Dataset Information

Interleukin 17A: a Janus-faced regulator of osteoporosis.

ABSTRACT: Interleukin (IL)-17A is a well-described mediator of bone resorption in inflammatory diseases, and postmenopausal osteoporosis is associated with increased serum levels of IL-17A. Ovariectomy (OVX) can be used as a model to study bone loss induced by estrogen deficiency and the role of IL-17A in osteoporosis development has previously been investigated using various methods to inhibit IL-17A signaling in this model. However, the studies show opposing results. While some publications reported IL-17A as a mediator of OVX-induced osteoporosis, others found a bone-protective role for IL-17 receptor signaling. In this study, we provide an explanation for the discrepancies in previous literature and show for the first time that loss of IL-17A has differential effects on OVX-induced osteoporosis; with IL-17A being important for cortical but not trabecular bone loss. Interestingly, the decrease in trabecular bone after OVX in IL-17A knock-out mice, was accompanied by increased adipogenesis depicted by elevated leptin levels. Additionally, the bone marrow adipose tissue expanded, and the bone-turnover decreased in ovariectomized mice lacking IL-17A compared to ovariectomized WT mice. Our results increase the understanding of how IL-17A signaling influences bone remodeling in the different bone compartments, which is of importance for the development of new treatments of post-menopausal osteoporosis.

SUBMITTER: Scheffler JM

PROVIDER: S-EPMC7105470 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Interleukin 17A: a Janus-faced regulator of osteoporosis.

Scheffler J M JM Grahnemo L L Engdahl C C Drevinge C C Gustafsson K L KL Corciulo C C Lawenius L L Iwakura Y Y Sjögren K K Lagerquist M K MK Carlsten H H Ohlsson C C Islander U U

Scientific reports 20200330 1

Interleukin (IL)-17A is a well-described mediator of bone resorption in inflammatory diseases, and postmenopausal osteoporosis is associated with increased serum levels of IL-17A. Ovariectomy (OVX) can be used as a model to study bone loss induced by estrogen deficiency and the role of IL-17A in osteoporosis development has previously been investigated using various methods to inhibit IL-17A signaling in this model. However, the studies show opposing results. While some publications reported IL- ...[more]

PMID: 32231224

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Project description:Antibiotics are miracle drugs that can cure infectious bacterial diseases. However, their utility is challenged by antibiotic-resistant bacteria emerging in clinics and straining modern medicine and our ways of life. Certain bacteria such as Gram-negative (Gram(-)) and Mycobacteriales species are intrinsically resistant to most clinical antibiotics and can further gain multidrug resistance through mutations and plasmid acquisition. These species stand out by the presence of an additional external lipidic membrane, the outer membrane (OM), that is composed of unique glycolipids. Although formidable, the OM is a passive permeability barrier that can reduce penetration of antibiotics but cannot affect intracellular steady-state concentrations of drugs. The two-membrane envelopes are further reinforced by active efflux transporters that expel antibiotics from cells against their concentration gradients. The major mechanism of antibiotic resistance in Gram(-) pathogens is the active efflux of drugs, which acts synergistically with the low permeability barrier of the OM and other mutational and plasmid-borne mechanisms of antibiotic resistance.The synergy between active efflux and slow uptake offers Gram(-) bacteria an impressive degree of protection from potentially harmful chemicals, but it is also their Achilles heel. Kinetic studies have revealed that even small changes in the efficiency of either of the two factors can have dramatic effects on drug penetration into the cell. In line with these expectations, two major approaches to overcome this antibiotic resistance mechanism are currently being explored: (1) facilitation of antibiotic penetration across the outer membranes and (2) avoidance and inhibition of clinically relevant multidrug efflux pumps. Herein we summarize the progress in the latter approach with a focus on efflux pumps from the resistance-nodulation-division (RND) superfamily. The ability to export various substrates across the OM at the expense of the proton-motive force acting on the inner membrane and the engagement of accessory proteins for their functions are the major mechanistic advantages of these pumps. Both the RND transporters and their accessory proteins are being targeted in the discovery of efflux pump inhibitors, which in combination with antibiotics can potentiate antibacterial activities. We discuss intriguing relationships between substrates and inhibitors of efflux pumps, as these two types of ligands face similar barriers and binding sites in the transporters and accessory proteins and both types of activities often occur with the same chemical scaffold. Several distinct chemical classes of efflux inhibitors have been discovered that are as structurally diverse as the substrates of efflux pumps. Recent mechanistic insights, both empirical and computational, have led to the identification of features that distinguish OM permeators and efflux pump avoiders as well as efflux inhibitors from substrates. These findings suggest a path forward for optimizing the OM permeation and efflux-inhibitory activities in antibiotics and other chemically diverse compounds.

Dataset Information

Interleukin 17A: a Janus-faced regulator of osteoporosis.

Publications

Interleukin 17A: a Janus-faced regulator of osteoporosis.

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