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PloS One 2023Lactate, which is synthesized as an end product by lactate dehydrogenase A (LDHA) from pyruvate during anaerobic glycolysis, has attracted attention for its energy...
Lactate, which is synthesized as an end product by lactate dehydrogenase A (LDHA) from pyruvate during anaerobic glycolysis, has attracted attention for its energy metabolism and oxidant effects. A novel histone modification-mediated gene regulation mechanism termed lactylation by lactate was recently discovered. The present study examined the involvement of histone lactylation in undifferentiated cells that underwent differentiation into osteoblasts. C2C12 cells cultured in medium with a high glucose content (4500 mg/L) showed increases in marker genes (Runx2, Sp7, Tnap) indicating BMP-2-induced osteoblast differentiation and ALP staining activity, as well as histone lactylation as compared to those cultured in medium with a low glucose content (900 mg/L). Furthermore, C2C12 cells stimulated with the LDH inhibitor oxamate had reduced levels of BMP-2-induced osteoblast differentiation and histone lactylation, while addition of lactate to C2C12 cells cultured in low glucose medium resulted in partial restoration of osteoblast differentiation and histone lactylation. These results indicate that lactate synthesized by LDHA during glucose metabolism is important for osteoblast differentiation of C2C12 cells induced by BMP-2. Additionally, silencing of p300, a possible modifier of histone lactylation, also inhibited osteoblast differentiation and reduced histone lactylation. Together, these findings suggest a role of histone lactylation in promotion of undifferentiated cells to undergo differentiation into osteoblasts.
Topics: Histones; Lactic Acid; Cell Differentiation; Osteoblasts; Glucose
PubMed: 38051708
DOI: 10.1371/journal.pone.0293676 -
Journal of Advanced Research Jul 2023Acute bone loss after fracture is associated with various effects on the complete recovery process and a risk of secondary fractures among patients. Studies have... (Review)
Review
BACKGROUND
Acute bone loss after fracture is associated with various effects on the complete recovery process and a risk of secondary fractures among patients. Studies have reported similarities in pathophysiological mechanisms involved in acute bone loss after fractures and osteoporosis. However, given the silence nature of bone loss and bone metabolism complexities, the actual underlying pathophysiological mechanisms have yet to be fully elucidated.
AIM OF REVIEW
To elaborate the latest findings in basic research with a focus on acute bone loss after fracture. To briefly highlight potential therapeutic targets and current representative drugs. To arouse researchers' attention and discussion on acute bone loss after fracture.
KEY SCIENTIFIC CONCEPTS OF REVIEW
Bone loss after fracture is associated with immobilization, mechanical unloading, blood supply damage, sympathetic nerve regulation, and crosstalk between musculoskeletals among other factors. Current treatment strategies rely on regulation of osteoblasts and osteoclasts, therefore, there is a need to elucidate on the underlying mechanisms of acute bone loss after fractures to inform the development of efficacious and safe drugs. In addition, attention should be paid towards ensuring long-term skeletal health.
Topics: Humans; Osteoporosis; Fractures, Bone; Osteoclasts; Osteoblasts; Sympathetic Nervous System
PubMed: 36115662
DOI: 10.1016/j.jare.2022.08.019 -
The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review.Frontiers in Immunology 2023The complicated connections and cross talk between the skeletal system and the immune system are attracting more attention, which is developing into the field of... (Review)
Review
The complicated connections and cross talk between the skeletal system and the immune system are attracting more attention, which is developing into the field of Osteoimmunology. In this field, cytokines that are among osteoblasts and osteoclasts play a critical role in bone remodeling, which is a pathological process in the pathogenesis and development of osteoporosis. Those cytokines include the tumor necrosis factor (TNF) family, the interleukin (IL) family, interferon (IFN), chemokines, and so on, most of which influence the bone microenvironment, osteoblasts, and osteoclasts. This review summarizes the effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis, aiming to providing the latest reference to the role of immunology in osteoporosis.
Topics: Humans; Osteoclasts; Cytokines; Osteoblasts; Bone Remodeling; Osteoporosis
PubMed: 37475866
DOI: 10.3389/fimmu.2023.1222129 -
Biomedicine & Pharmacotherapy =... Sep 2023The endoplasmic reticulum (ER) is the main site for protein synthesis, folding, and secretion, and accumulation of the unfolded/misfolded proteins in the ER may induce... (Review)
Review
The endoplasmic reticulum (ER) is the main site for protein synthesis, folding, and secretion, and accumulation of the unfolded/misfolded proteins in the ER may induce ER stress. ER stress is an important participant in various intracellular signaling pathways. Prolonged- or high-intensity ER stress may induce cell apoptosis. Osteoporosis, characterized by imbalanced bone remodeling, is a global disease caused by many factors, such as ER stress. ER stress stimulates osteoblast apoptosis, increases bone loss, and promotes osteoporosis development. Many factors, such as the drug's adverse effects, metabolic disorders, calcium ion imbalance, bad habits, and aging, have been reported to activate ER stress, resulting in the pathological development of osteoporosis. Increasing evidence shows that ER stress regulates osteogenic differentiation, osteoblast activity, and osteoclast formation and function. Various therapeutic agents have been developed to counteract ER stress and thereby suppress osteoporosis development. Thus, inhibition of ER stress has become a potential target for the therapeutic management of osteoporosis. However, the in-depth understanding of ER stress in the pathogenesis of osteoporosis still needs more effort.
