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International Journal of Molecular... Mar 2022Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in... (Review)
Review
Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients' quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.
Topics: Arthritis, Rheumatoid; Humans; Inflammation; Osteoclasts; Quality of Life; RANK Ligand; Synovitis
PubMed: 35270012
DOI: 10.3390/ijms23052871 -
Cell Death & Disease Oct 2020Osteoclasts are multinucleated giant cells with the ability to degrade bone tissue, and are closely related to abnormal bone metabolic diseases. Endoplasmic reticulum...
Osteoclasts are multinucleated giant cells with the ability to degrade bone tissue, and are closely related to abnormal bone metabolic diseases. Endoplasmic reticulum (ER) is an organelle responsible for protein modification, quality control, and transportation. The accumulation of unfolded or misfolded proteins in ER cavity induces ER stress. Double-stranded RNA-dependent protein kinase-like ER kinase (PERK) is an ER stress-sensing protein, which is ubiquitous in eukaryotic cells. Systemic PERK knockout mice show severe bone loss, suggesting that PERK is of great significance for maintaining the normal growth and development of bone tissue, but the role of PERK in osteoclastogenesis is still unclear. In this study, we found that PERK was significantly activated during RANKL-induced osteoclast differentiation; knockdown of PERK by siRNA and inhibition of PERK by GSK2606414, respectively, had significant negative regulatory effects on the formation and bone resorption of osteoclasts. PERK inhibitor GSK2606414 down-regulated the mRNA levels and protein expression of osteoclast differentiation marker genes, and inhibited RANKL-induced activation of Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Treatment with PERK inhibitor GSK2606414 in ovariectomized mouse model significantly suppressed bone loss and osteoclast formation. Thapsigargin activated ER stress to enhance autophagy, while GSK2606414 had a significant inhibitory effect on autophagy flux and autophagosome formation. Antioxidant N-acetylcysteine (NAC) could inhibit the expression of PERK phosphorylation, osteoclast-related proteins and autophagy-related proteins, but the use of PERK activator CCT020312 can reverse inhibition effect of NAC. Our findings demonstrate a key role for PERK in osteoclast differentiation and suggest its therapeutic potential.
Topics: Adenine; Animals; Bone and Bones; Cell Differentiation; Down-Regulation; Endoplasmic Reticulum Stress; Female; Homeostasis; Humans; Indoles; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoclasts; RANK Ligand; Random Allocation; Thapsigargin; eIF-2 Kinase
PubMed: 33051453
DOI: 10.1038/s41419-020-03046-z -
Nature Communications Feb 2022Bone metabolism is regulated by the cooperative activity between bone-forming osteoblasts and bone-resorbing osteoclasts. However, the mechanisms mediating the switch...
Bone metabolism is regulated by the cooperative activity between bone-forming osteoblasts and bone-resorbing osteoclasts. However, the mechanisms mediating the switch between the osteoblastic and osteoclastic phases have not been fully elucidated. Here, we identify a specific subset of mature osteoblast-derived extracellular vesicles that inhibit bone formation and enhance osteoclastogenesis. Intravital imaging reveals that mature osteoblasts secrete and capture extracellular vesicles, referred to as small osteoblast vesicles (SOVs). Co-culture experiments demonstrate that SOVs suppress osteoblast differentiation and enhance the expression of receptor activator of NF-κB ligand, thereby inducing osteoclast differentiation. We also elucidate that the SOV-enriched microRNA miR-143 inhibits Runt-related transcription factor 2, a master regulator of osteoblastogenesis, by targeting the mRNA expression of its dimerization partner, core-binding factor β. In summary, we identify SOVs as a mode of cell-to-cell communication, controlling the dynamic transition from bone-forming to bone-resorbing phases in vivo.
Topics: Bone Resorption; Cell Differentiation; Humans; Osteoblasts; Osteoclasts; Osteogenesis; RANK Ligand; Signal Transduction
PubMed: 35210428
DOI: 10.1038/s41467-022-28673-2 -
Bone Research Oct 2023Glycans, either alone or in complex with glycan-binding proteins, are essential structures that can regulate cell biology by mediating protein stability or receptor... (Review)
Review
Glycans, either alone or in complex with glycan-binding proteins, are essential structures that can regulate cell biology by mediating protein stability or receptor dimerization under physiological and pathological conditions. Certain glycans are ligands for lectins, which are carbohydrate-specific receptors. Bone is a complex tissue that provides mechanical support for muscles and joints, and the regulation of bone mass in mammals is governed by complex interplay between bone-forming cells, called osteoblasts, and bone-resorbing cells, called osteoclasts. Bone erosion occurs when bone resorption notably exceeds bone formation. Osteoclasts may be activated during cancer, leading to a range of symptoms, including bone pain, fracture, and spinal cord compression. Our understanding of the role of protein glycosylation in cells and tissues involved in osteoclastogenesis suggests that glycosylation-based treatments can be used in the management of diseases. The aims of this review are to clarify the process of bone resorption and investigate the signaling pathways mediated by glycosylation and their roles in osteoclast biology. Moreover, we aim to outline how the lessons learned about these approaches are paving the way for future glycobiology-focused therapeutics.
