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Celiac Disease and Its Role in the Development of Metabolic Bone Disease.
Micic, D, Rao, VL, Semrad, CE
Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2020;(2):190-199
Abstract
Celiac disease (CD) is an immune-mediated enteropathy that occurs in genetically susceptible hosts with the ingestion of gluten-containing products. Ongoing gluten consumption leads to intestinal damage, characterized by villous blunting and increased intraepithelial lymphocytes, resulting in malabsorption. Pertinent to the development of bone disease, malabsorption of calcium and vitamin D leads to secondary hyperparathyroidism and metabolic bone disease among individuals with CD. In this article, we review the pathogenesis of CD and the effects of malabsorption on bone health. Imbalances in bone resorption and formation particularly in individuals with CD and persistent disease activity ultimately lead to a state of bone loss and impaired mineralization. Initiation of a gluten-free diet is critical in the management of CD-related metabolic bone disease, demonstrating improvements in bone mineral density within the first year of dietary adherence.
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Microbial osteoporosis: The interplay between the gut microbiota and bones via host metabolism and immunity.
Li, L, Rao, S, Cheng, Y, Zhuo, X, Deng, C, Xu, N, Zhang, H, Yang, L
MicrobiologyOpen. 2019;(8):e00810
Abstract
The complex relationship between intestinal microbiota and host is a novel field in recent years. A large number of studies are being conducted on the relationship between intestinal microbiota and bone metabolism. Bone metabolism consisted of bone absorption and formation exists in the whole process of human growth and development. The nutrient components, inflammatory factors, and hormone environment play important roles in bone metabolism. Recently, intestinal microbiota has been found to influence bone metabolism via influencing the host metabolism, immune function, and hormone secretion. Here, we searched relevant literature on Pubmed and reviewed the effect of intestinal microbiota on bone metabolism through the three aspects, which may provide new ideas and targets for the clinical treatment of osteoporosis.
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R516Q mutation in Melanoma differentiation-associated protein 5 (MDA5) and its pathogenic role towards rare Singleton-Merten syndrome; a signature associated molecular dynamics study.
Raghuraman, P, Sudandiradoss, C
Journal of biomolecular structure & dynamics. 2019;(3):750-765
Abstract
Singleton-Merten syndrome, a critical and rare multifactorial disorder that is closely linked to R516Q mutation in MDA5 protein associated with an enhanced interferon response in the affected individual. In the present study, we provide conclusive key evidence on R516Q mutation and their connectivity towards sequence-structural basis dysfunction of MDA5 protein. Among the various mutations, we found R516Q is the most pathogenic mutation based on mutational signature Q-A-[RE]-G-R-[GA]-R-A-[ED]-[DE]-S-[ST]-Y-[TSAV]-L-V designed from our work. Further, we derived a distant ortholog for this mutational signature from which we identified 343 intra-residue interactions that fall communally in the position required to maintain the structural and functional integration of protein architecture. This identification served us to understand the critical role of hot spots in residual aggregation that holds a native form of folding conformation in the functional region. In addition, the long-range molecular dynamics simulation demarcated the residual dependencies of conformational transition in distinct regions (L29360-370α18, α19380-410L31, α21430-480L33-α22-L35 and α24510-520L38) occurring upon R516Q mutation. Together, our results emphasise that the dislocation of functional hot spots Pro229, Arg414, Val498, Met510, Ala513, Gly515 and Arg516 in MDA5 protein which is important for interior structural packing and fold arrangements. In a nutshell, our findings are perfectly conceded with other experimental reports and will have potential implications in immune therapeutical advancement for rare singleton-merten syndrome.
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4.
[Vitamin D metabolism and osteoporosis in systemic sclerosis].
Szamosi, S, Horváth, Á, Szekanecz, Z, Szűcs, G
Orvosi hetilap. 2017;(32):1252-1258
Abstract
In the past few years more and more data have become available on the important role of vitamin D in immunological processes and inflammation. The role of vitamin D deficiency in the pathogenesis as well as in disease progression of different autoimmune and inflammatory conditions is suspected. Vitamin D deficiency is prevalent in several autoimmune diseases, including systemic sclerosis. Hypovitaminosis has been found to be associated with low bone mineral density and higher prevalence of osteoporosis in this group of patients. Determinants of low bone density in SSc are poorly understood. Studies have shown the importance of both traditional osteoporotic as well as disease-specific factors (extent of skin involvement, presence of internal organ manifestation, malabsorption, systemic sclerosis subtype, serological profile, medication) in the development of low bone mineral density. The relationship between low bone density in systemic sclerosis patients and the above mentioned risk factors may be more complex and the real role of each factor is unclear. Yet very few studies reported clinically relevant low bone mass outcomes such as fracture risk assessment and fracture associated mortality in scleroderma. This review aims to synthesize data about the essential role of vitamin D in immune homeostasis as well as the prevalence of hypovitaminosis, low bone density, changes in bone turnover markers and presence of osteoporosis in scleroderma patients. Orv Hetil. 2017; 158(32): 1252-1258.
