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Scientific Reports Dec 2023Notch signaling is an evolutionary conserved pathway with a key role in tissue homeostasis, differentiation and proliferation. It was reported that Notch1 receptor...
Notch signaling is an evolutionary conserved pathway with a key role in tissue homeostasis, differentiation and proliferation. It was reported that Notch1 receptor negatively regulates mouse osteoclast development and formation by inhibiting the expression of macrophage colony-stimulating factor in mesenchymal cells. Nonetheless, the involvement of Notch1 pathway in the generation of human osteoclasts is still controversial. Here, we report that the constitutive activation of Notch1 signaling induced a differentiation block in human mononuclear CD14 cells directly isolated from peripheral blood mononuclear cells (PBMCs) upon in vitro stimulation to osteoclasts. Additionally, using a combined approach of single-cell RNA sequencing (scRNA-Seq) simultaneously with a panel of 31 oligo-conjugated antibodies against cell surface markers (AbSeq assay) as well as unsupervised learning methods, we detected four different cell stages of human RANKL-induced osteoclastogenesis after 5 days in which Notch1 signaling enforces the cell expansion of specific subsets. These cell populations were characterized by distinct gene expression and immunophenotypic profiles and active Notch1, JAK/STAT and WNT signaling pathways. Furthermore, cell-cell communication analyses revealed extrinsic modulators of osteoclast progenitors including the IL7/IL7R and WNT5a/RYK axes. Interestingly, we also report that Interleukin-7 receptor (IL7R) was a downstream effector of Notch1 pathway and that Notch1 and IL7R interplay promoted cell expansion of human RANKL-induced osteoclast progenitors. Taken together, these findings underline a novel cell pattern of human osteoclastogenesis, outlining the key role of Notch1 and IL-7R signaling pathways.
Topics: Humans; Cell Differentiation; Leukocytes, Mononuclear; Osteoclasts; Osteogenesis; RANK Ligand; Signal Transduction
PubMed: 38040752
DOI: 10.1038/s41598-023-48615-2 -
Frontiers in Immunology 2022Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation leading to joint destruction and deformity. The crucial role of osteoclasts in the... (Review)
Review
Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation leading to joint destruction and deformity. The crucial role of osteoclasts in the bone erosion in RA has been demonstrated. Deregulated osteoclastogenesis which is affected by environmental factors including the inflammatory state, as well as genetic and epigenetic factors, is one of hallmarks of RA pathogenesis. An enhanced-monocyte-to-osteoclast transition plays an important role in osteoclast upregulation in RA because under specific stimuli, circulating monocytes might migrate to a specific location in the bones and fuse with each other to become mature multinucleated osteoclasts. To understand the mechanism of bone damage in RA and to develop novel treatments targeting osteoclast upregulation, it is important to clarify our understanding of the monocyte-to-osteoclast transition in RA. Several potential targets which inhibit both inflammation and osteoclastogenesis, as well as regulators that affect the monocyte-to-osteoclast transition have been revealed by recent studies. Here, we review the factors affecting osteoclastogenesis in RA, summarize the anti-osteoclastogenic effects of current RA treatments, and identify promising therapeutic targets relating to both inflammation and osteoclastogenesis.
Topics: Arthritis, Rheumatoid; Humans; Inflammation; Monocytes; Osteoclasts; Osteogenesis
PubMed: 36172385
DOI: 10.3389/fimmu.2022.998554 -
Cells Nov 2023This review focuses on understanding the macroscopic and microscopic characteristics of bone tissue and reviews current knowledge of its physiology. It explores how... (Review)
Review
This review focuses on understanding the macroscopic and microscopic characteristics of bone tissue and reviews current knowledge of its physiology. It explores how these features intricately collaborate to maintain the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, which plays a pivotal role in shaping not only our physical framework but also overall health. In this work, a comprehensive exploration of microscopic and macroscopic features of bone tissue is presented.
