-mediated supply of calcium appears to be critical for activation of downstream signaling components.
Hypercalcemia of malignancy is the most common cause of hypercalcemia in the inpatient setting. The evaluation of these cases should consider ectopic production of calcitriol a cause of hypercalcemia.
The formation of osteoclasts involves a sequence of cellular events including monocyte migration towards each other, cell-cell contacts and fusion to multinucleated cells. Given that TRPC1 has a pivotal role in these specifi c processes in other cell types, the authors investigated the role of TRPC1 in osteoclastogenesis and studied the skeletal phenotype of TRPC1 −/− mice under physiological conditions as well as using an animal model of postmenopausal osteoporosis. For all in vitro experiments, bone marrow macrophages were isolated from TRPC1 −/− mice and corresponding wild type (WT) controls and were cultured in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor κ-B ligand. Osteoclast-like cells were characterised by staining for tartrate-resistant acid phosphatase (TRAP). Using quantitative real-time PCR mRNA levels of TRPC1 and NFATC1 were analysed. Time-lapse videomicroscopy was used to study osteoclast migration and fusion. The intracellular Ca 2+ concentration of osteoclasts was measured ratiometrically with the fl uorescent Ca 2+ dye Fura-2. The skeletal phenotype of 16-week old mice was investigated by μCT-analyses of trabecular bone in the lumbar spine. Ovariectomy was performed on 12-week old sex-and aged-matched littermates as a model for human postmenopausal bone loss. PCR analyses indicate that TRPC1 is hardly expressed in monocytes and preosteoclasts but gets upregulated during osteoclastdifferentiation. In osteoclast formation assays, the loss of TRPC1 leads to impaired osteoclast differentiation with a 75% reduction in large osteoclasts. While μCT analysis revealed no differences in bone phenotype of TRPC1 −/− mice compared to WT mice under physiological conditions, there were signifi cant effects in the ovariectomy model of estrogen-defi ciency mediated bone loss. In this model, TRPC1 −/− mice exhibited a reduced loss of trabecular bone volume (−28.9% in WT compared to −13.1% in TRPC1 −/− ) and BTD (−3.2% in WT compared to +0.9% in TRPC1 −/− ) in LW5. Analysing the underlying signaling pathways, the authors found no differences in Ca 2+ -oscillations and store-operated calcium entries and no differences in NFATC1 expression. In time-lapse microscopy, however, the authors observed a reduced capacity of TRPC1 −/− osteoclast precursors to migrate and to fuse, due to a reduced velocity, translocation and a reduced increase of cell area over time. These results indicate that TRPC1 dependent pathways contribute to the migration and fusion of osteoclasts and that the loss of TRPC1 while not affecting physiological bone turnover has a clear effect on accelerated bone loss as seen in estrogen defi ciency. Therefore, these data suggest that TRPC1 may be a new therapeutic target for rapid osteoporotic bone loss. on 11 April 2019 by guest. Protected by copyright.
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