ZMAT1 promotes osteoclast formation and bone loss through TRIM46 mediated YAP1 degradation II
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ABSTRACT:
PROVIDER: PRJNA1148497 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30253571_1.fastq.gz | Fastqsanger.gz | |||
| SRR30253571_2.fastq.gz | Fastqsanger.gz | |||
| SRR30253572_1.fastq.gz | Fastqsanger.gz | |||
| SRR30253572_2.fastq.gz | Fastqsanger.gz | |||
| SRR30253573_1.fastq.gz | Fastqsanger.gz |
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Project description:Osteoclasts and osteoblasts play a critical role in bone remodeling, and their dysregulation leads to pathological bone loss. However, precise regulation of their differentiation remains not fully elucidated. This study investigates the role of transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and reduced bone resorption. Mechanististically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which then regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency also enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis.
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Project description:Osteoclasts and osteoblasts play a critical role in bone remodeling, and their dysregulation leads to pathological bone loss. However, precise regulation of their differentiation remains not fully elucidated. This study investigates the role of transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and reduced bone resorption. Mechanististically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which then regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency also enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis.
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Project description:Osteoclasts and osteoblasts play a critical role in bone remodeling, and their dysregulation leads to pathological bone loss. However, precise regulation of their differentiation remains not fully elucidated. This study investigates the role of transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and reduced bone resorption. Mechanististically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which then regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency also enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis.
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Project description:ZMAT1 promotes osteoclast formation and bone loss through TRIM46 mediated YAP1 degradation.
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Project description:ZMAT1 promotes osteoclast formation and bone loss through TRIM46 mediated YAP1 degradation. [CUT&Tag]
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Project description:Osteoporosis and bone fractures affect millions of men and women worldwide and are often due to increased bone resorption (bone loss) mediated by osteoclasts. Here, we identify a novel role for the cytoplasmic protein ELMO1 as an important ‘signaling node’ controlling the bone resorption function of osteoclasts. Initially, we noted association of ELMO1 SNPs with bone abnormalities and altered bone density in humans. Experimentally, ELMO1 emerged as a promoter of bone loss wherein deletion of ELMO1 reversed osteoporosis / bone erosions in four in vivo mouse models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. However, ELMO1 did not promote bone loss under homeostatic conditions. Mechanistic studies pointed to a larger ELMO1 signaling network that regulates osteoclast activity at several levels. First, transcriptomics coupled with CRISPR/Cas9 genetic deletion approaches identified new regulators of osteoclast function associated with Elmo1. Second, defining the ‘ELMO1 interactome’ in osteoclasts via proteomics revealed proteins linked to bone degradation. Third, ELMO1 affects the formation of the actin ring /sealing zone on bone-like surfaces and the distribution of osteoclast-specific proteases. Finally, a 3D structure-based inhibitory peptide targeting a highly conserved region of ELMO1 reduced bone resorption in wild type osteoclasts. Collectively, these data identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to diseases such as osteoporosis and arthritis.
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Project description:Osteoclasts are multinucleated, bone-resorbing cells. However, they also digest cartilage during skeletal maintenance, development and in degradative conditions including osteoarthritis, rheumatoid arthritis and primary bone sarcoma. This study explores the mechanisms behind the osteoclast–cartilage interaction. Human osteoclasts differentiated on acellular human cartilage expressed osteoclast marker genes (e.g. CTSK, MMP9) and proteins (TRAP, VNR), visibly damaged the cartilage surface and released glycosaminoglycan in a contact-dependent manner. Direct co-culture with chondrocytes during differentiation increased large osteoclast formation (p < 0.0001) except when co-cultured on dentine, when osteoclast formation was inhibited (p = 0.0002). Osteoclasts cultured on dentine inhibited basal cartilage degradation (p = 0.012). RNA-seq identified MMP8 overexpression in osteoclasts differentiated on cartilage versus dentine (8.89-fold, p = 0.0133), while MMP9 was the most highly expressed MMP. Both MMP8 and MMP9 were produced by osteoclasts in osteosarcoma tissue. This study suggests that bone-resident osteoclasts and chondrocytes exert mutually protective effects on their ‘native’ tissue. However, when osteoclasts contact non-native cartilage they cause degradation via MMPs. Understanding the role of osteoclasts in cartilage maintenance and degradation might identify new therapeutic approaches for pathologies characterized by cartilage degeneration.