Topics: Animals; Humans; Osteoclasts; Glycomics; Bone Resorption; Carrier Proteins; Cell Differentiation; Polysaccharides; Mammals
PubMed: 37884496
DOI: 10.1038/s41413-023-00293-6 -
International Journal of Biological... 2020Steroid-induced osteonecrosis of the femoral head (ONFH) is a progressive bone disorder which typically results in femoral head collapse and hip joint dysfunction. It is...
Steroid-induced osteonecrosis of the femoral head (ONFH) is a progressive bone disorder which typically results in femoral head collapse and hip joint dysfunction. It is well-accepted that abnormal osteoclast activity contributes to loss of bone structural integrity and subchondral fracture in ONFH. However, the pathophysiologic mechanisms underlying the recruitment and hyperactivation of osteoclasts in ONFH remain incompletely understood. We assessed the changes of reactive oxygen species (ROS) level and subsequent osteoclast alterations in steroid-induced osteonecrotic femoral heads from both patients and rat ONFH models. When compared with healthy neighboring bone, the necrotic region of human femoral head was characterized by robust up-regulated expression of osteoclast-related proteins [cathepsin K and tartrate-resistant acid phosphatase(TRAP)] but pronounced down-regulation of antioxidant enzymes (catalase, γ-glutamylcysteine synthetase [γ-GCSc], and superoxide dismutase 1 [SOD1]). In addition, the ratio of (encoding RANKL)/ (encoding OPG) was increased within the necrotic bone. Consistently, in rat ONFH models induced by methylprednisolone (MPSL) and imiquimod (IMI), significant bone loss in the femoral head was observed, attributable to increased numbers of TRAP positive osteoclasts. Furthermore, the decreased expression of antioxidant enzymes observed by immunoblotting was accompanied by increased ROS fluorescence signals of dihydroethidium (DHE) in rat ONFH models. Therefore, this study lends support to the rationale that antioxidant agents may be a promising therapeutic avenue to prevent or mitigate the progression of steroid-induced ONFH by inhibiting ROS level and hyperactive osteoclasts.
Topics: Adjuvants, Immunologic; Adult; Animals; Biomarkers; Female; Femur Head; Femur Head Necrosis; Glucocorticoids; Humans; Imiquimod; Male; Methylprednisolone; Osteoclasts; Random Allocation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species
PubMed: 32398957
DOI: 10.7150/ijbs.40917 -
JCI Insight Apr 2020Increased subchondral bone angiogenesis with blood vessels breaching the tidemark into the avascular cartilage is a diagnostic feature of human osteoarthritis. However,...
Increased subchondral bone angiogenesis with blood vessels breaching the tidemark into the avascular cartilage is a diagnostic feature of human osteoarthritis. However, the mechanisms that initiate subchondral bone angiogenesis remain unclear. We show that abnormally increased platelet-derived growth factor-BB (PDGF-BB) secretion by mononuclear preosteoclasts induces subchondral bone angiogenesis, contributing to osteoarthritis development. In mice after destabilization of the medial meniscus (DMM), aberrant joint subchondral bone angiogenesis developed during an early stage of osteoarthritis, before articular cartilage damage occurred. Mononuclear preosteoclasts in subchondral bone secrete excessive amounts of PDGF-BB, which activates platelet-derived growth factor receptor-β (PDGFR-β) signaling in pericytes for neo-vessel formation. Selective knockout of PDGF-BB in preosteoclasts attenuates subchondral bone angiogenesis and abrogates joint degeneration and subchondral innervation induced by DMM. Transgenic mice that express PDGF-BB in preosteoclasts recapitulate pathological subchondral bone angiogenesis and develop joint degeneration and subchondral innervation spontaneously. Our study provides the first evidence to our knowledge that PDGF-BB derived from preosteoclasts is a key driver of pathological subchondral bone angiogenesis during osteoarthritis development and offers a new avenue for developing early treatments for this disease.
