Glucocorticoid-Induced Osteoporosis – A Disorder of Mesenchymal Stromal Cells?

Glucocorticoids are a class of steroid hormones that are essential to life but cause serious harm in excess. The main clinical features of glucocorticoid excess are due to adverse effects on cells and tissues that arise from a common developmental precursor – the mesenchymal stromal cell (MSC; sometimes referred to as the mesenchymal stem cell). Interestingly glucocorticoids appear essential for the differentiation of cells and tissues that arise from MSCs. High levels of glucocorticoids are used in tissue engineering strategies to enhance the formation of tissues such as bone, cartilage, and muscle. This article discusses the paradox that glucocorticoids both enhance and impair MSC development and function. It will describe how endogenous glucocorticoids are likely to be important in these processes in vivo and will discuss the implications for therapies aimed at reducing the damage associated with the use of therapeutic glucocorticoids

Exploring the interface between inflammatory and therapeutic glucocorticoid induced bone and muscle loss

Due to their potent immunomodulatory anti-inflammatory properties, synthetic glucocorticoids (GCs) are widely utilized in the treatment of chronic inflammatory disease. In this review, we examine our current understanding of how chronic inflammation and commonly used therapeutic GCs interact to regulate bone and muscle metabolism. Whilst both inflammation and therapeutic GCs directly promote systemic osteoporosis and muscle wasting, the mechanisms whereby they achieve this are distinct. Importantly, their interactions in vivo are greatly complicated secondary to the directly opposing actions of GCs on a wide array of pro-inflammatory signalling pathways that underpin catabolic and anti-anabolic metabolism. Several clinical studies have attempted to address the net effects of therapeutic glucocorticoids on inflammatory bone loss and muscle wasting using a range of approaches. These have yielded a wide array of results further complicated by the nature of inflammatory disease, underlying the disease management and regimen of GC therapy. Here, we report the latest findings related to these pathway interactions and explore the latest insights from murine models of disease aimed at modelling these processes and delineating the contribution of pre-receptor steroid metabolism. Understanding these processes remains paramount in the effective management of patients with chronic inflammatory disease

Cortisol excess in chronic kidney disease – A review of changes and impact on mortality

Chronic kidney disease (CKD) describes the long-term condition of impaired kidney function from any cause. CKD is common and associated with a wide array of complications including higher mortality, cardiovascular disease, hypertension, insulin resistance, dyslipidemia, sarcopenia, osteoporosis, aberrant immune function, cognitive impairment, mood disturbances and poor sleep quality. Glucocorticoids are endogenous pleiotropic steroid hormones and their excess produces a pattern of morbidity that possesses considerable overlap with CKD. Circulating levels of cortisol, the major active glucocorticoid in humans, are determined by a complex interplay between several processes. The hypothalamic-pituitary-adrenal axis (HPA) regulates cortisol synthesis and release, 11β-hydroxysteroid dehydrogenase enzymes mediate metabolic interconversion between active and inactive forms, and clearance from the circulation depends on irreversible metabolic inactivation in the liver followed by urinary excretion. Chronic stress, inflammatory states and other aspects of CKD can disturb these processes, enhancing cortisol secretion via the HPA axis and inducing tissue-resident amplification of glucocorticoid signals. Progressive renal impairment can further impact on cortisol metabolism and urinary clearance of cortisol metabolites. Consequently, significant interest exists to precisely understand the dysregulation of cortisol in CKD and its significance for adverse clinical outcomes. In this review, we summarize the latest literature on alterations in endogenous glucocorticoid regulation in adults with CKD and evaluate the available evidence on cortisol as a mechanistic driver of excess mortality and morbidity. The emerging picture is one of subclinical hypercortisolism with blunted diurnal decline of cortisol levels, impaired negative feedback regulation and reduced cortisol clearance. An association between cortisol and adjusted all-cause mortality has been reported in observational studies for patients with end-stage renal failure, but further research is required to assess links between cortisol and clinical outcomes in CKD. We propose recommendations for future research, including therapeutic strategies that aim to reduce complications of CKD by correcting or reversing dysregulation of cortisol