Topics: Humans; Osteoclasts; Bone Resorption; Bone and Bones; Osteoblasts; Cell Differentiation
PubMed: 37947654
DOI: 10.3390/cells12212576 -
Frontiers in Immunology 2022Macrophages comprise a variety of subsets with diverse biological functions, including inflammation, tissue repair, regeneration, and fibrosis. In the bone marrow,... (Review)
Review
Macrophages comprise a variety of subsets with diverse biological functions, including inflammation, tissue repair, regeneration, and fibrosis. In the bone marrow, macrophages differentiate into multinucleated osteoclasts, which have a unique bone-destroying capacity and play key roles in physiological bone remodelling. In contrast, osteoclasts are also involved in inflammatory bone erosion in arthritis and it has been unclear whether the osteoclasts in different tissue settings arise from similar monocytoid precursors and share similar phenotypes. Rapid progresses in the sequencing technologies have provided many important insights regarding the heterogeneity of different types of osteoclasts. The application of single-cell RNA sequencing (scRNA-seq) to the osteoclast precursor-containing macrophages enabled to identify the specific subpopulation differentiating into pathological mature osteoclasts in joints. Furthermore, an intravital imaging technology using two-photon microscopy has succeeded in visualizing the real-time dynamics of immune cells in the synovial microenvironment. These technologies together contributed to characterize the unique macrophages in the inflamed synovium, termed "arthritis-associated osteoclastogenic macrophages (AtoMs)", causing the pathological bone destruction in inflammatory arthritis. Here, we review and discuss how novel technologies help to better understand the role of macrophages in inflammatory arthritis, especially focusing of osteoclastogenesis at the pannus-bone interface.
Topics: Arthritis, Rheumatoid; Humans; Macrophages; Osteoclasts; Osteogenesis; Synovial Membrane
PubMed: 35464401
DOI: 10.3389/fimmu.2022.867368 -
Journal of Cellular and Molecular... Jun 2023Bone remodelling is mediated by orchestrated communication between osteoclasts and osteoblasts which, in part, is regulated by coupling and anti-coupling factors....
Bone remodelling is mediated by orchestrated communication between osteoclasts and osteoblasts which, in part, is regulated by coupling and anti-coupling factors. Amongst formally known anti-coupling factors, Semaphorin 4D (Sema4D), produced by osteoclasts, plays a key role in downmodulating osteoblastogenesis. Sema4D is produced in both membrane-bound and soluble forms; however, the mechanism responsible for producing sSema4D from osteoclasts is unknown. Sema4D, TACE and MT1-MMP are all expressed on the surface of RANKL-primed osteoclast precursors. However, only Sema4D and TACE were colocalized, not Sema4D and MT1-MMP. When TACE and MT1-MMP were either chemically inhibited or suppressed by siRNA, TACE was found to be more engaged in shedding Sema4D. Anti-TACE-mAb inhibited sSema4D release from osteoclast precursors by ~90%. Supernatant collected from osteoclast precursors (OC-sup) suppressed osteoblastogenesis from MC3T3-E1 cells, as measured by alkaline phosphatase activity, but OC-sup harvested from the osteoclast precursors treated with anti-TACE-mAb restored osteoblastogenesis activity in a manner that compensates for diminished sSema4D. Finally, systemic administration of anti-TACE-mAb downregulated the generation of sSema4D in the mouse model of critical-sized bone defect, whereas local injection of recombinant sSema4D to anti-TACE-mAb-treated defect upregulated local osteoblastogenesis. Therefore, a novel pathway is proposed whereby TACE-mediated shedding of Sema4D expressed on the osteoclast precursors generates functionally active sSema4D to suppress osteoblastogenesis.
Topics: Animals; Mice; Disease Models, Animal; Matrix Metalloproteinase 14; Osteoblasts; Osteoclasts; Semaphorins
PubMed: 37170687
DOI: 10.1111/jcmm.17416 -
Clinical & Experimental Metastasis Oct 2022Metastasis to bone is the leading cause of death from prostate cancer. Interaction between tumor cells and bone cells can promote progression and influence tumor...
Metastasis to bone is the leading cause of death from prostate cancer. Interaction between tumor cells and bone cells can promote progression and influence tumor phenotype. It is known that prostate cancer cells support osteoclast differentiation, and degradation of bone matrix by osteoclasts releases growth factors stimulating tumor cell proliferation and invasion. In the present study osteolytic (PC-3) and osteoblastic (LNCaP-19) castration-resistant prostate cancer (CRPC) cells were co-cultured with mature osteoclasts or their precursor cells (RAW 264.7) to characterize direct effects of mature osteoclasts on CRPC cells. Osteoclasts increased proliferation and decrease apoptosis of CRPC cells as assessed with flow cytometry. RNA sequencing revealed that osteolytic CRPC cells were more responsive to osteoclast stimulation regarding gene expression, but the overall induced expression patterns were similar between the prostate cancer cell lines. Genes related to DNA repair were upregulated by osteoclasts, while genes related to endoplasmic reticulum stress-induced apoptosis and cholesterol synthesis were downregulated. The results of this study shows that osteoclasts directly influence CRPC cells, increasing proliferation, decreasing apoptosis, and affecting gene expression pathways that can affect sensitivity to DNA damage and endoplasmic reticulum function. This suggests targeting of osteoclasts to be a possible way to affect efficacy of other drugs by combination regimens in treating prostate cancer metastases.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Male; Osteoclasts; Prostatic Neoplasms, Castration-Resistant
PubMed: 35971022
DOI: 10.1007/s10585-022-10179-2 -
Biomolecules May 2021Osteoclasts (OCs) are important cells that are involved in the regulation of bone metabolism and are mainly responsible for coordinating bone resorption with bone... (Review)
Review
Osteoclasts (OCs) are important cells that are involved in the regulation of bone metabolism and are mainly responsible for coordinating bone resorption with bone formation to regulate bone remodeling. The imbalance between bone resorption and formation significantly affects bone metabolism. When the activity of osteoclasts exceeds the osteoblasts, it results in a condition called osteoporosis, which is characterized by reduced bone microarchitecture, decreased bone mass, and increased occurrences of fracture. Molecules, including transcription factors, proteins, hormones, nucleic acids, such as non-coding RNAs, play an important role in osteoclast proliferation, differentiation, and function. In this review, we have highlighted the role of these molecules in osteoclasts regulation and osteoporosis. The developed therapeutics targeting these molecules for the treatment of osteoporosis in recent years have also been discussed with challenges faced in clinical application.