Topics: Animals; Becaplermin; Bone and Bones; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Osteoarthritis; Osteoclasts
PubMed: 32208385
DOI: 10.1172/jci.insight.135446 -
Current Osteoporosis Reports Dec 2023Osteoclasts are crucial for the dynamic remodeling of bone as they resorb old and damaged bone, making space for new bone. Metabolic reprogramming in these cells not... (Review)
Review
PURPOSE OF REVIEW
Osteoclasts are crucial for the dynamic remodeling of bone as they resorb old and damaged bone, making space for new bone. Metabolic reprogramming in these cells not only supports phenotypic changes, but also provides the necessary energy for their highly energy-consuming activity, bone resorption. In this review, we highlight recent developments in our understanding of the metabolic adaptations that influence osteoclast behavior and the overall remodeling of bone tissue.
RECENT FINDINGS
Osteoclasts undergo metabolic reprogramming to meet the energy demands during their transition from precursor cells to fully mature bone-resorbing osteoclasts. Recent research has made considerable progress in pinpointing crucial metabolic adaptations and checkpoint proteins in this process. Notably, glucose metabolism, mitochondrial biogenesis, and oxidative respiration were identified as essential pathways involved in osteoclast differentiation, cytoskeletal organization, and resorptive activity. Furthermore, the interaction between these pathways and amino acid and lipid metabolism adds to the complexity of the process. These interconnected processes can function as diverse fuel sources or have independent regulatory effects, significantly influencing osteoclast function. Energy metabolism in osteoclasts involves various substrates and pathways to meet the energetic requirements of osteoclasts throughout their maturation stages. This understanding of osteoclast biology may provide valuable insights for modulating osteoclast activity during the pathogenesis of bone-related disorders and may pave the way for the development of innovative therapeutic strategies.
Topics: Humans; Osteoclasts; Energy Metabolism; Bone Resorption; Bone and Bones; Cell Differentiation
PubMed: 37816910
DOI: 10.1007/s11914-023-00825-3 -
Frontiers in Endocrinology 2023The skeleton is an organ of dual functionality; on the one hand, it provides protection and structural competence. On the other hand, it participates extensively in... (Review)
Review
The skeleton is an organ of dual functionality; on the one hand, it provides protection and structural competence. On the other hand, it participates extensively in coordinating homeostasis globally given that it is a mineral and hormonal reservoir. Bone is the only tissue in the body that goes through strategically consistent bouts of bone resorption to ensure its integrity and organismal survival in a temporally and spatially coordinated process, known as bone remodeling. Bone remodeling is directly enacted by three skeletal cell types, osteoclasts, osteoblasts, and osteocytes; these cells represent the acting force in a basic multicellular unit and ensure bone health maintenance. The osteocyte is an excellent mechanosensory cell and has been positioned as the choreographer of bone remodeling. It is, therefore, not surprising that a holistic grasp of the osteocyte entity in the bone is warranted. This review discusses osteocytogenesis and associated molecular and morphological changes and describes the osteocytic lacunocanalicular network (LCN) and its organization. We highlight new knowledge obtained from transcriptomic analyses of osteocytes and discuss the regulatory role of osteocytes in promoting osteoclastogenesis with an emphasis on the case of osteoclastogenesis in anosteocytic bones. We arrive at the conclusion that osteocytes exhibit several redundant means through which osteoclast formation can be initiated. However, whether osteocytes are true "orchestrators of bone remodeling" cannot be verified from the animal models used to study osteocyte biology . Results from studying osteocyte biology using current animal models should come with the caveat that these models are not osteocyte-specific, and conclusions from these studies should be interpreted cautiously.
Topics: Animals; Osteogenesis; Osteoclasts; Bone and Bones; Bone Resorption; Osteocytes
PubMed: 37293482
DOI: 10.3389/fendo.2023.1121727 -
Stem Cell Research & Therapy Dec 2019Aspirin has been demonstrated to promote osteoblast-mediated bone formation and inhibit osteoclast (OC)-mediated bone resorption. However, it remains unclear whether...
BACKGROUND
Aspirin has been demonstrated to promote osteoblast-mediated bone formation and inhibit osteoclast (OC)-mediated bone resorption. However, it remains unclear whether aspirin influences other immune cells during bone resorption. Dendritic cells (DCs), the most potent antigen-presenting cells, can also transdifferentiate into active OCs in the presence of receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The effects of aspirin on DC-derived OCs (DDOCs) were investigated in the current study.