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5.
Bone health, vitamin D and lupus.
Sangüesa Gómez, C, Flores Robles, BJ, Andréu, JL
Reumatologia clinica. 2015;(4):232-6
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Abstract
The prevalence of vitamin D deficiency and insufficiency among patients with systemic lupus erythematosus is high. This is likely due to photoprotection measures in addition to intrinsic factors of the disease. Low levels of vitamin D increase the risk of low bone mineral density and fracture. Vitamin D deficiency could also have undesirable effects on patients' immune response, enhancing mechanisms of loss of tolerance and autoimmunity. Vitamin D levels should be periodically monitored and patients should be treated with the objective of reaching vitamin D levels higher than 30-40 ng/ml.
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[Gastrointestinal diseases and bone].
Iijima, H, Tsujii, M, Takehara, T
Clinical calcium. 2013;(2):243-8
Abstract
Bone mineral density is decreased in inflammatory bowel diseases, which are intractable inflammation in the digestive tract. The causes of decreased bone mineral density are multifactorial including steroid use, insufficiency of nutritional intake, malabsorption in the gastrointestinal tract and activation of mucosal immune system. Insufficient levels of vitamins D and K are reported in patients with inflammatory bowel diseases and are also suggested to be involved in acceleration of intestinal inflammation.
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Serum 25-hydroxyvitamin D levels modulate the acute-phase response associated with the first nitrogen-containing bisphosphonate infusion.
Bertoldo, F, Pancheri, S, Zenari, S, Boldini, S, Giovanazzi, B, Zanatta, M, Valenti, MT, Dalle Carbonare, L, Lo Cascio, V
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2010;(3):447-54
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Abstract
The acute-phase response (APR) is the most frequent side effect after the first dose of intravenous nitrogen-containing bisphosphonates (N-BPs). It has been demonstrated in vitro that N-BPs stimulate gammadelta T-cell proliferation and production of cytokines and that vitamin D is able to modulate them. Therefore, we have studied the relationship between bone metabolism parameters, particularly for 25-hydroxyvitamin D [25(OH)D], and APR in patients treated with 5 mg zoledronic acid intravenously. Ninety N-BP-naive osteoporotic women (63.7 +/- 10.6 years of age) were stratified for the occurrence of APR (APR(+)) or not (APR(-)) and quantified by body temperature and C-reactive protein (CRP). The APR(+) women had significantly lower 25(OH)D levels than the APR(-) women. Levels of 25(OH)D were normal (>30 ng/mL) in 31% of APR(+) women and in 76% of APR(-) women. The odds ratio (OR) to have APR in 25(OH)D-depleted women was 5.8 [95% confidence interval (CI) 5.30-6.29; p < .0002] unadjusted and 2.38 (95% CI 1.85-2.81; p < .028) after multiple adjustments (for age, body mass index, CRP, calcium, parathyroid hormone, and C-telopeptide of type I collagen). Levels of 25(OH)D were negatively correlated with postdose body temperature (r = -0.64, p < .0001) and CRP (r = -0.79, p < .001). An exponential increase in fever and CRP has been found with 25(OH)D levels lower than 30 ng/mL and body temperature less than 37 degrees C, whereas normal CRP was associated with 25(OH)D levels above 40 ng/mL. The association between post-N-BPs APR and 25(OH)D suggests an interesting interplay among N-BPs, 25(OH)D, and the immune system, but a causal role of 25(OH)D in APR has to be proven by a randomized, controlled trial. However, if confirmed, it should have some practical implications in preventing APR.
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Current and emerging therapies for osteoporosis.
Mitchner, NA, Harris, ST
The Journal of family practice. 2009;(7 Suppl Osteoporosis):S45-9
Abstract
Bone remodeling is a dynamic process in which activated osteoclasts resorb bone and osteoblasts generate a bone matrix that undergoes mineralization. This process repairs microdamage' the microscopic cracks that develop in bone during regular activity-and ensures skeletal strength. A number of local and systemic factors mediate bone cell activity. Systemic regulators include endogenous parathyroid hormone (PTH), vitamin D metabolites, prostaglandins, cortisol, and sex hormones. A number of cytokines and growth factors regulate bone cell function at the local level. For example, bone resorption and formation are tightly orchestrated via the RANK/receptor activator of NF-kappa B ligand (RANKL)/osteoprotegerin (OPG) system. Estrogen deficiency, glucocorticoid use, and immune-mediated conditions lead to an imbalance in the RANKL-OPG ratio, inducing osteoclastogenesis and accelerated bone resorption. A number of steps in the tightly orchestrated bone remodeling process can be targeted with pharmacotherapy. This article reviews the available and emerging treatments that inhibit resorption (the antiresorptive or anticatabolic agents) or augment bone formation (anabolic therapy).