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Seminars in Immunopathology Sep 2019Skeleton undergoes constant remodeling process to maintain healthy bone mass. However, in pathological conditions, bone remodeling is deregulated, resulting in... (Review)
Review
Skeleton undergoes constant remodeling process to maintain healthy bone mass. However, in pathological conditions, bone remodeling is deregulated, resulting in unbalanced bone resorption and formation. Abnormal osteoclast formation and activation play a key role in osteolysis, such as in rheumatoid arthritis and osteoporosis. As potential therapeutic targets or biomarkers, miRNAs have gained rapidly growing research and clinical attention. miRNA-based therapeutics is recently entering a new era for disease treatment. Such progress is emerging in treatment of skeletal diseases. In this review, we discuss miRNA biogenesis, advances in the strategies for miRNA target identification, important miRNAs involved in osteoclastogenesis and disease models, their regulated mechanisms, and translational potential and challenges in bone homeostasis and related diseases.
Topics: Bone Diseases; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; MicroRNAs; Osteoclasts; Osteogenesis; Protein Biosynthesis; RNA Interference
PubMed: 31591677
DOI: 10.1007/s00281-019-00761-4 -
International Journal of Molecular... May 2020The increasing of intracellular calcium concentration is a fundamental process for mediating osteoclastogenesis, which is involved in osteoclastic bone resorption.... (Review)
Review
The increasing of intracellular calcium concentration is a fundamental process for mediating osteoclastogenesis, which is involved in osteoclastic bone resorption. Cytosolic calcium binds to calmodulin and subsequently activates calcineurin, leading to NFATc1 activation, a master transcription factor required for osteoclast differentiation. Targeting the various activation processes in osteoclastogenesis provides various therapeutic strategies for bone loss. Diverse compounds that modulate calcium signaling have been applied to regulate osteoclast differentiation and, subsequently, attenuate bone loss. Thus, in this review, we summarized the modulation of the NFATc1 pathway through various compounds that regulate calcium signaling and the calcium influx machinery. Furthermore, we addressed the involvement of transient receptor potential channels in osteoclastogenesis.
Topics: Animals; Calcium Signaling; Humans; NFATC Transcription Factors; Osteoclasts; Osteogenesis; Transient Receptor Potential Channels
PubMed: 32455661
DOI: 10.3390/ijms21103646 -
Experimental & Molecular Medicine Jun 2022Branched-chain aminotransferase 1 (BCAT1) transfers the amine group on branched-chain amino acids (BCAAs) to alpha-ketoglutarate. This generates glutamate along with...
Branched-chain aminotransferase 1 (BCAT1) transfers the amine group on branched-chain amino acids (BCAAs) to alpha-ketoglutarate. This generates glutamate along with alpha-keto acids that are eventually oxidized to provide the cell with energy. BCAT1 thus plays a critical role in sustaining BCAA concentrations and availability as an energy source. Osteoclasts have high metabolic needs during differentiation. When we assessed the levels of amino acids in bone marrow macrophages (BMMs) that were undergoing receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation, we found that the BCAA levels steadily increase during this process. In vitro analyses then showed that all three BCAAs but especially valine were needed for osteoclast maturation. Moreover, selective inhibition of BCAT1 with gabapentin significantly reduced osteoclast maturation. Expression of enzymatically dead BCAT1 also abrogated osteoclast maturation. Importantly, gabapentin inhibited lipopolysaccharide (LPS)-induced bone loss of calvaria in mice. These findings suggest that BCAT1 could serve as a therapeutic target that dampens osteoclast formation.
Topics: Amino Acids, Branched-Chain; Animals; Cell Differentiation; Gabapentin; Mice; Osteoclasts; RANK Ligand; Transaminases
PubMed: 35760874
DOI: 10.1038/s12276-022-00775-3 -
STAR Protocols Jun 2021Mesenchymal-derived osteoblasts play a key role in bone formation via synthesis and mineralization of the bone and bone remodeling. Osteoclasts are multinucleated cells...
Mesenchymal-derived osteoblasts play a key role in bone formation via synthesis and mineralization of the bone and bone remodeling. Osteoclasts are multinucleated cells of hematopoietic origin with a role in bone resorption. Here, we describe a protocol for generating primary cultures of these two cell types from bone tissue including the femur, tibia, and humerus of young mice. We describe methods for addressing their activity and/or differentiation, enabling studying the effects of various treatments during or following differentiation . For further practical example of using these protocols, please refer to Chevalier et al. (2020).