Psychosis and sexual abuse: an interpretative phenomenological analysis

This is the peer reviewed version of the following article: J. E. Rhodes, N. D. O’Neill, and P. W. Nel, ‘Psychosis and sexual abuse: An interpretative phenomenological analysis’, Clinical Psychology & Psychotherapy, March 2018, which has been published in final form at https://doi.org/10.1002/cpp.2189. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Objectives: This study aimed to investigate the first-person perspective of psychosis sufferers who survived childhood sexual abuse. Methods: Interpretative phenomenological analysis was employed to explore the experiences of 7 women with a history of sexual abuse and psychosis. Results: Analysis generated six themes: (a) degradation of self, interlinking shame, guilt, and sometimes disgust; (b) body-self entrapment, experiencing bodily constraint and distortion; (c) a sense of being different to others, involving interpersonal problems; (d) unending struggle and depression, a pervasive sense of defeat; (e) psychotic condemnations and abuse, describing psychotic phenomena related to harm and sexual abuse; and (f) perception of links to the past, the links made from past abuse to current functioning. Conclusion: Participants suffered extreme psychological, physical, and interpersonal difficulties past and present. Psychotic experiences reported exhibited themes of condemnation by external entities and reflected the topic of sexual abuse. Participants did not generally link psychosis to their past abusive experiences.Peer reviewedFinal Accepted Versio

Cerebral oxidative stress and microvasculature defects in TNF-α expressing transgenic and Porphyromonas gingivalis-infected ApoE-/- mice

The polymicrobial dysbiotic subgingival biofilm microbes associated with periodontal disease appear to contribute to developing pathologies in distal body sites, including the brain. This study examined oxidative stress, in the form of increased protein carbonylation and oxidative protein damage, in the tumour necrosis factor-α (TNF-α) transgenic mouse that models inflammatory TNF-α excess during bacterial infection; and in the apolipoprotein knockout (ApoE-/-) mouse brains, following Porphyromonas gingivalis gingival monoinfection. Following 2,4-dinitrophenylhydrazine derivatization, carbonyl groups were detected in frontal lobe brain tissue lysates by immunoblotting and immunohistochemical analysis of fixed tissue sections from the frontotemporal lobe and the hippocampus. Immunoblot analysis confirmed the presence of variable carbonyl content and oxidative protein damage in all lysates, with TNF-α transgenic blots exhibiting increased protein carbonyl content, with consistently prominent bands at 25 kDa (p = 0.0001), 43 kDa and 68 kDa, over wild-type mice. Compared to sham-infected ApoE-/- mouse blots, P. gingivalis-infected brain tissue blots demonstrated the greatest detectable protein carbonyl content overall, with numerous prominent bands at 25 kDa (p = 0.001) and 43 kDa (p = 0.0001) and an exclusive band to this group between 30-43 kDa* (p = 0.0001). In addition, marked immunostaining was detected exclusively in the microvasculature in P. gingivalis-infected hippocampal tissue sections, compared to sham-infected, wild-type and TNF-α transgenic mice. This study revealed that the hippocampal microvascular structure of P. gingivalis-infected ApoE-/- mice possesses elevated oxidative stress levels, resulting in the associated tight junction proteins being susceptible to increased oxidative/proteolytic degradation, leading to a loss of functional integrity

TNFα depleting therapy improves fertility and animal welfare in TNFα-driven transgenic models of polyarthritis when administered in their routine breeding

Transgenic tumour necrosis factor alpha (TNFα)-driven models of polyarthritis such as the TNFΔARE mouse have proven to be invaluable in delineating aspects of inflammatory disease pathophysiology in humans. Unfortunately, the onset of joint destruction and inflammation in these models represents a significant detriment to breeding management. We examined whether TNFα depleting therapy ‘infliximab’ might represent a significant refinement in routine breeding. Clinical scores of joint inflammation were assessed in TNFΔARE males receiving either infliximab (10 mg/kg) or saline by twice-weekly intraperitoneal injection. Joint histology and bone morphology were assessed by histological analysis and micro-computed tomography (CT), respectively. Analysis of breeding was examined retrospectively in TNFΔARE males prior to, and following, regular introduction of infliximab. Clinical scores of inflammation were significantly reduced in TNFΔARE males receiving infliximab (control 6.6 arbitrary units [AU] ± 0.88 versus infliximab 4.4 AU ± 1.4; P &lt; 0.05), while measures of pannus invasion and bone erosion by histology and micro-CT were markedly reduced. In the breeding groups, TNFΔARE males receiving infliximab injections sired more litters over their breeding lifespan (control 1.69 ± 0.22 versus infliximab 3.00 ± 0.19; P &lt; 0.005). Furthermore, prior to infliximab, TNFΔARE males had a 26% risk of failing to sire any litters. This was reduced to 7% after the introduction of infliximab. This study is the first to report that regular administration of infliximab is effective at suppressing disease activity and improving animal welfare in TNFΔARE animals. In addition, we have shown that infliximab is highly efficacious in improving breeding behaviour and increasing the number of litters sired by TNFΔARE males. </jats:p