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Molecules (Basel, Switzerland) Apr 2021Although the anti-tumor and anti-infective properties of β-glucans have been well-discussed, their role in bone metabolism has not been reviewed so far. This review... (Review)
Review
Although the anti-tumor and anti-infective properties of β-glucans have been well-discussed, their role in bone metabolism has not been reviewed so far. This review discusses the biological effects of β-glucans on bone metabolisms, especially on bone-resorbing osteoclasts, which are differentiated from hematopoietic precursors. Multiple immunoreceptors that can recognize β-glucans were reported to be expressed in osteoclast precursors. Coordinated co-stimulatory signals mediated by these immunoreceptors are important for the regulation of osteoclastogenesis and bone remodeling. Curdlan from the bacterium negatively regulates osteoclast differentiation in vitro by affecting both the osteoclast precursors and osteoclast-supporting cells. We also showed that laminarin, lichenan, and glucan from baker's yeast, as well as β-1,3-glucan from inhibit the osteoclast formation in bone marrow cells. Consistent with these findings, systemic and local administration of β-glucan derived from and suppressed bone resorption in vivo. However, zymosan derived from stimulated the bone resorption activity and is widely used to induce arthritis in animal models. Additional research concerning the relationship between the molecular structure of β-glucan and its effect on osteoclastic bone resorption will be beneficial for the development of novel treatment strategies for bone-related diseases.
Topics: Animals; Bone Regeneration; Bone Resorption; Bone and Bones; Cartilage; Cell Differentiation; Glucans; Humans; Immunomodulation; Osteoclasts; Osteogenesis; Receptors, Immunologic
PubMed: 33915775
DOI: 10.3390/molecules26071982 -
Cell Communication and Signaling : CCS Jul 2022Osteoporosis is a common skeletal disease with marked bone loss, deterioration of the bone microstructure and bone fragility. An abnormal bone remodelling cycle with... (Review)
Review
Osteoporosis is a common skeletal disease with marked bone loss, deterioration of the bone microstructure and bone fragility. An abnormal bone remodelling cycle with relatively increased bone resorption is the crucial pathophysiological mechanism. Bone remodelling is predominantly controlled by osteoblasts and osteoclasts, which are specialized cell types that are regulated by a variety of osteogenic and osteoclastic factors, including cytokines expressed within the bone microenvironment under local or systemic inflammatory conditions. Signal transducer and activator of transcription 3 (STAT3) plays a prominent role in the communication between cytokines and kinases by binding downstream gene promotors and is involved in a wide range of biological or pathological processes. Emerging evidence suggests that STAT3 and its network participate in bone remodelling and the development of osteoporosis, and this factor may be a potent target for osteoporosis treatment. This review focuses on the role and molecular mechanism of the STAT3 signalling pathway in osteogenesis, osteoclastogenesis and osteoporosis, particularly the bone-related cytokines that regulate the osteoblastic differentiation of bone marrow stromal cells and the osteoclastic differentiation of bone marrow macrophages by initiating STAT3 signalling. This review also examines the cellular interactions among immune cells, haematopoietic cells and osteoblastic/osteoclastic cells. Video abstract.
Topics: Bone Resorption; Cell Differentiation; Cytokines; Humans; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; RANK Ligand; STAT3 Transcription Factor
PubMed: 35879773
DOI: 10.1186/s12964-022-00924-1 -
Nature Communications Dec 2023Osteoclasts are the primary target for osteoporosis drug development. Recent animal studies revealed the crucial roles of osteoblasts in regulating osteoclastogenesis...
Osteoclasts are the primary target for osteoporosis drug development. Recent animal studies revealed the crucial roles of osteoblasts in regulating osteoclastogenesis and the longer lifespans of osteoclasts than previously thought with fission and recycling. However, existing culture platforms are limited to replicating these newly identified cellular processes. We report a demineralized bone paper (DBP)-based osteoblast culture and osteoclast assay platform that replicates osteoclast fusion, fission, resorption, and apoptosis with high fidelity and analytical power. An osteoid-inspired DBP supports rapid and structural mineral deposition by osteoblasts. Coculture osteoblasts and bone marrow monocytes under biochemical stimulation recapitulate osteoclast differentiation and function. The DBP-based bone model allows longitudinal quantitative fluorescent monitoring of osteoclast responses to bisphosphonate drug, substantiating significantly reducing their number and lifespan. Finally, we demonstrate the feasibility of humanizing the bone model. The DBP-based osteo assay platforms are expected to advance bone remodeling-targeting drug development with improved prediction of clinical outcomes.