Topics: Humans; Osteogenesis; Endoplasmic Reticulum Stress; Osteoclasts; Osteoblasts; Osteoporosis; Unfolded Protein Response; Apoptosis
PubMed: 37437374
DOI: 10.1016/j.biopha.2023.115134 -
Oral Diseases Jul 2023Exploring the role of OPN N-glycosylation in osteoblasts and osteoclasts.
OBJECTIVES
Exploring the role of OPN N-glycosylation in osteoblasts and osteoclasts.
METHODS
Immunohistochemistry was used to detect the expression of OPN in mice with apical periodontitis. The asparagine at position 79 of the OPN protein was mutated to glutamine, and the above plasmids were transfected into osteoblasts and osteoclasts. The effect of OPN N-glycosylation on proliferation of osteoblasts and osteoclasts was detected by CCK8 assays. Western blotting was used to detect the expression of OPN N-glycosylation on osteoclasts and osteoblasts. Detection of N-glycosylation of OPN activated the NF-κB signaling pathway to regulate osteoblasts and osteoclasts.
RESULTS
OPN increased the expression in a mice model of apical periodontitis. The expression curve of OPN resembled a reverse V shape. The OPN N-glycosylation site was identified as 79 by MS. N-glycosylation of OPN promoted the proliferation of osteoclasts. But the N79 glycosylation site of mutant OPN could not increase the proliferation of osteoblasts. OPN N-glycosylation modulated the expression of osteoclast- and osteoblast-associated factors through the NF-κB signaling pathway. N-glycosylation of OPN promoted nuclear translocation of NF-κB in osteoclasts and osteoblasts.
CONCLUSIONS
The N-glycosylation site of OPN is 79. N-glycosylation of OPN played an important role in the biological function of OPN protein.
Topics: Mice; Animals; NF-kappa B; Osteopontin; Glycosylation; Osteoclasts; Osteoblasts; Periapical Periodontitis; Cell Differentiation
PubMed: 35451542
DOI: 10.1111/odi.14218 -
Endocrine Reviews Jan 2024The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by... (Review)
Review
The homeostasis of bone microenvironment is the foundation of bone health and comprises 2 concerted events: bone formation by osteoblasts and bone resorption by osteoclasts. In the early 21st century, leptin, an adipocytes-derived hormone, was found to affect bone homeostasis through hypothalamic relay and the sympathetic nervous system, involving neurotransmitters like serotonin and norepinephrine. This discovery has provided a new perspective regarding the synergistic effects of endocrine and nervous systems on skeletal homeostasis. Since then, more studies have been conducted, gradually uncovering the complex neuroendocrine regulation underlying bone homeostasis. Intriguingly, bone is also considered as an endocrine organ that can produce regulatory factors that in turn exert effects on neuroendocrine activities. After decades of exploration into bone regulation mechanisms, separate bioactive factors have been extensively investigated, whereas few studies have systematically shown a global view of bone homeostasis regulation. Therefore, we summarized the previously studied regulatory patterns from the nervous system and endocrine system to bone. This review will provide readers with a panoramic view of the intimate relationship between the neuroendocrine system and bone, compensating for the current understanding of the regulation patterns of bone homeostasis, and probably developing new therapeutic strategies for its related disorders.
Topics: Humans; Bone and Bones; Bone Resorption; Osteoblasts; Neurosecretory Systems; Homeostasis
PubMed: 37459436
DOI: 10.1210/endrev/bnad025 -
Cell Death & Disease Sep 2023Osteoporosis is not well treated due to the difficulty of finding commonalities between the various types of it. Iron homeostasis is a vital component in supporting...
Osteoporosis is not well treated due to the difficulty of finding commonalities between the various types of it. Iron homeostasis is a vital component in supporting biochemical functions, and iron overload is recognized as a common risk factor for osteoporosis. In this research, we found that there is indeed evidence of iron accumulation in the bone tissue of patients with osteoporosis and REPIN1, as an origin specific DNA binding protein, may play a key role in this process. We revealed that sh-Repin1 therapy can rescue bone loss in an iron-overload-induced osteoporosis mouse model. Knockdown of Repin1 can inhibit apoptosis and enhance the resistance of osteoblasts to iron overload toxicity. REPIN1 promoted apoptosis by regulating iron metabolism in osteoblasts. Mechanistically, knockdown of Repin1 decreased the expression of Lcn2, which ameliorated the toxic effects of intracellular iron overload. The anti-iron effect of lentivirus sh-Repin1 was partially reversed or replicated by changing LCN2 expression level via si-RNA or plasmid, which indirectly verified the key regulatory role of LCN2 as a downstream target. Furthermore, the levels of BCL2 and BAX, which play a key role in the mitochondrial apoptosis pathway, were affected. In summary, based on the results of clinical specimens, animal models and in vitro experiments, for the first time, we proved the key role of REPIN1 in iron metabolism-related osteoporosis.
