The Role of IL-17 and TH17 Cells in the Bone Catabolic Activity of PTH

Osteoimmunology is field of research dedicated to the study of the interactions between the immune system and bone. Among the cells of the immune system that regulate the skeleton in health and disease are T lymphocytes. T cells secrete inflammatory/osteoclastogenic cytokines such as RANKL, TNF and IL-17, as well as factors that stimulate bone formation, including Wnt ligands. In addition, T cells regulate the differentiation and life span of stromal cells via CD40L and other costimulatory molecules expressed on their surface. Consensus exists that parathyroid hormone (PTH) induces bone loss by increasing the production of RANKL by osteocytes and osteoblast. However, new evidence suggests that PTH expands Th17 cells and increases IL-17 levels in mice and humans. Studies in the mouse of further shown that Th17 cell produced IL-17 acts as an upstream cytokine that increases the sensitivity of osteoblasts and osteocytes to PTH. As a result, PTH stimulates osteocytic and osteoblastic release of RANKL/. Therefore, PTH cause bone loss only in the presence of IL-17 signaling. This article reviews the evidence that the effects of PTH are mediated not only by osteoblasts and osteocytes, but also T cells and IL-17

The microbiome restrains melanoma bone growth by promoting intestinal NK and Th1 cell homing to bone

Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells into mice, we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal NK cells and Th1 cells and their migration from the gut to tumor-bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to the bone marrow (BM) in bone metastasis, blockade of S1P-mediated intestinal egress of NK and Th1 cells, or inhibition of their CXCR3/CXCL9-mediated influx into the BM, prevented the expansion of BM NK and Th1 cells and accelerated tumor growth and osteolysis. Using a mouse model, this study revealed mechanisms of microbiota-mediated gut-bone crosstalk that are relevant to the immunological restraint of melanoma metastasis and tumor growth in bone. Microbiome modifications induced by antibiotics might have negative clinical consequences in patients with melanoma

Gender disparity in addiction: an Italian epidemiological sketch

Introduction. Gender disparity in different fields of addiction such as tobacco smoking, alcohol use, drugs of abuse consumption and doping practice has been investigated in Italian population. Methods. We used the surveys and studies carried out for the above reported issues in recent years as revised by the “National Observatory on Tobacco smoke, Drugs of abuse, Alcohol and Doping” at Istituto Superiore di Sanità. Results. Concerning tobacco habit, the trend of smoking women has been in constant decrease from a 19.7% in 2010 to a 16.9% in 2015, differently from men who passed from a 23.9% in 2010 to a 25.1% in 2015 with a slight increase in the habit. With respect to alcohol, in the last five years an increasing trend of consumption has been observed in 18-24 years old women, with 53% drinking women in the age range of 18-19 years overcoming the 50.4% general female population. Generally speaking, a one to four ratio can be underlined in the percentage of elderly women with a risky alcohol consumption with respect to men, while in case of adolescents and young adults gender disparity is not so pronounced. Drug abuse still remains a prevalent male phenomenon. However, an increase in cannabis users for both genders has been reported with a prevalence of “once in the life” around 20%, although more pronounced in females (+2.66 percentage points for females vs +0.93 percentage points in male). With respect to cocaine, the secondmost consumed drug, a reduction in consumption has been recently observed mainly in female population (-42.1%) than in men one (-27.5%). Finally, there are significant gender differences in doping attitude and/or in doping profiling. First of all, males seem to be more exposed to doping than females The prohibited substances most frequently used by females athletes are “Diuretics and Masking Agents” (38.3% positive female vs 14% males) compared to males athletes who use mostly anabolic agents (20.1% males vs 11.2% females). Conclusions. Results presented for the different fields of addiction show that a gender disparity is apparent and that females are less prone in having an addiction behaviour, although the young generation seems to increase that tendency

The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users

Aims: Activation of PPARγ by pioglitazone (PIO) has shown some efficacy in attenuating addictive-like responses in laboratory animals. The ability of PIO to alter the effects of opioids in humans has not been characterized in a controlled laboratory setting. The proposed investigation sought to examine the effects of PIO on the subjective, analgesic, physiological and cognitive effects of oxycodone (OXY). Methods: During this investigation, nondependent prescription opioid abusers (N = 17 completers) were maintained for 2-3 weeks on ascending daily doses of PIO (0 mg, 15 mg, 45 mg) prior to completing a laboratory session assessing the aforementioned effects of OXY [using a within-session cumulative dosing procedure (0, 10, and 20 mg, cumulative dose = 30 mg)]. Results: OXY produced typical mu opioid agonist effects: miosis, decreased pain perception, and decreased respiratory rate. OXY also produced dose-dependent increases in positive subjective responses. Yet, ratings such as: drug "liking," "high," and "good drug effect," were not significantly altered as a function of PIO maintenance dose. Discussion: These data suggest that PIO may not be useful for reducing the abuse liability of OXY. These data were obtained with a sample of nondependent opioid users and therefore may not be applicable to dependent populations or to other opioids. Although PIO failed to alter the abuse liability of OXY, the interaction between glia and opioid receptors is not well understood so the possibility remains that medications that interact with glia in other ways may show more promise

T Lymphocytes Amplify the Anabolic Activity of Parathyroid Hormone through Wnt10b Signaling

SummaryIntermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis because it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here, we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells and induces these lymphocytes to activate canonical Wnt signaling in preosteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in preosteoblasts and blunted osteoblastic commitment, proliferation, differentiation, and life span, which result in decreased trabecular bone anabolism and no increase in strength. Demonstrating the specific role of lymphocytic Wnt10b, iPTH has no anabolic activity in mice lacking T-cell-produced Wnt10b. Therefore, T-cell-mediated activation of Wnt signaling in osteoblastic cells plays a key permissive role in the mechanism by which iPTH increases bone strength, suggesting that T cell osteoblast crosstalk pathways may provide pharmacological targets for bone anabolism