Topics: Animals; Osteoclasts; Bone Resorption; Bone and Bones; Osteoblasts; Biology; Cell Differentiation; RANK Ligand
PubMed: 38062034
DOI: 10.1038/s41467-023-44000-9 -
Biomolecules Dec 2020Rheumatoid arthritis is characterized by synovial inflammation and irreversible bone erosions, both highlighting the immense reciprocal relationship between the immune... (Review)
Review
Rheumatoid arthritis is characterized by synovial inflammation and irreversible bone erosions, both highlighting the immense reciprocal relationship between the immune and bone systems, designed osteoimmunology two decades ago. Osteoclast-mediated resorption at the interface between synovium and bone is responsible for the articular bone erosions. The main triggers of this local bone resorption are autoantibodies directed against citrullinated proteins, as well as pro-inflammatory cytokines and the receptor activator of nuclear factor-κB ligand, that regulate both the formation and activity of the osteoclast, as well as immune cell functions. In addition, local bone loss is due to the suppression of osteoblast-mediated bone formation and repair by inflammatory cytokines. Similarly, inflammation affects systemic bone remodeling in rheumatoid arthritis with the net increase in bone resorption, leading to systemic osteoporosis. This review summarizes the substantial progress that has been made in understanding the pathophysiology of systemic and local bone loss in rheumatoid arthritis.
Topics: Arthritis, Rheumatoid; Autoantibodies; Bone Remodeling; Bone Resorption; Cell Differentiation; Humans; Inflammation; Osteoblasts; Osteoclasts; Synovial Membrane
PubMed: 33396412
DOI: 10.3390/biom11010048 -
Biochemical and Biophysical Research... Sep 2023Nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) is a master regulator of antioxidant response and protects cells from excessive oxidative stress. Nrf2...
Nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) is a master regulator of antioxidant response and protects cells from excessive oxidative stress. Nrf2 emerges as a prospective therapeutic target for metabolic bone disorders, in which the balance between osteoblastic bone formation and osteoclastic bone resorption is disrupted. However, the molecular mechanism through which Nrf2 modulates bone homeostasis remains unclear. In this study, we compared the differences in Nrf2-mediated antioxidant response and ROS regulation in osteoblasts and osteoclasts, both in vitro and in vivo. Findings indicated a close connection between the Nrf2 expression and its related antioxidant response with osteoclasts than osteoblasts. We next pharmacologically manipulated the Nrf2-mediated antioxidant response during osteoclast or osteoblast differentiation. Nrf2 inhibition enhanced osteoclastogenesis, while its activation suppressed it. In contrast, osteogenesis decreased irrespective of whether Nrf2 was inhibited or activated. These findings highlight the distinct ways in which the Nrf2-mediated antioxidant response regulates osteoclast and osteoblast differentiation, thereby contributing to the development of Nrf2 targeted therapies for metabolic bone diseases.
Topics: Humans; Antioxidants; Bone Resorption; Cell Differentiation; Homeostasis; NF-E2-Related Factor 2; Osteoblasts; Osteoclasts; Osteogenesis; RANK Ligand
PubMed: 37393640
DOI: 10.1016/j.bbrc.2023.06.080 -
Biomolecules May 2020The precise regulation of osteoclast differentiation and function is crucial for the maintenance of healthy bone. Despite several reports of collagenase expression in...
The precise regulation of osteoclast differentiation and function is crucial for the maintenance of healthy bone. Despite several reports of collagenase expression in bone tissues, the precise isoform expression as well as the role in osteoclasts are still unclear. In the present report, the expression of matrix metalloprotease (MMP)8 and MMP13 was confirmed in mouse bone marrow macrophage osteoclast precursors. The mRNA and protein expressions of both collagenases were significantly reduced by receptor activator of nuclear factor κB ligand (RANKL) stimulation. Notably, either inhibition of MMP expression by siRNA or treatment of cells with collagenase inhibitor Ro 32-3555 significantly augmented osteoclast fusion and resorption activity without affecting the osteoclast number. The inhibition of collagenase by Ro 32-3555 increased the expression of osteoclast fusion genes, and , without affecting nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) protein expression. The enhanced osteoclast fusion by collagenase inhibition appears to be mediated through an extracellular signal regulated kinase (ERK)-dependent pathway. Collectively, these data provide novel information on the regulation of osteoclast fusion process.
Topics: Animals; Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Female; Humans; Imidazoles; MAP Kinase Signaling System; Matrix Metalloproteinase 13; Matrix Metalloproteinase 8; Matrix Metalloproteinase Inhibitors; Membrane Proteins; Mice; Mice, Inbred ICR; NFATC Transcription Factors; Osteoclasts; RANK Ligand; Vacuolar Proton-Translocating ATPases
PubMed: 32370054
DOI: 10.3390/biom10050705 -
JCI Insight Jul 2023We previously reported that measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) of patients with Paget disease (PD) or targeted to the OCL lineage...
