Academic Journal
Spautin-1 inhibits osteoclast differentiation and attenuates bone loss by blocking USP10/JIP1-mediated JNK pathway.
| Τίτλος: | Spautin-1 inhibits osteoclast differentiation and attenuates bone loss by blocking USP10/JIP1-mediated JNK pathway. |
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| Συγγραφείς: | Chen X; School of Pharmaceutical Sciences, Marshall Laboratory of Biomedical Engineering, Shenzhen University, Shenzhen, China., Xiao Y; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Immunology, Institute of Biological Therapy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China., Wu H; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Immunology, Institute of Biological Therapy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China., Zhong M; Department of Spine Surgery, Ganzhou People's Hospital, Ganzhou 341000, China., Zhong R; Department of Neurosurgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China., Chen S; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Immunology, Institute of Biological Therapy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China., Tang H; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Immunology, Institute of Biological Therapy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China., Di Q; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Immunology, Institute of Biological Therapy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China., Zhao X; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Immunology, Institute of Biological Therapy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China., Gao Y; School of Pharmaceutical Sciences, Marshall Laboratory of Biomedical Engineering, Shenzhen University, Shenzhen, China., Chen W; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Immunology, Institute of Biological Therapy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China., Huang Q; Department of Pediatric Orthopaedics, Shenzhen Children's Hospital, Shenzhen University Medical School, Shenzhen University, Shenzhen 518035, China. Electronic address: hqi0606@163.com., Chen W; School of Pharmaceutical Sciences, Marshall Laboratory of Biomedical Engineering, Shenzhen University, Shenzhen, China; Guangdong Provincial Key Laboratory of Infection Immunity and Inflammation, Department of Immunology, Institute of Biological Therapy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China. Electronic address: cwl@szu.edu.cn. |
| Πηγή: | Biochemical pharmacology [Biochem Pharmacol] 2026 Aug; Vol. 250 (Pt 1), pp. 117996. Date of Electronic Publication: 2026 Apr 20. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Elsevier Science Original Publication: Oxford, New York [etc.] Paragamon Press. |
| Ιατρικοί όροι (MeSH): | Osteoclasts*/drug effects , Osteoclasts*/metabolism , Osteoclasts*/cytology , Cell Differentiation*/drug effects , Cell Differentiation*/physiology , Ubiquitin Thiolesterase*/metabolism , Ubiquitin Thiolesterase*/antagonists & inhibitors , Bone Resorption*/metabolism , Bone Resorption*/drug therapy , Bone Resorption*/prevention & control , Adaptor Proteins, Signal Transducing*/metabolism , Adaptor Proteins, Signal Transducing*/antagonists & inhibitors , MAP Kinase Signaling System*/drug effects , MAP Kinase Signaling System*/physiology, Animals ; Mice ; Mice, Inbred C57BL ; Male ; Humans ; RANK Ligand ; Cells, Cultured ; Intracellular Signaling Peptides and Proteins |
| Περίληψη: | Osteoclast hyperactivity is a key factor in the pathogenesis of several skeletal disorders, including inflammatory bone loss, periprosthetic osteolysis, and rheumatoid arthritis. The ubiquitin-proteasome system (UPS) is pivotal in bone homeostasis and disease pathogenesis, modulating critical osteogenic and osteolytic signaling cascades. Our study identified Spautin-1, an inhibitor of ubiquitin-specific protease 10 (USP10), with the capacity to suppress osteoclastogenesis and the expression of genes associated with osteoclast activity, triggered by the nuclear factor-κB (NF-κB) ligand (RANKL) in bone marrow-derived macrophages (BMMs). Spautin-1 also effectively inhibited RANKL-induced bone resorption in vitro assays. At the molecular level, Spautin-1 reduced the expression of JNK interacting protein 1 (JIP1) by impeding USP10-mediated JIP1 deubiquitination, consequently dampening the RANKL-activated c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) signaling axis and curbing nuclear factor of activated T cells 1 (NFATc1) activation. Consistent with this mechanism, silencing of USP10 similarly reduced the expression of osteoclast‑related genes, mirroring the effects observed with Spautin‑1 treatment, whereas overexpression of JIP1 reversed these inhibitory effects. Additionally, Spautin-1 was found to ameliorate lipopolysaccharide (LPS)-induced bone loss in murine models. Notably, a positive correlation was observed between USP10 and JIP1 expression levels in bone tissues from osteoporotic patients. Collectively, our results position Spautin-1 as a potential therapeutic agent for osteoclast-mediated bone diseases. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: JIP1; JNK; Osteoclasts; RANKL; Spautin-1; USP10 |
| Substance Nomenclature: | EC 3.4.19.12 (Ubiquitin Thiolesterase) 0 (Adaptor Proteins, Signal Transducing) 0 (PLEKHO1 protein, mouse) 0 (RANK Ligand) 0 (Intracellular Signaling Peptides and Proteins) |
| Entry Date(s): | Date Created: 20260422 Date Completed: 20260611 Latest Revision: 20260611 |
| Update Code: | 20260612 |
| DOI: | 10.1016/j.bcp.2026.117996 |
| PMID: | 42019891 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-2968 |
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| DOI: | 10.1016/j.bcp.2026.117996 |