NFAT restricts osteochondroma formation from entheseal progenitors

Ge, Xianpeng; Tsang, Kelly; He, Lizhi; Garcı́a, Roberto; Ermann, Joerg; Mizoguchi, Fumitaka; Zhang, Minjie; Zhou, Bin; Aliprantis, Antonios O.

doi:10.1172/jci.insight.86254

Cited by 16 publications

(41 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NFATc1 and NFATc2 also play an important role in chondrogenesis, and disruption of Nfatc1/c2 is associated with osteoarthritis, and alterations in NFAT signaling may explain bone and cartilage disorders associated with inflammation . NFATc1 and NFATc2 oppose osteoarthritis progression, NFATc1 inhibit chondrogenesis, and the deletion of Nfatc1 and Nfatc2 result in entheseal osteochondromas reflecting a restrictive role of these transcription factors on osteochondral growth …”

Section: Discussionmentioning

confidence: 99%

Nuclear factor of activated T cells 2 is required for osteoclast differentiation and function in vitro but not in vivo

Zanotti

Schilling

et al. 2018

J of Cellular Biochemistry

View full text Add to dashboard Cite

Nuclear factor of activated T cells (NFAT) c2 is important for the immune response and it compensates for NFATc1 for its effects on osteoclastogenesis, but its role in this process is not established. To study the function of NFATc2 in the skeleton, Nfatc2 mice, where the Nfact2 exon 2 is flanked by loxP sequences, were created and mated with mice expressing the Cre recombinase under the control of the Lyz2 promoter. Bone marrow-derived macrophage (BMM) from Lyz2 ;Nfatc2 mice cultured in the presence of macrophage-colony stimulating factor and receptor activator of NF-κB ligand exhibited a decrease in the number and size of osteoclasts and a smaller sealing zone when compared to BMMs from Nfatc2 littermate controls. Bone resorption was decreased in osteoclasts from Lyz2 ;Nfatc2 mice. This demonstrates that NFATc2 is necessary for optimal osteoclast maturation and function in vitro. Male and female Lyz2 ;Nfatc2 mice did not exhibit an obvious skeletal phenotype by microcomputed tomography (μCT) at either 1 or 4 months of age when compared to Nfatc2 sex-matched littermates. Bone histomorphometry confirmed the μCT results, and conditional 4-month-old Lyz2 ;Nfatc2 mice did not exhibit changes in parameters of bone histomorphometry. In conclusion, NFATc2 is necessary for optimal osteoclastogenesis in vitro, but its downregulation in the myeloid lineage has no consequences in skeletal remodeling in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

Nuclear factor of activated T cells 2 is required for osteoclast differentiation and function in vitro but not in vivo

Zanotti

Schilling

et al. 2018

J of Cellular Biochemistry

View full text Add to dashboard Cite

show abstract

“…3c). To further characterize the role of CHMP5 in regulating cellular senescence, we utilized CRISPR/CAS9 technology to delete Chmp5 in a periskeletal progenitor cell line ATDC5 26 ( Supplementary Fig. 3e).…”

Section: Chmp5 Deficiency Induces Cellular Senescence and Increases Tmentioning

confidence: 99%

“…The periskeletal progenitors were isolated from hindlimbs of Ctsk-Cre;Rosa26 mTmG/+ , Chmp5 Ctsk/+ ;Rosa26 mTmG/+ , and Chmp5 Ctsk ; Rosa26 mTmG/+ mice at 2 weeks of age according to the previously established method 26 . Briefly, the periskeletal tissues were dissected, minced into small pieces, and digested with 1 mg/ml collagenase type I (Worthington), 1 mg/ml collagenase type II (Worthington) and 1.5 mg/ml dispase (Roche) for 30 min at 37°C.…”

Section: Skeletal Progenitor Cell Isolation and Sortingmentioning

confidence: 99%

“…Cell number was counted with a Countess II FL Automated Cell Counter (ThermoFisher) at indicated time intervals. AlamarBlue cell viability assay was performed as previously described 26 . Cell cycle was determined using the APC-BrdU Flow Kit (BD Biosciences).…”

