Osteoclasts
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MiR-21 is being gradually more and more recognized as a molecule regulating bone tissue homeostasis. However, its function is not fully understood due to the dual role of miR-21 on bone-forming and bone-resorbing cells. In this study, we investigated the impact of miR-21 inhibition on pre-osteoblastic cells differentiation and paracrine signaling towards pre-osteoclasts using indirect co-culture model of mouse pre-osteoblast (MC3T3) and pre-osteoclast (4B12) cell lines. The inhibition of miR-21 in MC3T3 cells (MC3T3inh21) modulated expression of genes encoding osteogenic markers including collagen type I (Coll-1), osteocalcin (Ocl), osteopontin (Opn), and runt-related transcription factor 2 (Runx-2). Inhibition of miR-21 in osteogenic cultures of MC3T3 also inflected the synthesis of OPN protein which is essential for proper mineralization of extracellular matrix (ECM) and anchoring osteoclasts to the bones. Furthermore, it was shown that in osteoblasts miR-21 regulates expression of factors that are vital for survival of pre-osteoclast, such as receptor activator of nuclear factor κB ligand (RANKL). The pre-osteoclast cultured with MC3T3inh21 cells was characterized by lowered expression of several markers associated with osteoclasts' differentiation, foremost tartrate-resistant acid phosphatase (Trap) but also receptor activator of nuclear factor-κB ligand (Rank), cathepsin K (Ctsk), carbonic anhydrase II (CaII), and matrix metalloproteinase (Mmp-9). Collectively, our data indicate that the inhibition of miR-21 in MC3T3 cells impairs the differentiation and ECM mineralization as well as influences paracrine signaling leading to decreased viability of pre-osteoclasts.
- MeSH
- buněčná diferenciace genetika MeSH
- buněčné linie MeSH
- extracelulární matrix metabolismus MeSH
- kokultivační techniky MeSH
- kyselá fosfatasa rezistentní k tartarátu metabolismus MeSH
- messenger RNA genetika MeSH
- mikro RNA genetika metabolismus MeSH
- myši MeSH
- osteoblasty metabolismus MeSH
- osteogeneze genetika MeSH
- osteoklasty metabolismus MeSH
- osteopontin genetika metabolismus MeSH
- parakrinní signalizace genetika MeSH
- protein PEBP2alfaA genetika metabolismus MeSH
- resorpce kosti metabolismus MeSH
- signální transdukce genetika MeSH
- transfekce MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
c-Fos homozygous mice lack osteoclasts with a failure of the teeth to erupt and with an arrest of root development. Here, we characterize the defects associated with the failure in root development and the loss of the tooth-bone interface, and we investigate the underlying causes. We show that, while homozygous c-Fos mice have no multinucleated osteoclasts, heterozygous mice have a reduction in the number of osteoclasts with a reduction in the tooth-bone interface during development and subtle skeletal defects postnatally. In the homozygous mutants bone is found to penetrate the tooth, particularly at the apical end, physically disrupting the root forming HERS (Hertwig's epithelial root sheath) cells. The cells of the HERS continue to proliferate but cannot extend downward due to the presence of bone, leading to a loss of root formation. Tooth germ culture showed that the developing tooth invaded the static bone in mutant tissue, rather than the bone encroaching on the tooth. Although c-Fos has been shown to be expressed in developing teeth, the defect in maintenance of the tooth-bone interface appears to be driven solely by the lack of osteoclasts, as this defect can be rescued in the presence of donor osteoclasts. The rescue suggests that signals from the tooth recruit osteoclasts to clear the bone from around the tooth, allowing the tooth to grow, form roots, and later erupt.
- MeSH
- abnormality čelisti genetika patofyziologie MeSH
- homozygot MeSH
- maxilofaciální vývoj genetika fyziologie MeSH
- mutantní kmeny myší MeSH
- myši inbrední C57BL genetika MeSH
- myši MeSH
- osteoklasty fyziologie MeSH
- prořezávání zubů genetika fyziologie MeSH
- protoonkogenní proteiny c-fos genetika fyziologie MeSH
- zubní kořen abnormality růst a vývoj MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We aimed to explore the development and cell communication of osteoblasts and osteoclasts with aneuploidy variation in giant cell tumour of bone (GCTB). We predicted the diploid and aneuploid cells in tissue samples using the CopyKAT package. The Monocle2 package was used to analyse differentiation trajectories of aneuploid cells. We used the CellChat package to observe the signalling pathways and ligand-receptor pairs for the two interaction types, "Cell-Cell Contact" and "Secreted Signalling", respectively. A total of 9,117 cells were obtained including eight cell types. Most aneuploid cells were osteoblasts. As the cell differentiation trajectory matured, we found that aneuploid osteoblasts first increased the inflammatory response activity and then enhanced the ability to activate T cells, whereas osteoclasts gradually enhanced the cellular energy metabolism, cell adhesion, cell proliferation and immune response; the activated biological functions were gradually weakened. The analysis by CellChat indicated that CTLA4 or TIGIT might act as important immune checkpoint genes to attenuate the inhibitory effect of aneuploid osteoclasts on NK/T cells, thereby enhancing the activity of NK/T cells. Our study found that both osteoblasts and osteoclasts might be involved in the development of GCTB, which may provide a new direction for the treatment of GCTB.
- MeSH
- analýza jednotlivých buněk * MeSH
- aneuploidie * MeSH
- buněčná diferenciace genetika MeSH
- lidé MeSH
- mezibuněčná komunikace * genetika MeSH
- nádory kostí genetika patologie metabolismus MeSH
- obrovskobuněčný nádor kosti * genetika patologie MeSH
- osteoblasty * metabolismus MeSH
- osteoklasty * metabolismus patologie MeSH
- sekvenční analýza RNA metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- dospělí MeSH
- finanční podpora výzkumu jako téma MeSH
- kalcitonin krev metabolismus MeSH
- kolagen biosyntéza krev MeSH
- lidé MeSH
- mladiství MeSH
- osteoklasty metabolismus účinky léků MeSH
- resorpce kosti metabolismus MeSH
- tyreoidektomie MeSH
- vápník farmakologie krev MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
Kostní tkáň představuje dynamický systém, který velmi citlivě reaguje na podněty vnějšího prostředí i potřeby organizmu. Řada závažných onemocnění, která jsou spojena s poruchami v rovnováze mezi resorpcí a novotvorbou kostní tkáně, sdílí společný problém, kterým je abnormální stimulace diferenciace, funkce nebo aktivity osteoklastů. Pokrok v osteoimunologii a molekulární biologii objasnil řadu kontrolních mechanizmů řídících diferenciaci osteoklastů, jejichž znalost může umožnit potenciální terapii některých dosud obtížně léčitelných onemocnění.
Bone remodelling is process of constant resorption and formation of a bone. Osteoclasts are the cells responsible for bone resorption. Deregulation of osteoclast differentiation, activity or function can cause severe diseases, such as osteoporosis, osteopetrosis or rheumatoid arthritis. Advances in molecular biology of osteoclasts and osteoimmunology open new approaches for the specific and efficient therapy.