Topics: Animals; Mice; Osteoblasts; Osteoclasts; Primary Cell Culture
PubMed: 33912848
DOI: 10.1016/j.xpro.2021.100452 -
Genetics Oct 2023There has been a growing interest in the role of the subchondral bone and its resident osteoclasts in the progression of osteoarthritis (OA). A recent genome-wide...
There has been a growing interest in the role of the subchondral bone and its resident osteoclasts in the progression of osteoarthritis (OA). A recent genome-wide association study (GWAS) identified 100 independent association signals for OA traits. Most of these signals are led by noncoding variants, suggesting that genetic regulatory effects may drive many of the associations. We have generated a unique human osteoclast-like cell-specific expression quantitative trait locus (eQTL) resource for studying the genetics of bone disease. Considering the potential role of osteoclasts in the pathogenesis of OA, we performed an integrative analysis of this dataset with the recently published OA GWAS results. Summary data-based Mendelian randomization (SMR) and colocalization analyses identified 38 genes with a potential role in OA, including some that have been implicated in Mendelian diseases with joint/skeletal abnormalities, such as BICRA, EIF6, CHST3, and FBN2. Several OA GWAS signals demonstrated colocalization with more than one eQTL peak, including at 19q13.32 (hip OA with BCAM, PRKD2, and BICRA eQTL). We also identified a number of eQTL signals colocalizing with more than one OA trait, including FAM53A, GCAT, HMGN1, MGAT4A, RRP7BP, and TRIOBP. An SMR analysis identified 3 loci with evidence of pleiotropic effects on OA-risk and gene expression: LINC01481, CPNE1, and EIF6. Both CPNE1 and EIF6 are located at 20q11.22, a locus harboring 2 other strong OA candidate genes, GDF5 and UQCC1, suggesting the presence of an OA-risk gene cluster. In summary, we have used our osteoclast-specific eQTL dataset to identify genes potentially involved with the pathogenesis of OA.
Topics: Humans; Osteoclasts; Genome-Wide Association Study; Genetic Predisposition to Disease; Gene Expression Regulation; Osteoarthritis
PubMed: 37579195
DOI: 10.1093/genetics/iyad150 -
International Journal of Molecular... Dec 2020Calcium (Ca) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in... (Review)
Review
Calcium (Ca) plays an important role in regulating the differentiation and function of osteoclasts. Calcium oscillations (Ca oscillations) are well-known phenomena in receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption via calcineurin. Many modifiers are involved in the fine-tuning of Ca oscillations in osteoclasts. In addition to macrophage colony-stimulating factors (M-CSF; CSF-1) and RANKL, costimulatory signaling by immunoreceptor tyrosine-based activation motif-harboring adaptors is important for Ca oscillation generation and osteoclast differentiation. DNAX-activating protein of 12 kD is always necessary for osteoclastogenesis. In contrast, Fc receptor gamma (FcRγ) works as a key controller of osteoclastogenesis especially in inflammatory situation. FcRγ has a cofactor in fine-tuning of Ca oscillations. Some calcium channels and transporters are also necessary for Ca oscillations. Transient receptor potential (TRP) channels are well-known environmental sensors, and TRP vanilloid channels play an important role in osteoclastogenesis. Lysosomes, mitochondria, and endoplasmic reticulum (ER) are typical organelles for intracellular Ca storage. Ryanodine receptor, inositol trisphosphate receptor, and sarco/endoplasmic reticulum Ca ATPase on the ER modulate Ca oscillations. Research on Ca oscillations in osteoclasts has still many problems. Surprisingly, there is no objective definition of Ca oscillations. Causality between Ca oscillations and osteoclast differentiation and/or function remains to be examined.
Topics: Animals; Bone Resorption; Calcium; Calcium Channels; Calcium Signaling; Cell Differentiation; Humans; Osteoclasts; Osteogenesis
PubMed: 33375370
DOI: 10.3390/ijms22010180 -
International Journal of Molecular... Jan 2021Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell... (Review)
Review
Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/β-catenin, BMP and RANKL/OPG, are outlined.
