Diabetes mellitus and obesity are rapidly growing worldwide. Aside from metabolic disturbances, these two disorders also affect bone with a higher prevalence of bone fractures. In the last decade, a ...growing body of evidence suggested that several gut hormones, including ghrelin, gastrin, glucose-dependent insulinotropic polypeptide (GIP), glucagon, and glucagon-like peptide-1 and 2 (GLP-1 and GLP-2, respectively) may affect bone physiology. Several gut hormone analogues have been developed for the treatment of type 2 diabetes and obesity, and could represent a new alternative in the therapeutic arsenal against bone fragility. In the present review, a summary of the physiological roles of these gut hormones and their analogues is presented at the cellular level but also in several preclinical models of bone fragility disorders including type 2 diabetes mellitus, especially on bone mineral density, microarchitecture and bone material properties. The present review also summarizes the impact of GLP-1 receptor agonists approved for the treatment of type 2 diabetes mellitus and the more recent dual or triple analogue on bone physiology and strength.
•Ghrelin, gastrin, GIP, Glucagon, GLP-1 and GLP-2 may modulate bone physiology.•GIP, GLP-1 and GLP-2 modulate bone material properties.•In rodent models, GLP-1 receptor agonists are beneficial to bone health through amelioration of bone material properties.•Dual GIP/GLP-2 analogues might represent a new option to treat bone fragility disorders.
•The incidence of fragility fractures increases progressively with advance in age.•The consequences of fractures are more serious in older adults.•The falls play an essential role in the occurrence ...of fractures in older adults.•The main treatments of osteoporosis have shown efficacy in older adults.
The incidence of fragility fractures increases progressively with advance in age after 50 years, and the phenomenon of population ageing will lead to an increased proportion of the world population having osteoporosis and fractures. The consequences of fractures are more serious in older adults: all low-trauma fractures were associated with increased mortality risk and the risk of a second major osteoporotic fracture after a first one also increased with advance in age. Along with the decrease in bone mineral density, falls play an essential role in the occurrence of fragility fractures in older adults, and the assessment of the risk of falling is part of the fracture risk assessment. Despite advances in the diagnosis of osteoporosis, the assessment of fracture risk, and a wide range of effective anti-osteoporosis medications, with parenteral route which can improve observance, many data indicate that the therapeutic care gap is particularly wide in the elderly in whom the importance and impact of a treatment are high and even more in those living in institutions.
Glucose-dependent insulinotropic polypeptide (GIP) is absolutely crucial in order to obtain optimal bone strength and collagen quality. However, as the GIPR is expressed in several tissues other than ...bone, it is difficult to ascertain whether the observed modifications of collagen maturity, reported in animal studies, were due to direct effects on osteoblasts or indirect through regulation of signals originating from other tissues. The aims of the present study were to investigate whether GIP can directly affect collagen biosynthesis and processing in osteoblast cultures and to decipher which molecular pathways were necessary for such effects. MC3T3-E1 cells were cultured in the presence of GIP ranged between 10 and 100pM. Collagen fibril diameter was investigated by electron microscopy whilst collagen maturity was determined by Fourier transform infra-red microspectroscopy (FTIRM). GIP treatment resulted in dose-dependent increases in lysyl oxidase activity and collagen maturity. Furthermore, GIP treatment shifted the collagen fiber diameter towards lower value but did not significantly affect collagen heterogeneity. GIP acted directly on osteoblasts by activating the adenylyl cyclase-cAMP pathway. This study provides evidences that GIP acts directly on osteoblasts and is capable of improving collagen maturity and fibril diameter.
