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International Journal of Molecular... Jul 2019Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can... (Review)
Review
Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction-oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to be responsible for the development of several diseases. The biphasic role of ROS in cellular functions has been a target of pharmacological research. Osteoclasts are derived from hematopoietic progenitors in the bone and are essential for skeletal growth and remodeling, for the maintenance of bone architecture throughout lifespan, and for calcium metabolism during bone homeostasis. ROS, including superoxide ion (O) and hydrogen peroxide (HO), are important components that regulate the differentiation of osteoclasts. Under normal physiological conditions, ROS produced by osteoclasts stimulate and facilitate resorption of bone tissue. Thus, elucidating the effects of ROS during osteoclast differentiation is important when studying diseases associated with bone resorption such as osteoporosis. This review examines the effect of ROS on osteoclast differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases.
Topics: Animals; Biomarkers; Bone Remodeling; Bone Resorption; Cell Differentiation; Humans; Molecular Targeted Therapy; Osteoclasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 31336616
DOI: 10.3390/ijms20143576 -
Cell Host & Microbe Jul 2017Diabetes is a risk factor for periodontitis, an inflammatory bone disorder and the greatest cause of tooth loss in adults. Diabetes has a significant impact on the gut...
Diabetes is a risk factor for periodontitis, an inflammatory bone disorder and the greatest cause of tooth loss in adults. Diabetes has a significant impact on the gut microbiota; however, studies in the oral cavity have been inconclusive. By 16S rRNA sequencing, we show here that diabetes causes a shift in oral bacterial composition and, by transfer to germ-free mice, that the oral microbiota of diabetic mice is more pathogenic. Furthermore, treatment with IL-17 antibody decreases the pathogenicity of the oral microbiota in diabetic mice; when transferred to recipient germ-free mice, oral microbiota from IL-17-treated donors induced reduced neutrophil recruitment, reduced IL-6 and RANKL, and less bone resorption. Thus, diabetes-enhanced IL-17 alters the oral microbiota and renders it more pathogenic. Our findings provide a mechanistic basis to better understand how diabetes can increase the risk and severity of tooth loss.
Topics: Alveolar Bone Loss; Animals; Bacteria; Bone Resorption; Colony Count, Microbial; DNA, Bacterial; Diabetes Mellitus, Experimental; Genes, Bacterial; Inflammation; Interleukin-17; Interleukin-6; Mice; Mice, Inbred C57BL; Microbiota; Mouth; Neutrophil Infiltration; Osteoclasts; Periodontitis; RANK Ligand; RNA, Ribosomal, 16S; Sequence Analysis; Tooth Loss; Virulence
PubMed: 28704648
DOI: 10.1016/j.chom.2017.06.014 -
The Journal of Clinical Investigation Dec 2020Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our...
Homeostasis of bone metabolism is regulated by the central nervous system, and mood disorders such as anxiety are associated with bone metabolism abnormalities, yet our understanding of the central neural circuits regulating bone metabolism is limited. Here, we demonstrate that chronic stress in crewmembers resulted in decreased bone density and elevated anxiety in an isolated habitat mimicking a space station. We then used a mouse model to demonstrate that GABAergic neural circuitry in the ventromedial hypothalamus (VMH) mediates chronic stress-induced bone loss. We show that GABAergic inputs in the dorsomedial VMH arise from a specific group of somatostatin neurons in the posterior region of the bed nucleus of the stria terminalis, which is indispensable for stress-induced bone loss and is able to trigger bone loss in the absence of stressors. In addition, the sympathetic system and glutamatergic neurons in the nucleus tractus solitarius were employed to regulate stress-induced bone loss. Our study has therefore identified the central neural mechanism by which chronic stress-induced mood disorders, such as anxiety, influence bone metabolism.
Topics: Adult; Animals; Anxiety Disorders; Bone Resorption; Chronic Disease; Female; Humans; Hypothalamus; Male; Mice; Mice, Transgenic; Middle Aged; Nerve Net; Neurons; Somatostatin; Stress, Psychological
PubMed: 32910804
DOI: 10.1172/JCI136105 -
Biology Letters Feb 2018Activation of the immune system is associated with an increase in the breakdown of various peripheral tissues, including bone. Despite the widely appreciated role of... (Review)
Review
Activation of the immune system is associated with an increase in the breakdown of various peripheral tissues, including bone. Despite the widely appreciated role of inflammatory mediators in promoting bone resorption, the functional value behind this process is not completely understood. Recent advances in the field of immunometabolism have highlighted the metabolic reprogramming that takes place in activated immune cells. It is now believed that the breakdown of peripheral tissue provides metabolic substrates to fuel metabolic anabolism in activated immune cells. We argue that phosphate, liberated by bone resorption, plays an indispensable role in sustaining immune cell metabolism. The liberated phosphate is then incorporated into macromolecules such as nucleotides and phospholipids, and is also used for the phosphorylation of metabolites (e.g. glycolytic intermediates). In addition, magnesium, also liberated during the breakdown of bone, is an essential cofactor required by various metabolic enzymes which are upregulated in activated immune cells. Finally, calcium activates various additional molecules involved in immune cell migration. Taken together, these factors suggest a key role for bone resorption during infection.