Section: Cell Cycle Proliferation and Apoptosis Analysesmentioning

confidence: 99%

“…Primer sequences were used for qPCR are as following: Primer sequences for Col2a1, Sox9, and Hprt are as previously reported 26 .…”

Section: Quantitative Pcr and Western Blottingmentioning

confidence: 99%

See 2 more Smart Citations

The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The endocytic pathway actively interacts with mitochondria in maintaining cellular homeostasis. However, how the dysfunction of this inter-organelle interaction causing pathological outcomes remains less understood. Here we show that an aberrant endocytic pathway from the deficiency of CHMP5 in skeletal progenitor cells causes accumulation of functionally compromised mitochondria, which induce cellular senescence via reactive oxygen species (ROS)-mediated oxidative stress and DNA damage. These senescent progenitors can lead to distorted skeletal growth via a combination of cell-autonomous and non-autonomous mechanisms. Consequently, mice lacking Chmp5 in Ctsk-expressing periskeletal progenitors or Dmp1-expressing musculoskeletal progenitors develop multiple skeletal/muscular abnormalities, including robust bone overgrowth, progressive joint stiffness, and myopathy. Targeting senescent cells using senolytic drugs significantly alleviates these lesions and improves animal motility. Overall, our results reveal that CHMP5 restricts skeletal progenitor cell senescence through maintaining the endo-lysosomal-mitochondrial network and cell senescence represents a yet unexplored mechanism for detrimental alterations from the perturbed organelle network.

show abstract

Involvement of Transient Receptor Potential Vanilloid Channel 2 in the Induction of Lubricin and Suppression of Ectopic Endochondral Ossification in Mouse Articular Cartilage

Nakamoto

Katanosaka

Chijimatsu

et al. 2021

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective. Transient receptor potential vanilloid channel 2 (TRPV2) is a Ca 2+ -permeable channel and plays a role in mediating intracellular Ca 2+ current via mechanical stimuli. This study was undertaken to examine the expression and role of TRPV2 in adult articular cartilage and the development of osteoarthritis (OA).Methods. We examined TRPV2 expression in mouse and human articular cartilage. We analyzed the development of OA in Col2a1-Cre ERt2 ;Trpv2 fl/fl mice and Trpv2 fl/fl littermates in the resection of the medial meniscus and medial collateral ligament model (n = 5 each), the destabilization of the medial meniscus model (n = 5 each), and the aging mouse model (n = 8-9 each). We examined marker protein expression in these joints, Ca 2+ influx by mechanical stimuli, and downstream pathways in vitro.Results. TRPV2 was expressed in mouse and human articular cartilage and ectopic ossification lesions. In all mouse models of OA examined, Col2a1-Cre ERt2 ;Trpv2 fl/fl mice were observed to have enhanced degradation of articular cartilage accompanied by decreased expression of lubricin/Prg4, and marked formation of periarticular ectopic ossification. Mechanical stress-induced Ca 2+ influx was decreased by Trpv2 knockout (KO). Prg4 induction by fluidflow shear stress was diminished in Trpv2-KO mouse chondrocytes, and this was mediated by the Ca 2+ /calmodulindependent protein kinase kinase-cyclic AMP response element binding protein axis. Hypertrophic differentiation was enhanced in Trpv2-KO mouse chondrocytes. Increased activity of calcineurin and nuclear translocation of nuclear factor in activated T cells 1 induced by fluid-flow shear stress or TRP agonist treatment was reversed by Trpv2 knockout.Conclusion. Our findings demonstrate regulation of articular cartilage by TRPV2 through Prg4 induction and suppression of ectopic ossification.

show abstract

NFAT restricts osteochondroma formation from entheseal progenitors

Cited by 16 publications

References 59 publications

Nuclear factor of activated T cells 2 is required for osteoclast differentiation and function in vitro but not in vivo

Nuclear factor of activated T cells 2 is required for osteoclast differentiation and function in vitro but not in vivo

The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence

Involvement of Transient Receptor Potential Vanilloid Channel 2 in the Induction of Lubricin and Suppression of Ectopic Endochondral Ossification in Mouse Articular Cartilage

Contact Info

Product

Resources

About