Diabetes is associated with an increase in skeletal fragility and risk of fracture. However, the underlying mechanism for the same is not well understood. Specifically, the results from osteoblast ...cell culture studies are ambiguous due to contradicting reports. The use of supraphysiological concentrations in these studies, unachievable in vivo
,
might be the reason for the same. Therefore, here, we studied the effect of physiologically relevant levels of high glucose during diabetes (11.1 mM) on MC3T3-E1 osteoblast cell functions. The results showed that high glucose exposure to osteoblast cells increases their differentiation and mineralization without any effect on the proliferation. However, high glucose decreases their migratory potential and chemotaxis with a decrease in the associated cell signaling. Notably, this decrease in cell migration in high glucose conditions was accompanied by aberrant localization of Dynamin 2 in osteoblast cells. Besides, high glucose also caused a shift in mitochondrial dynamics towards the appearance of more fused and lesser fragmented mitochondria, with a concomitant decrease in the expression of DRP1, suggesting decreased mitochondrial biogenesis. In conclusion, here we are reporting for the first time that hyperglycemia causes a reduction in osteoblast cell migration and chemotaxis. This decrease might lead to an inefficient movement of osteoblasts to the erosion site resulting in uneven mineralization and skeletal fragility found in type 2 diabetes patients, in spite of having normal bone mineral density (BMD).
Maternal nutrition is crucial for the offspring’s skeleton development and the onset of osteoporosis later in life. While maternal low protein diet has been shown to regulate bone mass negatively, ...the effect of a high protein diet (HP) remains unexplored. Here, we found that C57BL/6 mice fed with HP delivered offspring with decreased skeletal mineralization at birth and reduced bone mass throughout their life due to a decline in their osteoblast maturation. A small RNA sequencing study revealed that miR-24-1-5p was highly upregulated in HP group osteoblasts. Target prediction and validation studies identified SMAD-5 as a direct target of miR-24-1-5p. Furthermore, mimic and inhibitor studies showed a negative correlation between miR-24-1-5p expression and osteoblast function. Moreover, ex vivo inhibition of miR-24-1-5p reversed the reduced maturation and SMAD-5 expression in the HP group osteoblasts. Together, we show that maternal HP diminishes the bone mass of the offspring through miR-24-1-5p.
Tryptophan, an essential amino acid through a series of enzymatic reactions gives rise to various metabolites, viz. serotonin and melatonin, that regulate distinct biological functions. We show here ...that tryptophan metabolism in the pineal gland favors bone mass accrual through production of melatonin, a pineal‐derived neurohormone. Pineal gland‐specific deletion of Tph1, the enzyme that catalyzes the first step in the melatonin biosynthesis lead to a decrease in melatonin levels and a low bone mass due to an isolated decrease in bone formation while bone resorption parameters remained unaffected. Skeletal analysis of the mice deficient in MT1 or MT2 melatonin receptors showed a low bone mass in MT2−/− mice while MT1−/− mice had a normal bone mass compared to the WT mice. This low bone mass in the MT2−/− mice was due to an isolated decrease in osteoblast numbers and bone formation. In vitro assays of the osteoblast cultures derived from the MT1−/− and MT2−/− mice showed a cell intrinsic defect in the proliferation, differentiation and mineralization abilities of MT2−/− osteoblasts compared to WT counterparts, and the mutant cells did not respond to melatonin addition. Finally, we demonstrate that daily oral administration of melatonin can increase bone accrual during growth and can cure ovariectomy‐induced structural and functional degeneration of bone by specifically increasing bone formation. By identifying pineal‐derived melatonin as a regulator of bone mass through MT2 receptors, this study expands the role played by tryptophan derivatives in the regulation of bone mass and underscores its therapeutic relevance in postmenopausal osteoporosis.
Hypothalamic control of bone metabolism Sharan, Kunal, Ph.D; Yadav, Vijay K., Ph.D
Best Practice & Research Clinical Endocrinology & Metabolism,
10/2014, Volume:
28, Issue:
5
Journal Article
Peer reviewed
Bones are structures in vertebrates that provide support to organs, protect soft organs, and give them shape and defined features, functions that are essential for their survival. To perform these ...functions, bones are constantly renewed throughout life. The process through which bones are renewed is known as bone remodeling, an energy demanding process sensitive to changes in energy homeostasis of the organism. A close interplay takes place between the diversity of nutritional cues and metabolic signals with different elements of the hypothalamic circuits to co-ordinate energy metabolism with the regulation of bone mass. In this review, we focus on how mouse and human genetics have elucidated the roles of hormonal signals and neural circuits that originate in, or impinge on, the hypothalamus in the regulation of bone mass. This will help to understand the mechanisms whereby regulation of bone is gated and dynamically regulated by the hypothalamus.