Topics: Animals; Humans; Mice; Apoptosis; Disease Models, Animal; DNA-Binding Proteins; Iron; Iron Overload; Osteoblasts; Osteoporosis; RNA-Binding Proteins
PubMed: 37749079
DOI: 10.1038/s41419-023-06160-w -
Calcified Tissue International Jul 2023Maintenance of skeletal health is tightly regulated by osteocytes, osteoblasts, and osteoclasts via coordinated secretion of bone-derived factors, termed osteokines.... (Review)
Review
Maintenance of skeletal health is tightly regulated by osteocytes, osteoblasts, and osteoclasts via coordinated secretion of bone-derived factors, termed osteokines. Disruption of this coordinated process due to aging and metabolic disease promotes loss of bone mass and increased risk of fracture. Indeed, growing evidence demonstrates that metabolic diseases, including type 2 diabetes, liver disease and cancer are accompanied by bone loss and altered osteokine levels. With the persistent prevalence of cancer and the growing epidemic of metabolic disorders, investigations into the role of inter-tissue communication during disease progression are on the rise. While osteokines are imperative for bone homeostasis, work from us and others have identified that osteokines possess endocrine functions, exerting effects on distant tissues including skeletal muscle and liver. In this review we first discuss the prevalence of bone loss and osteokine alterations in patients with type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cirrhosis, and cancer. We then discuss the effects of osteokines in mediating skeletal muscle and liver homeostasis, including RANKL, sclerostin, osteocalcin, FGF23, PGE, TGF-β, BMPs, IGF-1 and PTHrP. To better understand how inter-tissue communication contributes to disease progression, it is essential that we include the bone secretome and the systemic roles of osteokines.
Topics: Humans; Diabetes Mellitus, Type 2; Bone and Bones; Osteoblasts; Osteoclasts; Bone Density; Bone Diseases, Metabolic
PubMed: 37193929
DOI: 10.1007/s00223-023-01093-0 -
Calcified Tissue International Jul 2023Bone is a highly dynamic tissue, and the constant actions of bone-forming and bone-resorbing cells are responsible for attaining peak bone mass, maintaining bone mass in... (Review)
Review
Bone is a highly dynamic tissue, and the constant actions of bone-forming and bone-resorbing cells are responsible for attaining peak bone mass, maintaining bone mass in the adults, and the subsequent bone loss with aging and menopause, as well as skeletal complications of diseases and drug side-effects. It is now accepted that the generation and activity of bone-forming osteoblasts and bone-resorbing osteoclasts is modulated by osteocytes, osteoblast-derived cells embedded in the bone matrix. The interaction among bone cells occurs through direct contact and via secreted molecules. In addition to the regulation of bone cell function, molecules released by these cells are also able to reach the circulation and have effects in other tissues and organs in healthy individuals. Moreover, bone cell products have also been associated with the establishment or progression of diseases, including cancer and muscle weakness. In this review, we will discuss the role of bone as an endocrine organ, and the effect of selected, osteoblast-, osteocyte-, and osteoclast-secreted molecules on other tissues.
Topics: Humans; Osteocytes; Osteoblasts; Bone and Bones; Osteoclasts; Minerals; Cell Differentiation
PubMed: 37171619
DOI: 10.1007/s00223-023-01091-2 -
Experimental & Molecular Medicine Jul 2023Although the normal physiological level of oxidative stress is beneficial for maintaining bone homeostasis, imbalance between reactive oxygen species (ROS) production...
Although the normal physiological level of oxidative stress is beneficial for maintaining bone homeostasis, imbalance between reactive oxygen species (ROS) production and antioxidant defense can cause various bone diseases. The purpose of this study was to determine whether nicotinamide (NAM), an NAD precursor, can support the maintenance of bone homeostasis by regulating osteoblasts. Here, we found that NAM enhances osteoblast differentiation and mitochondrial metabolism. NAM increases the expression of antioxidant enzymes, which is due to increased FOXO3A transcriptional activity via SIRT3 activation. NAM has not only a preventive effect against weak and chronic oxidative stress but also a therapeutic effect against strong and acute exposure to HO in osteoblast differentiation. Collectively, the results indicate that NAM increases mitochondrial biogenesis and antioxidant enzyme expression through activation of the SIRT3-FOXO3A axis, which consequently enhances osteoblast differentiation. These results suggest that NAM could be a potential preventive or therapeutic agent for bone diseases caused by ROS.
Topics: Humans; Antioxidants; Reactive Oxygen Species; Niacinamide; Sirtuin 3; Hydrogen Peroxide; Oxidative Stress; Osteoblasts; Bone Diseases
PubMed: 37464093
DOI: 10.1038/s12276-023-01041-w