METHODS
Flow cytometry and mixed lymphocyte reaction (MLR) assays were used for DC identification. The proliferative capacity of DCs was determined by BrdU assays. Apoptosis was examined by flow cytometry. The osteoclastic potential of DCs was tested using tartrate-resistant acid phosphatase (TRAP) staining, western blotting, and reverse transcription polymerase chain reaction (RT-PCR). Western blotting was also used to examine signaling pathways. A mandibular bone defect model was established to assess the effect of aspirin on bone resorption.
RESULTS
Aspirin had no influence on the surface phenotype, proliferation, or apoptosis of DCs, though aspirin significantly inhibited osteoclast differentiation in RANKL-stimulated DCs. DC osteoclast differentiation was modulated by aspirin via the nuclear factor kappa B (NF-κB)/nuclear factor of activated T cell, cytoplasmic 1 (NFATc1) signaling pathway. Aspirin treatment also had favorable therapeutic effects on bone regeneration in the bone defect model, and the number of osteoclasts was decreased.
CONCLUSIONS
Aspirin inhibited RANKL-induced OC differentiation in DCs via the NF-κB pathway, downregulating expression of NFATc1. Aspirin treatment promoted bone regeneration by inhibiting DDOC activation in the early stages of inflammation in a rat mandibular bone defect model.
Topics: Animals; Apoptosis; Aspirin; Bone Diseases; Bone Regeneration; CD11c Antigen; Cell Differentiation; Dendritic Cells; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; NF-kappa B; NFATC Transcription Factors; Osteoclasts; RANK Ligand; Rats; Signal Transduction
PubMed: 31805984
DOI: 10.1186/s13287-019-1500-x -
Acta Pharmacologica Sinica Feb 2020In chronic infectious diseases caused by gram-negative bacteria, such as osteomyelitis, septic arthritis, and periodontitis, osteoclastic activity is enhanced with...
In chronic infectious diseases caused by gram-negative bacteria, such as osteomyelitis, septic arthritis, and periodontitis, osteoclastic activity is enhanced with elevated inflammation, which disturbs the bone homeostasis and results in osteolysis. Lipopolysaccharide (LPS), as a bacteria product, plays an important role in this process. Recent evidence shows that an antimalarial drug artesunate attenuates LPS-induced osteolysis independent of RANKL. In this study we evaluated the effects of artesunate on LPS-induced osteoclastogenesis in vitro and femur osteolysis in vivo, and explored the mechanisms underlying the effects of artesunate on LPS-induced osteoclast differentiation independent of RANKL. In preosteoclastic RAW264.7 cells, we found that artesunate (1.56-12.5 μM) dose dependently inhibited LPS-induced osteoclast formation accompanied by suppressing LPS-stimulated osteoclast-related gene expression (Fra-2, TRAP, Cathepsin K, β3-integrin, DC-STAMP, and Atp6v0d2). We showed that artesunate (3.125-12.5 µM) inhibited LPS-stimulated nuclear factor of activated T cells c1 (NFATc1) but not NF-κB transcriptional activity; artesunate (6.25, 12.5 μM) significantly inhibited LPS-stimulated NFATc1 protein expression. Furthermore, artesunate treatment markedly suppressed LPS-induced Ca influx, and decreased the expression of PP2B-Aα (calcineurin) and pPLCγ1 in the cells. In addition, artesunate treatment significantly decreased the expression of upstream signals TLR4 and TRAF6 during LPS-induced osteoclastogenesis. Administration of artesunate (10 mg/kg, ip) for 8 days effectively inhibited serum TNF-α levels and ameliorated LPS (5 mg/kg, ip)-induced inflammatory bone loss in vivo. Taken together, artesunate attenuates LPS-induced inflammatory osteoclastogenesis by inhibiting the expression of TLR4/TRAF6 and the downstream PLCγ1-Ca-NFATc1 signaling pathway. Artesunate is a valuable choice to treat bone loss induced by gram-negative bacteria infection or inflammation in RANKL-independent pathway.
Topics: Animals; Antimalarials; Artesunate; Calcium; Dose-Response Relationship, Drug; Female; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred ICR; NFATC Transcription Factors; Osteoclasts; Osteogenesis; Phospholipase C gamma; RAW 264.7 Cells; Signal Transduction; TNF Receptor-Associated Factor 6; Toll-Like Receptor 4
PubMed: 31431733
DOI: 10.1038/s41401-019-0289-6