We previously reported that measles virus nucleocapsid protein (MVNP) expression in osteoclasts (OCLs) of patients with Paget disease (PD) or targeted to the OCL lineage in MVNP-transgenic mice (MVNP mice) increases IGF1 production in osteoclasts (OCL-IGF1) and leads to development of PD OCLs and pagetic bone lesions (PDLs). Conditional deletion of Igf1 in OCLs of MVNP mice fully blocked development of PDLs. In this study, we examined whether osteocytes (OCys), key regulators of normal bone remodeling, contribute to PD. OCys in PDLs of patients and of MVNP mice expressed less sclerostin, and had increased RANKL expression compared with OCys in bones from WT mice or normal patients. To test whether increased OCL-IGF1 is sufficient to induce PDLs and PD phenotypes, we generated TRAP-Igf1 (T-Igf1) transgenic mice to determine whether increased IGF1 expression in the absence of MVNP in OCLs is sufficient to induce PDLs and pagetic OCLs. We found that T-Igf1 mice at 16 months of age developed PD OCLs, PDLs, and OCys, with decreased sclerostin and increased RANKL, similar to MVNP mice. Thus, pagetic phenotypes could be induced by OCLs expressing increased IGF1. OCL-IGF1 in turn increased RANKL production in OCys to induce PD OCLs and PDLs.
Topics: Animals; Mice; Bone and Bones; Gene Expression; Mice, Transgenic; Osteitis Deformans; Osteoclasts; Osteocytes
PubMed: 37338990
DOI: 10.1172/jci.insight.159838 -
Biomedicine & Pharmacotherapy =... Oct 2023Bone loss is a major issue for patients with osteoporosis, arthritis, periodontitis, and bone metastasis; however, anti-resorption drugs used to treat bone loss have...
Bone loss is a major issue for patients with osteoporosis, arthritis, periodontitis, and bone metastasis; however, anti-resorption drugs used to treat bone loss have been linked to a variety of adverse effects. Helminthostachys zeylanica (L.) Hook, belonging to the family Ophioglossaceae, is commonly used in traditional Chinese medicine to treat inflammation and liver problems. In the current study, ugonin L extracted from H. zeylanica was shown to reduce the receptor activator of nuclear factor kappa beta ligand (RANKL)-induced osteoclastogenesis in RAW264.7 cells in a concentration-dependent manner. Ugonin L treatment also inhibited the mRNA expression of osteoclast markers. Ugonin L was also shown to promote cell apoptosis in mature osteoclasts and suppress RANKL-induced ERK, p38, JNK, and NF-κB activation. Taken together, ugonin L appears to be a promising candidate for the development of novel anti-resorption therapies.
Topics: Humans; Apoptosis; Bone Diseases, Metabolic; NF-kappa B; Osteoclasts; Osteogenesis; Signal Transduction; Drugs, Chinese Herbal; RANK Ligand
PubMed: 37651802
DOI: 10.1016/j.biopha.2023.115392 -
ELife Jun 2023A subtype of myeloid monocyte mediates the transition from autoimmunity to joint destruction in rheumatoid arthritis.
A subtype of myeloid monocyte mediates the transition from autoimmunity to joint destruction in rheumatoid arthritis.
Topics: Humans; Arthritis, Rheumatoid; Autoimmunity; Osteoclasts
PubMed: 37366155
DOI: 10.7554/eLife.89778 -
European Journal of Cell Biology 2022Osteoclasts are bone resorbing cells that are responsible for physiological and pathological bone resorption. Macrophage colony stimulating factor (M-CSF) binds to the...
Osteoclasts are bone resorbing cells that are responsible for physiological and pathological bone resorption. Macrophage colony stimulating factor (M-CSF) binds to the M-CSF receptor (c-FMS) and plays a key role in the differentiation and survival of macrophages and osteoclasts. THOC5, a member of the THO complex, has been shown to regulate hematopoiesis and M-CSF-induced macrophage differentiation. However, the role of THOC5 in osteoclasts remains unclear. Here, our study reveals a new role of THOC5 in osteoclast formation. We found that THOC5 shuttles between nucleus and cytoplasm in an M-CSF signaling dependent manner. THOC5 bound to FICD, a proteolytic cleavage product of c-FMS, and THOC5 facilitates the nuclear translocations of FICD. Decreased expression of THOC5 by siRNA-mediated knock down suppressed osteoclast differentiation, in part, by regulating RANK, a key receptor of osteoclasts. Mechanistically, knock down of THOC5 inhibited the expression of RANKL-induced FOS and NFATc1. Our findings highlight THOC5's function as a positive regulator of osteoclasts.
Topics: Bone Resorption; Cell Differentiation; Humans; Macrophage Colony-Stimulating Factor; Nuclear Proteins; Osteoclasts; Osteogenesis
PubMed: 35688054
DOI: 10.1016/j.ejcb.2022.151248