Children suffering from autism have been reported to have low bone mineral density and increased risk for fracture, yet the cellular origin of the bone phenotype remains unknown. Here we have ...utilized a mouse model of autism that duplicates 6.3 Mb region of chromosome 7 (Dp/+) corresponding to a region of chromosome 15q11-13, duplication of which is recurrent in humans to characterize the bone phenotype. Paternally inherited Dp/+ (patDp/+) mice showed expected increases in the gene expression in bone, normal postnatal growth and body weight acquisition compared to the littermate controls. Four weeks-old patDp/+ mice develop a low bone mass phenotype in the appendicular but not the axial skeleton compared to the littermate controls. This low bone mass in the mutant mice was secondary to a decrease in the number of osteoblasts and bone formation rate while the osteoclasts remained relatively unaffected. Further in vitro cell culture experiments and gene expression analysis revealed a major defect in the proliferation, differentiation and mineralization abilities of patDp/+ osteoblasts while osteoclast differentiation remained unchanged compared to controls. This study therefore characterizes the structural and cellular bone phenotype in a mouse model of autism that can be further utilized to investigate therapeutic avenues to treat bone fractures in children with autism.
Estrogen deficiency leads to an upregulation of TNF-α producing T cells and B-lymphopoesis which augments osteoclastogenesis. Estrogen deficiency also increases the population of premature senescent ...CD4⁺ CD28null T cells which secrete a higher amount of TNF-α thus leading to enhanced osteoclastogenesis. Isoflavonoids like daidzein and genistein are found mostly in soybeans, legumes, and peas. These share structural similarity with 17β-stradiol (E2) and have osteoprotective role. This study explores the effect of daidzein (Daid) on the proliferation of TNF-α producing T cells, premature senescent T cells and B cell lymphopoesis under estrogen deficient conditions. For this study adult Balb/c mice were treated with Daid at 10 mg/kg body weight dose by oral gavage daily post ovariectomy (Ovx). After six weeks animals were autopsied and bone marrow and spleen cells were collected for FACS analysis. Blood serum was collected for ELISA. It was observed that Ovx mice treated with Daid for six weeks show reduction in Ovx induced expansion of CD4⁺ T cells in bone marrow and spleen when analysed by flow cytometry. Estrogen deficiency led to increased prevalence of TNF-α secreting CD4⁺CD28null T cells, however, treatment with Daid increased the percentage of CD4⁺CD28⁺ T cells. Co-culture of CD4⁺CD28null T cells and bone marrow resulted in enhanced osteoclastogenesis as evident by increased tartarate resistant acid phosphatase (TRAP) expression, an osteoclast marker. However, treatment with Daid resulted in reduced osteoclastogenesis in CD4⁺CD28null T cells and bone marrow cell co-culture. Daid also regulated B lymphopoesis and decreased mRNA levels of RANKL in B220⁺ cells. Taken together, we propose that one of the mechanisms by which Daid prevents bone loss is by reversing the detrimental immune changes as a result of estrogen deficiency.
Despite improved health care, hygiene, and modern facilities, there is a global rise in autoimmune and metabolic disorders. Coinciding with this is the overall weakening of immunity and increase in ...allergic reactions. Food and nutrition play an essential role in developing, maintaining, and activating the immune system.
Understanding how an individual's diet and nutritional status impact the immune system can unravel many opportunities and challenges. In this review, we discuss the immunomodulatory potential of nutritional and non-nutritional components of food. We will also delineate the mechanism by which diet and its ingredients affect the immune system's development and regulation. Besides, we will give a brief overview of food allergens and the mechanism by which they induce allergenicity. Finally, we will discuss immune-enhancing functional foods and the associated concerns.
Food and nutrition is a significant determinant of immunity of an individual. Diet not only affects the development of immune system, but it also helps in the maintenance of immunity.
•Dietary pattern is a significant factor underlying the increase in incidents of metabolic, allergic, and autoimmune diseases.•Nutrient and non-nutrient components in food play a crucial role in development, maintenance, and modulation of immune system.•Gut microbiome and epigenetic modulation are the important mechanisms for diet induced immunomodulation.•Bridging the gap between the popularised immunomodulatory functions of food and its scientific validation is urgently needed.
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