Abstract
Whipple disease (WD) is a rare infectious systemic disease. Rheumatologists are at the frontline of WD diagnosis due to the early rheumatological manifestations. An early diagnosis is ...crucial, as usual anti-rheumatic drugs, especially TNF inhibitors, may worsen the disease course. We conducted a retrospective multicentre national study from January 2010 to April 2020 to better characterize the rheumatological features of WD. Classic WD (CWD) was defined by positive periodic acid-Schiff (PAS) staining of a small-bowel biopsy sample, and non-CWD (NCWD) was defined by negative PAS staining of a small-bowel biopsy sample but at least one positive Tropheryma whipplei (TW) polymerase chain reaction (PCR) for a digestive or extradigestive specimen. Sixty-eight patients were enrolled, including 11 CWD patients. Twenty patients (30%) received TNF inhibitors during the WD course, with inefficacy or symptom worsening. More digestive symptoms and systemic biological features were observed in CWD patients than in NCWD patients, but both patient groups had similar outcomes, especially concerning the response to antibiotics and relapse rate. Stool and saliva TW PCR sensitivity were both 100% for CWD and 75% for NCWD and 89% and 60% for small-bowel biopsy sample PCR, respectively. WD encountered in rheumatology units has many presentations, which might result from different pathophysiologies that are dependent on host immunity. Given the heterogeneous presentations and the presence of chronic carriage, multiple TW PCR tests on samples from specific rheumatological sites when possible should be performed, but samples from nonspecific digestive and extradigestive sites also have great value.
Interleukin-26 (IL-26), a member of the IL-10 cytokine family, induces the production of proinflammatory cytokines by epithelial cells. IL-26 has been also reported overexpressed in Crohn's disease, ...suggesting that it may be involved in the physiopathology of chronic inflammatory disorders. Here, we have analyzed the expression and role of IL-26 in rheumatoid arthritis (RA), a chronic inflammatory disorder characterized by joint synovial inflammation. We report that the concentrations of IL-26 are higher in the serums of RA patients than of healthy subjects and dramatically elevated in RA synovial fluids compared to RA serums. Immunohistochemistry reveals that synoviolin(+) fibroblast-like synoviocytes and CD68(+) macrophage-like synoviocytes are the main IL-26-producing cells in RA joints. Fibroblast-like synoviocytes from RA patients constitutively produce IL-26 and this production is upregulated by IL-1-beta and IL-17A. We have therefore investigated the role of IL-26 in the inflammatory process. Results show that IL-26 induces the production of the proinflammatory cytokines IL-1-beta, IL-6, and tumor necrosis factor (TNF)-alpha by human monocytes and also upregulates the expression of numerous chemokines (mainly CCL20). Interestingly, IL-26-stimulated monocytes selectively promote the generation of RORgamma t(+) Th17 cells, through IL-1-beta secretion by monocytes. More precisely, IL-26-stimulated monocytes switch non-Th17 committed (IL-23R(-) or CCR6(-) CD161(-)) CD4(+) memory T cells into Th17 cells. Finally, synovial fluids from RA patients also induce Th17 cell generation and this effect is reduced after IL-26 depletion. These findings show that IL-26 is constitutively produced by RA synoviocytes, induces proinflammatory cytokine secretion by myeloid cells, and favors Th17 cell generation. IL-26 thereby appears as a novel proinflammatory cytokine, located upstream of the proinflammatory cascade, that may constitute a promising target to treat RA and chronic inflammatory disorders.
Recently, Objective Structured Clinical Examinations (OSCE) became an official evaluation modality for 6-year medical students in France. Before, standard examination modalities were: written ...progressive clinical cases (PCC), written critical reading of scientific articles (CRA), and internship evaluation (IE). The aim of this study was to assess the performances of 6-year medical students in their final faculty tests by comparing OSCE-exams with standard examination modalities.
This was a prospective observational study. We included all 6-year medical students in our university from 2020 to 2021. The endpoints were the scores obtained at the following final faculty tests during the 6
year of medical studies: OSCE-training, OSCE-exams, written PCC, written CRA, and IE. All scores were compared in a paired-analysis.