Topics: Animals; Bone Resorption; Cell Movement; Cellular Reprogramming; Humans
PubMed: 29491030
DOI: 10.1098/rsbl.2017.0783 -
Molecular Nutrition & Food Research Jun 2022A dose-ranging study is performed using young estrogen-depleted rats to determine whether dietary isoliquiritigenin (ILQ) alters bone metabolism and if the effects are...
SCOPE
A dose-ranging study is performed using young estrogen-depleted rats to determine whether dietary isoliquiritigenin (ILQ) alters bone metabolism and if the effects are associated with estrogen receptor signaling.
METHODS AND RESULTS
Six-week-old rats (ovariectomized at 4 weeks of age) are fed diets containing 0, 100, 250, or 750 ppm ILQ (n = 5/treatment) for 7 days. Gene expression in femur and uterus, blood markers of bone turnover, body composition, and uterine weight and epithelial cell height are determined. Because ILQ lowers bone resorption, the effect of ILQ on in vitro differentiation of osteoclasts from bone marrow of mice is assessed. Treatment resulted in a dose-dependent increases in serum ILQ but no changes in serum osteocalcin, a marker of global bone formation. Contrastingly, ILQ administration results in reduced serum CTX-1, a marker of global bone resorption, and reduces tartrate resistant acid phosphatase expression in osteoclast culture. ILQ treatment and endogenous estrogen production had limited overlap on gene expression in femur and uterus. However, uterine epithelial cell hyperplasia is observed in two of five animals treated with 750 ppm.
CONCLUSIONS
In conclusion, dietary ILQ reduces bone resorption in vivo and osteoclast differentiation in vitro, by mechanisms likely differing from actions of ovarian hormones.
Topics: Animals; Bone Resorption; Cell Differentiation; Chalcones; Estrogens; Female; Humans; Mice; Osteoclasts; Ovariectomy; Rats; Tartrate-Resistant Acid Phosphatase
PubMed: 35319818
DOI: 10.1002/mnfr.202100974 -
Current Osteoporosis Reports Sep 2013Cancer is a major risk factor for bone loss and fractures. This is due both to direct effects of cancer cells on the skeleton and to deleterious effects of... (Review)
Review
Cancer is a major risk factor for bone loss and fractures. This is due both to direct effects of cancer cells on the skeleton and to deleterious effects of cancer-specific therapies on bone cells. Marked improvements in survival for many cancers mean that strategies to limit bone loss and reduce fracture risk must be incorporated into the care plans for nearly all patients with cancer. The vast majority of effort thus far has focused on bone loss in patients with breast and prostate cancers, with comparatively few studies in other malignancies. Antiresorptive therapies have proven nearly universally effective for limiting bone loss in cancer patients, although few studies have been powered sufficiently to include fractures as primary endpoints, and patients are frequently neither identified nor treated according to published guidelines. Nonpharmacologic approaches to limit falls, particularly in elderly patients, are also likely important adjunctive measures for most cancer patients.
Topics: Bone Resorption; Breast Neoplasms; Female; Humans; Incidence; Male; Neoplasms; Osteoporosis; Prostatic Neoplasms; Risk Factors
PubMed: 23877475
DOI: 10.1007/s11914-013-0154-3 -
Arthritis Research & Therapy 2011The concept of osteoimmunology is based on growing insight into the links between the immune system and bone at the anatomical, vascular, cellular, and molecular levels.... (Review)
Review
The concept of osteoimmunology is based on growing insight into the links between the immune system and bone at the anatomical, vascular, cellular, and molecular levels. In both rheumatoid arthritis (RA) and ankylosing spondylitis (AS), bone is a target of inflammation. Activated immune cells at sites of inflammation produce a wide spectrum of cytokines in favor of increased bone resorption in RA and AS, resulting in bone erosions, osteitis, and peri-inflammatory and systemic bone loss. Peri-inflammatory bone formation is impaired in RA, resulting in non-healing of erosions, and this allows a local vicious circle of inflammation between synovitis, osteitis, and local bone loss. In contrast, peri-inflammatory bone formation is increased in AS, resulting in healing of erosions, ossifying enthesitis, and potential ankylosis of sacroiliac joints and intervertebral connections, and this changes the biomechanical competence of the spine. These changes in bone remodeling and structure contribute to the increased risk of vertebral fractures (in RA and AS) and non-vertebral fractures (in RA), and this risk is related to severity of disease and is independent of and superimposed on background fracture risk. Identifying patients who have RA and AS and are at high fracture risk and considering fracture prevention are, therefore, advocated in guidelines. Local peri-inflammatory bone loss and osteitis occur early and precede and predict erosive bone destruction in RA and AS and syndesmophytes in AS, which can occur despite clinically detectable inflammation (the so-called 'disconnection'). With the availability of new techniques to evaluate peri-inflammatory bone loss, osteitis, and erosions, peri-inflammatory bone changes are an exciting field for further research in the context of osteoimmunology.