Topics: Animals; Biological Products; Biomarkers; Cell Differentiation; Cell Proliferation; Gene Expression Regulation; Humans; Osteoclasts; Osteoporosis
PubMed: 34067783
DOI: 10.3390/biom11050747 -
Aging Cell Apr 2024Osteoarthritis (OA), a chronic degenerative joint disease, is highly prevalent among the aging population, and often leads to joint pain, disability, and a diminished... (Review)
Review
Osteoarthritis (OA), a chronic degenerative joint disease, is highly prevalent among the aging population, and often leads to joint pain, disability, and a diminished quality of life. Although considerable research has been conducted, the precise molecular mechanisms propelling OA pathogenesis continue to be elusive, thereby impeding the development of effective therapeutics. Notably, recent studies have revealed subchondral bone lesions precede cartilage degeneration in the early stage of OA. This development is marked by escalated osteoclast-mediated bone resorption, subsequent imbalances in bone metabolism, accelerated bone turnover, and a decrease in bone volume, thereby contributing significantly to the pathological changes. While the role of aging hallmarks in OA has been extensively elucidated from the perspective of chondrocytes, their connection with osteoclasts is not yet fully understood. There is compelling evidence to suggest that age-related abnormalities such as epigenetic alterations, proteostasis network disruption, cellular senescence, and mitochondrial dysfunction, can stimulate osteoclast activity. This review intends to systematically discuss how aging hallmarks contribute to OA pathogenesis, placing particular emphasis on the age-induced shifts in osteoclast activity. It also aims to stimulate future studies probing into the pathological mechanisms and therapeutic approaches targeting osteoclasts in OA during aging.
Topics: Humans; Aged; Osteoclasts; Quality of Life; Osteoarthritis; Bone Resorption; Aging; Cartilage, Articular
PubMed: 38287696
DOI: 10.1111/acel.14092 -
Frontiers in Endocrinology 2022
Topics: Bone and Bones; Osteoclasts; Cell Differentiation
PubMed: 36589851
DOI: 10.3389/fendo.2022.1115444 -
International Journal of Molecular... May 2021Gut microbiota has emerged as an important regulator of bone homeostasis. In particular, the modulation of innate immunity and bone homeostasis is mediated through the... (Review)
Review
Gut microbiota has emerged as an important regulator of bone homeostasis. In particular, the modulation of innate immunity and bone homeostasis is mediated through the interaction between microbe-associated molecular patterns (MAMPs) and the host pattern recognition receptors including Toll-like receptors and nucleotide-binding oligomerization domains. Pathogenic bacteria such as and tend to induce bone destruction and cause various inflammatory bone diseases including periodontal diseases, osteomyelitis, and septic arthritis. On the other hand, probiotic bacteria such as and species can prevent bone loss. In addition, bacterial metabolites and various secretory molecules such as short chain fatty acids and cyclic nucleotides can also affect bone homeostasis. This review focuses on the regulation of osteoclast and osteoblast by MAMPs including cell wall components and secretory microbial molecules under in vitro and in vivo conditions. MAMPs could be used as potential molecular targets for treating bone-related diseases such as osteoporosis and periodontal diseases.
Topics: Animals; Cell Differentiation; Gastrointestinal Microbiome; Homeostasis; Humans; Osteoblasts; Osteoclasts; Osteocytes; Receptors, Pattern Recognition; Toll-Like Receptors
PubMed: 34071605
DOI: 10.3390/ijms22115805