2021-12-01 | GSE166535 | GEO
Project description:Osteoclasts are absorptive cells and play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic regulation of osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation during osteoclast formation. DOT1L and H3K79me2 levels were upregulated during osteoclast differentiation. Small molecule inhibitor- (EPZ5676 or EPZ004777) or short hairpin RNA-mediated reduction in DOT1L expression promoted osteoclast differentiation and resorption. DOT1L inhibition also increased osteoclast area and accelerated bone mass reduction in a mouse ovariectomy (OVX) model of osteoporosis. DOT1L inhibitors did not alter osteoblast differentiation in vitro and in vivo. Proteomics data, together with bioinformatics analysis, revealed that DOT1L inhibition altered reactive oxygen species (ROS) generation, autophagy activation, and cell fusion-related protein expression. ROS generation increased, and autophagy activation and cell migration ability enhancement were verified subsequently by flow cytometry and transwell migration assays. DOT1L inhibition increased NFATc1 nuclear translocation and NF-κB activation and strengthend osteoclast fusion and expression of resorption-related protein CD9, and MMP9 in osteoclasts derived from RAW264.7. Our findings support a new mechanism of DOT1L-mediated H3K79me2 epigenetic regulation of osteoclast differentiation, implicating DOT1L as a new therapeutic target for osteoclast dysregulation-induced disease.
2018-01-24 | PXD006448 | Pride
Project description:Osteoporosis and bone fractures affect millions of men and women worldwide and are often due to increased bone resorption (bone loss) mediated by osteoclasts. Here, we identify a novel role for the cytoplasmic protein ELMO1 as an important ‘signaling node’ controlling the bone resorption function of osteoclasts. Initially, we noted association of ELMO1 SNPs with bone abnormalities and altered bone density in humans. Experimentally, ELMO1 emerged as a promoter of bone loss wherein deletion of ELMO1 reversed osteoporosis / bone erosions in four in vivo mouse models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. However, ELMO1 did not promote bone loss under homeostatic conditions. Mechanistic studies pointed to a larger ELMO1 signaling network that regulates osteoclast activity at several levels. First, transcriptomics coupled with CRISPR/Cas9 genetic deletion approaches identified new regulators of osteoclast function associated with Elmo1, including cathepsin G and myeloperoxidase. Second, defining the ‘ELMO1 interactome’ in osteoclasts via proteomics revealed membrane proteins and v-ATPases required for bone degradation. Third, ELMO1 affects the formation of the actin ring /sealing zone on bone-like surfaces and the distribution of osteoclast-specific proteases. Finally, a 3D structure-based inhibitory peptide targeting a highly conserved region of ELMO1 reduced bone resorption in wild type osteoclasts. Collectively, these data identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to diseases such as osteoporosis and arthritis.
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Project description:Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity. Total bone marrow cells were prepared from the femurs and tibias of 8-10-week-old C57BL/6 mice and cultured in the presence of M-CSF (100ng/ml) for 3 days as described previously (Takeshita et al., 2000 JBMR 15:1477-1488). Cells were harvested with 0.02% EDTA/PBS and used as bone marrow macrophages (BMMs). These BMMs were cultured in the presence of M-CSF (100 ng/ml) and RANKL (100ng/ml) for 2 days. TRAP positive mononuclear cells were harvested and used as pre-osteoclasts (pOC). These pOC cells were further cultured in the presence of M-CSF and RANKL for 2 days in normal plastic plate or on dentin slices. After 2 days, multinucleated TRAP positive mature osteoclasts were generated as mature osteoclasts on plate (mOCp) and mature resorbing osteoclasts on dentin (mOCd), respectively. RNAs were extracted from four different stages of osteoclast lineage cells; BMMs, pOC, mOCp and mOCd, and used for microarray analysis.
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