Topics: Animals; Bone Resorption; Humans; Osteoclasts; Osteoporosis
PubMed: 21996023
DOI: 10.1186/ar3375 -
Cellular and Molecular Life Sciences :... May 2022Osteoclast-mediated bone resorption is responsible for bone metabolic diseases, negatively impacting people's health and life. It has been demonstrated that microRNA... (Review)
Review
Osteoclast-mediated bone resorption is responsible for bone metabolic diseases, negatively impacting people's health and life. It has been demonstrated that microRNA influences the differentiation of osteoclasts by regulating the signaling pathways during osteoclast-mediated bone resorption. So far, the involved mechanisms have not been fully elucidated. This review introduced the pathways involved in osteoclastogenesis and summarized the related microRNAs binding to their specific targets to mediate the downstream pathways in osteoclast-mediated bone resorption. We also discuss the clinical potential of targeting microRNAs to treat osteoclast-mediated bone resorption as well as the challenges of avoiding potential side effects and producing efficient delivery methods.
Topics: Bone Resorption; Cell Differentiation; Humans; MicroRNAs; Osteoclasts; Osteogenesis; RANK Ligand
PubMed: 35536437
DOI: 10.1007/s00018-022-04298-y -
Arthritis Research & Therapy 2007Multiple myeloma, a cancer of plasma cells, is associated with excessive tumor-induced, osteoclast-mediated bone destruction. Hypercalcemia remains the most frequent... (Review)
Review
Multiple myeloma, a cancer of plasma cells, is associated with excessive tumor-induced, osteoclast-mediated bone destruction. Hypercalcemia remains the most frequent metabolic complication of myeloma in patients, and excessive osteolysis plays a major contributory role in its pathogenesis. The clinical presentation of hypercalcemia in patients varies depending on the level of ionized calcium; it can be life threatening, as in the case of hypercalcemic crisis, requiring immediate medical treatment to prevent death. During the past few years there have been exciting developments in our understanding of the pathogenesis of myeloma bone disease; in particular, key mediators of the osteoclastic bone resorption in myeloma have been identified, including receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage inflammatory protein-1alpha. There is also increasing evidence that Dickkopf 1, which has been shown to be over-expressed in myeloma patients, is also a potent stimulator of osteoclast formation and activity. Importantly, the available data suggest that RANKL is the final common mediator of osteoclastic bone resorption, irrespective of the upstream initiator molecule. This brief review presents an overview of the roles played by these mediators in inducing osteolysis in myeloma bone disease, and it discusses targeting RANKL as a potential new treatment strategy in myeloma bone disease and myeloma-associated hypercalcemia.
Topics: Animals; Bone Resorption; Humans; Hypercalcemia; Multiple Myeloma; RANK Ligand
PubMed: 17634143
DOI: 10.1186/ar2168 -
Archives of Endocrinology and Metabolism Nov 2022Anabolic agents for the treatment of osteoporosis increase bone density, improve bone strength, and reduce fracture risk. They are distinguished from antiresorptive... (Review)
Review
Anabolic agents for the treatment of osteoporosis increase bone density, improve bone strength, and reduce fracture risk. They are distinguished from antiresorptive drugs by their property of increasing osteoblastic bone formation. Teriparatide and abaloparatide are parathyroid hormone receptor agonists that increase bone remodeling with bone formation increasing more than bone resorption. Romosozumab is a humanized monoclonal antibody to sclerostin that has a "dual effect" of increasing bone formation while decreasing bone resorption. The bone forming effects of anabolic therapy appear to be self-limited, making it imperative that it be followed by antiresorptive therapy to enhance or consolidate the beneficial effects achieved. Teriparatide, abaloparatide, and romosozumab each have unique pharmacological properties that must be appreciated when using them to treat patients at high risk for fracture. Clinical trials have shown a favorable balance of expected benefits and possible risks. Anabolic therapy is superior to bisphosphonates for high-risk patients, with greater benefit when initial treatment is with an anabolic agent followed by an antiresorptive drug, rather than the reverse sequence of therapy. Recent clinical practice guidelines have included recommendations with examples of patients who are candidates with anabolic therapy.
Topics: Humans; Teriparatide; Osteoporosis; Bone Density Conservation Agents; Bone Density; Bone Resorption
PubMed: 36382760
DOI: 10.20945/2359-3997000000566