Topics: Animals; Bone Regeneration; Bone and Bones; Humans; Osteoblasts; Osteoclasts; Osteocytes; Receptors, Notch; Signal Transduction
PubMed: 33572704
DOI: 10.3390/ijms22031325 -
Cells Jan 2021Bone is a dynamic tissue and is constantly being remodeled by bone cells. Metabolic reprogramming plays a critical role in the activation of these bone cells and... (Review)
Review
Bone is a dynamic tissue and is constantly being remodeled by bone cells. Metabolic reprogramming plays a critical role in the activation of these bone cells and skeletal metabolism, which fulfills the energy demand for bone remodeling. Among various metabolic pathways, the importance of lipid metabolism in bone cells has long been appreciated. More recent studies also establish the link between bone loss and lipid-altering conditions-such as atherosclerotic vascular disease, hyperlipidemia, and obesity-and uncover the detrimental effect of fat accumulation on skeletal homeostasis and increased risk of fracture. Targeting lipid metabolism with statin, a lipid-lowering drug, has been shown to improve bone density and quality in metabolic bone diseases. However, the molecular mechanisms of lipid-mediated regulation in osteoclasts are not completely understood. Thus, a better understanding of lipid metabolism in osteoclasts can be used to harness bone cell activity to treat pathological bone disorders. This review summarizes the recent developments of the contribution of lipid metabolism to the function and phenotype of osteoclasts.
Topics: Animals; Bone and Bones; Cell Differentiation; Cholesterol; Humans; Lipid Metabolism; Osteoclasts; Sterol Regulatory Element Binding Proteins
PubMed: 33430327
DOI: 10.3390/cells10010089 -
Frontiers in Immunology 2024As the world population ages, osteoporosis, the most common disease of bone metabolism, affects more than 200 million people worldwide. The etiology is an imbalance in... (Review)
Review
As the world population ages, osteoporosis, the most common disease of bone metabolism, affects more than 200 million people worldwide. The etiology is an imbalance in bone remodeling process resulting in more significant bone resorption than bone remodeling. With the advent of the osteoimmunology field, the immune system's role in skeletal pathologies is gradually being discovered. The cytokine interferon-gamma (IFN-γ), a member of the interferon family, is an important factor in the etiology and treatment of osteoporosis because it mediates bone remodeling. This review starts with bone remodeling process and includes the cellular and key signaling pathways of bone remodeling. The effects of IFN-γ on osteoblasts, osteoclasts, and bone mass are discussed separately, while the overall effects of IFN-γ on primary and secondary osteoporosis are summarized. The net effect of IFN-γ on bone appears to be highly dependent on the environment, dose, concentration, and stage of cellular differentiation. This review focuses on the mechanisms of bone remodeling and bone immunology, with a comprehensive discussion of the relationship between IFN-γ and osteoporosis. Finding the paradoxical balance of IFN-γ in bone immunology and exploring the potential of its clinical application provide new ideas for the clinical treatment of osteoporosis and drug development.
Topics: Humans; Bone Remodeling; Osteoporosis; Interferon-gamma; Animals; Osteoclasts; Osteoblasts; Signal Transduction; Bone and Bones
PubMed: 38817601
DOI: 10.3389/fimmu.2024.1396122 -
JCI Insight Dec 2023Osteoclasts specialize in bone resorption and are critical for bone remodeling. Previous studies have shown that osteoclasts possess abundant mitochondria and derive...
Osteoclasts specialize in bone resorption and are critical for bone remodeling. Previous studies have shown that osteoclasts possess abundant mitochondria and derive most energy through oxidative phosphorylation (OXPHOS). However, the energy substrates fueling OXPHOS in osteoclasts remain to be fully defined. Here, we showed that osteoclast differentiation was coupled with increased oxidation of glucose, glutamine, and oleate. Transcriptomic analyses with RNA sequencing revealed marked upregulation of genes participating in OXPHOS and mitochondrial fatty acid oxidation, during osteoclast differentiation. Increased mitochondrial oxidation of long-chain fatty acids was required for osteoclast differentiation in vitro. However, blocking fatty acid oxidation in vivo, by deletion of carnitine palmitoyltransferase 1a (Cpt1a) in osteoclast progenitors, impaired osteoclast formation only in the female mice. The Cpt1a-deficient females were further protected from osteoclast activation by a high-fat diet. The males, on the contrary, exhibited normal bone resorption despite Cpt1a deletion, regardless of the dietary fat content. Moreover, concurrent deletion of mitochondrial pyruvate carrier 1 and Cpt1a, blocking mitochondrial oxidation of both glucose and fatty acids in the osteoclast lineage, failed to impede bone resorption in the males. The study therefore uncovers a female-specific dependence on mitochondrial oxidation of fatty acids and glucose in osteoclasts in vivo.
Topics: Male; Mice; Female; Animals; Osteoclasts; Sex Characteristics; Bone Resorption; Mitochondria; Fatty Acids; Glucose
PubMed: 37917194
DOI: 10.1172/jci.insight.174293