ArticleCell death & disease2019
eIF2α signaling regulates autophagy of osteoblasts and the development of osteoclasts in OVX mice.
Article in Cell death & disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 92 citations in OpenAlex.
- Stage-dependent endoplasmic reticulum homeostasis in osteogenic differentiation.Frontiers in cell and developmental biology · 2026Review
- The role of the unfolded protein response pathway in bone homeostasis and potential therapeutic target in cancer-associated bone disease.Bone research · 2025Review
- Sex-specific transcriptomic profiling reveals key players in bone loss associated with Alzheimer's disease.GeroScience · 2025Article
- The Critical Role of Autophagy in the Pathogenesis of Diabetic Osteoporosis: Mechanisms and Therapeutic Measures.Drug design, development and therapy · 2025Review
- Low-molecular-weight estrogenic phytoprotein suppresses osteoporosis development through positive modulation of skeletal estrogen receptors.Bioactive materials · 2024Article
- LINE-1 RNA triggers matrix formation in bone cells via a PKR-mediated inflammatory response.The EMBO journal · 2024Article
- Tumour necrosis factor α regulates the miR-27a-3p-Sfrp1 axis in a mouse model of osteoporosis.Experimental physiology · 2024Article
- Mammalian integrated stress responses in stressed organelles and their functions.Acta pharmacologica Sinica · 2024Review
- Injectable and high-strength PLGA/CPC loaded ALN/MgO bone cement for bone regeneration by facilitating osteogenesis and inhibiting osteoclastogenesis in osteoporotic bone defects.Materials today. Bio · 2024Article
- Inhibition of PPP1R15A alleviates osteoporosis via suppressing RANKL-induced osteoclastogenesis.Acta pharmacologica Sinica · 2024Article
- Cyclin A1 (CCNA1) inhibits osteoporosis by suppressing transforming growth factor-beta (TGF-beta) pathway in osteoblasts.BMC musculoskeletal disorders · 2024Article
- Wnt10b regulates osteogenesis of adipose-derived stem cells through Wnt/β-catenin signalling pathway in osteoporosis.Cell proliferation · 2024Article
- Urine-derived stem cells-extracellular vesicles ameliorate diabetic osteoporosis through HDAC4/HIF-1α/VEGFA axis by delivering microRNA-26a-5p.Cell biology and toxicology · 2023Article
- Association between dietary folate intake and bone mineral density in a diverse population: a cross-sectional study.Journal of orthopaedic surgery and research · 2023Article
- Dlk2 interacts with Syap1 to activate Akt signaling pathway during osteoclast formation.Cell death & disease · 2023Article
- ASPN Synergizes with HAPLN1 to Inhibit the Osteogenic Differentiation of Bone Marrow Mesenchymal Stromal Cells and Extracellular Matrix Mineralization of Osteoblasts.Orthopaedic surgery · 2023Article
- Bone and the Unfolded Protein Response: In Sickness and in Health.Calcified tissue international · 2023Review
- ER Stress, the Unfolded Protein Response and Osteoclastogenesis: A Review.Biomolecules · 2023Review
- Metformin reverses oxidative stress‑induced mitochondrial dysfunction in pre‑osteoblasts via the EGFR/GSK‑3β/calcium pathway.International journal of molecular medicine · 2023Article
- Boric Acid Inhibits RANKL-Stimulated Osteoclastogenesis In Vitro and Attenuates LPS-Induced Bone Loss In Vivo.Biological trace element research · 2023Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Bone loss in postmenopausal osteoporosis is induced chiefly by an imbalance of bone-forming osteoblasts and bone-resorbing osteoclasts. Salubrinal is a synthetic compound that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Phosphorylation of eIF2α alleviates endoplasmic reticulum (ER) stress, which may activate autophagy. We hypothesized that eIF2α signaling regulates bone homeostasis by promoting autophagy in osteoblasts and inhibiting osteoclast development. To test the hypothesis, we employed salubrinal to elevate the phosphorylation of eIF2α in an ovariectomized (OVX) mouse model and cell cultures. In the OVX model, salubrinal prevented abnormal expansion of rough ER and decreased the number of acidic vesiculars. It regulated ER stress-associated signaling molecules such as Bip, p-eIF2α, ATF4 and CHOP, and promoted autophagy of osteoblasts via regulation of eIF2α, Atg7, LC3, and p62. Salubrinal markedly alleviated OVX-induced symptoms such as reduction of bone mineral density and bone volume fraction. In primary bone-marrow-derived cells, salubrinal increased the differentiation of osteoblasts, and decreased the formation of osteoclasts by inhibiting nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Live cell imaging and RNA interference demonstrated that suppression of osteoclastogenesis is in part mediated by Rac1 GTPase. Collectively, this study demonstrates that ER stress-autophagy axis plays an important role in OVX mice. Bone-forming osteoblasts are restored by maintaining phosphorylation of eIF2α, and bone-resorbing osteoclasts are regulated by inhibiting NFATc1 and Rac1 GTPase.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.