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IL13Rα2 as a crucial receptor for Chi3l1 in osteoclast differentiation and bone resorption through the MAPK/AKT pathway.

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  • معلومة اضافية
    • المصدر:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: [London] : BioMed Central, c2003-
    • الموضوع:
      Bone Resorption*/drug therapy ; Interleukin-13 Receptor alpha2 Subunit*/metabolism ; Interleukin-13 Receptor alpha2 Subunit*/therapeutic use ; Osteolysis*/metabolism; Animals ; Mice ; Cell Differentiation ; Chitinase-3-Like Protein 1/metabolism ; Lipopolysaccharides/pharmacology ; NFATC Transcription Factors/metabolism ; Osteoclasts ; Proto-Oncogene Proteins c-akt/metabolism ; RANK Ligand/metabolism ; Recombinant Proteins/pharmacology ; RNA, Small Interfering/metabolism
    • نبذة مختصرة :
      Background: Previous research has revealed that the 18 glycoside hydrolase gene family (GH18) member Chitinase 3-like 1 (Chi3l1) can regulate osteoclast differentiation and bone resorption. However, its downstream receptors and molecular mechanisms during osteoclastogenesis have yet to be elucidated.
      Methods: Initially, we conducted a comprehensive investigation to evaluate the effects of recombinant Chi3l1 protein or Chi3l1 siRNA on osteoclast differentiation and the RANKL-induced MAPK/AKT signaling pathways. Moreover, we used immunofluorescence and immunoprecipitation assays to identify IL13Rα2 as the downstream receptor of Chi3l1. Subsequently, we investigated the impact of IL13Rα2 recombinant protein or IL13Rα2-siRNA on osteoclast differentiation and the associated signaling pathways. Finally, we performed in vivo experiments to examine the effect of recombinant IL13Rα2 protein in an LPS-induced mouse model of cranial osteolysis.
      Results: Our findings highlight that the administration of recombinant Chi3l1 protein increased the formation of osteoclasts and bolstered the expression of several osteoclast-specific genes (TRAP, NFATC1, CTR, CTSK, V-ATPase d2, and Dc-STAMP). Additionally, Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK) and AKT pathway activation, whereas Chi3l1 silencing inhibited this process. Next, using immunofluorescence and co-immunoprecipitation assays, we identified IL13Rα2 as the binding partner of Chi3l1 during osteoclastogenesis. IL13Rα2 recombinant protein or IL13Rα2-siRNA also inhibited osteoclast differentiation, and IL13Rα2-siRNA attenuated the RANKL-induced activation of the MAPK (ERK/P38/JNK) and AKT pathways, similar to the effects observed upon silencing of Chi3l1. Moreover, the promoting effect of recombinant Chi3l1 protein on osteoclastogenesis and the activation of the MAPK and AKT pathways was reversed by IL13Rα2 siRNA. Finally, recombinant LI13Rα2 protein significantly attenuated the LPS-induced cranial osteolysis and the number of osteoclasts in vivo.
      Conclusions: Our findings suggested that IL13Rα2 served as a crucial receptor for Chi3l1, enhancing RANKL-induced MAPK and AKT activation to promote osteoclast differentiation. These findings provide valuable insights into the molecular mechanisms of Chi3l1 in osteoclastogenesis, with potential therapeutic implications for osteoclast-related diseases. Video Abstract.
      (© 2024. The Author(s).)
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    • Contributed Indexing:
      Keywords: AKT; Chi3l1; IL13Rα2; MAPK; Osteoclast differentiation
    • الرقم المعرف:
      0 (Chitinase-3-Like Protein 1)
      0 (Interleukin-13 Receptor alpha2 Subunit)
      0 (Lipopolysaccharides)
      0 (NFATC Transcription Factors)
      EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
      0 (RANK Ligand)
      0 (Recombinant Proteins)
      0 (RNA, Small Interfering)
      0 (Chil1 protein, mouse)
    • الموضوع:
      Date Created: 20240130 Date Completed: 20240208 Latest Revision: 20241023
    • الموضوع:
      20241023
    • الرقم المعرف:
      PMC10826115
    • الرقم المعرف:
      10.1186/s12964-023-01423-7
    • الرقم المعرف:
      38291404