A total of 400 students were included in the study. No student was excluded in the final analysis. The mean scores obtained at the OSCE-exams were significantly different from those obtained at OSCE-training, PCC, CRA, and IE (12.6 ± 1.7, 11.7 ± 1.7, 13.4 ± 1.4, 13.2 ± 1.5, 14.7 ± 0.9, respectively; p < 0.001). OSCE-exams scores were moderately and significantly correlated with OSCE-training and PCC (Spearman rho coefficient = 0.4, p < 0.001); OSCE examination scores were lowly but significantly correlated with CRA and IE (Spearman rho coefficient = 0.3, p < 0.001). OSCE-scores significantly increased after an OSCE training session.
In our faculty, 6-year medical students obtained lower scores at OSCE exams compared to other standard evaluation modalities. The correlation was weak to moderate but significant. These results suggest that OSCE are not redundant with the other evaluation modalities. Interestingly, a single OSCE training session led to an improvement in OSCE scores underlining the importance of a specific training.
Proinflammatory cytokines play an important role in the systemic and focal bone loss associated with chronic inflammatory diseases. Targeting these cytokines with biologics and small molecules has ...led to a major improvement of the bone health of patients with inflammatory arthritis. Cytokines from the IL-17 family have been shown to be involved in the pathogenesis of several diseases such as spondyloarthritis, psoriatic arthritis, or psoriasis. IL-17A has been the first described and the most studied. The recent development of targeted therapies against IL-17A or its receptor and their efficacy has confirmed the importance of this cytokine in the development of inflammatory diseases. The aim of this review was to describe the effects of the IL-17 family and more particularly of IL-17A on bone and cartilage tissues. At the cellular level, IL-17A is proosteoclastogenic whereas its effects on osteoblasts depend on the stage of differentiation of these cells. In vivo, IL-17A is not required for normal bone homeostasis but plays an important role in bone loss notably in an ovariectomized mouse model of osteoporosis. Preliminary data from clinical trials showed a stabilisation of bone density in patients treated with anti-IL-17A antibodies. IL-17A plays a central role in the cartilage damage through the induction of collagenases and by decreasing the expression of their inhibitors in synergy with the other proinflammatory cytokines. The prevention of structural damage by anti-IL-17A therapies has been demonstrated in several pivotal clinical trials. Overall, blocking the IL-17A pathway seems to have a positive effect on the bone and cartilage damage observed in inflammatory arthritis. Differences and specificity of these effects compared to those already described with other biologics such as anti-TNF therapies remain to be explored.
•Type 2 diabetes mellitus is associated with a higher prevalence of bone fracture.•The GIP/GIPr pathway controls bone remodeling and quality.•The GLP-1/GLP-1 receptor pathway exerts beneficial ...effects on bone quality.•Approved GLP-1RA do not exacerbate bone alterations in type 2 diabetes mellitus.
Bone fractures are common comorbidities of type 2 diabetes mellitus (T2DM). Bone fracture incidence seems to develop due to increased risk of falls, poor bone quality and/or anti-diabetic medications. Previously, a relation between gut hormones and bone has been suspected. Most recent evidences suggest indeed that two gut hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may control bone remodeling and quality. The GIP receptor is expressed in bone cells and knockout of either GIP or its receptor induces severe bone quality alterations. Similar alterations are also encountered in GLP-1 receptor knock-out animals associated with abnormal osteoclast resorption. Some GLP-1 receptor agonist (GLP-1RA) have been approved for the treatment of type 2 diabetes mellitus and although clinical trials may not have been designed to investigate bone fracture, first results suggest that GLP-1RA may not exacerbate abnormal bone quality observed in T2DM. The recent design of double and triple gut hormone agonists may also represent a suitable alternative for restoring compromised bone quality observed in T2DM. However, although most of these new molecules demonstrated weight loss action, little is known on their bone safety. The present review summarizes the most recent findings on peptide-based incretin therapy and bone physiology.
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