ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2014
Activation of EPAC1/2 is essential for osteoclast formation by modulating NFκB nuclear translocation and actin cytoskeleton rearrangements.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 46 citations in OpenAlex.
- Rapgef3 modulates macrophage reprogramming and exacerbates synovitis and osteoarthritis under excessive mechanical loading.iScience · 2025Article
- Genomic analysis of mobility measures on 5-month-old gilts associated with structural soundness.Journal of animal science · 2025Article
- Effect of Roflumilast, a Selective PDE4 Inhibitor, on Bone Phenotypes in ADO2 Mice.Calcified tissue international · 2024Article
- Energy Regulation in Inflammatory Sarcopenia by the Purinergic System.International journal of molecular sciences · 2023Review
- Novel alendronate-CGS21680 conjugate reduces bone resorption and induces new bone formation in post-menopausal osteoporosis and inflammatory osteolysis mouse models.Arthritis research & therapy · 2022Article
- Review
- The role of Rho GTPases' substrates Rac and Cdc42 in osteoclastogenesis and relevant natural medicinal products study.Bioscience reports · 2020Review
- Modulation of the bacterial CobB sirtuin deacylase activity by N-terminal acetylation.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- The novel exchange protein activated by cyclic AMP 1 (EPAC1) agonist, I942, regulates inflammatory gene expression in human umbilical vascular endothelial cells (HUVECs).Biochimica et biophysica acta. Molecular cell research · 2019Article
- Adenosine AFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2018Article
- Suppression of osteoclastogenesis via α2-adrenergic receptors.Biomedical reports · 2018Article
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- Deletion of exchange proteins directly activated by cAMP (Epac) causes defects in hippocampal signaling in female mice.PloS one · 2018Article
- Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression.Nature communications · 2017Article
- Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets.Bioorganic & medicinal chemistry letters · 2017Review
- Epac1 agonist decreased inflammatory proteins in retinal endothelial cells, and loss of Epac1 increased inflammatory proteins in the retinal vasculature of mice.Molecular vision · 2017Article
- Adenosine ABritish journal of pharmacology · 2016Article
- Article
- Exchange factors directly activated by cAMP mediate melanocortin 4 receptor-induced gene expression.Scientific reports · 2016Article
- Osteoclasts-Key Players in Skeletal Health and Disease.Microbiology spectrum · 2016Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Bisphosphonates inhibit osteoclast differentiation/function via inhibition of Rap1A isoprenylation. As Rap1 is the effector of exchange protein directly activated by cAMP (EPAC) proteins, we determined the role of EPAC in osteoclast differentiation. We examined osteoclast differentiation as the number of primary murine/human bone-marrow precursors that differentiated into multinucleated TRAP-positive cells in the presence of EPAC-selective stimulus (8-pCTP-2'-O-Me-cAMP, 100 μM; 8-pCTP-2'-O-Me-cAMP-AM, 1 μM) or inhibitor brefeldin A (BFA), ESI-05, and ESI-09 (10 μM each). Rap1 activity was assessed, and signaling events, as well as differentiation in EPAC1/2-knockdown RAW264.7 cells, were studied. Direct EPAC1/2 stimulation significantly increased osteoclast differentiation, whereas EPAC1/2 inhibition diminished differentiation (113 ± 6%, P < 0.05, and 42 ± 10%, P < 0.001, of basal, respectively). Rap1 activation was maximal 15 min after RANKL stimulation (147 ± 9% of basal, P < 0.001), whereas silencing of EPAC1/2 diminished activated Rap1 (43 ± 13 and 20 ± 15% of control, P < 0.001) and NFkB nuclear translocation. TRAP-staining revealed no osteoclast differentiation in EPAC1/2-KO cells. Cathepsin K, NFATc1, and osteopontin mRNA expression decreased in EPAC1/2-KO cells when compared to control. RhoA, cdc42, Rac1, and FAK were activated in an EPAC1/2-dependent manner, and there was diminished cytoskeletal assembly in EPAC1/2-KO cells. In summary, EPAC1 and EPAC2 are critical signaling intermediates in osteoclast differentiation that permit RANKL-stimulated NFkB nuclear translocation and actin rearrangements. Targeting this signaling intermediate may diminish bone destruction in inflammatory arthritis.
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