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Increased Sparc release from subchondral osteoblasts promotes articular chondrocyte degeneration under estrogen withdrawal

  • Author Footnotes
    a The authors contributed equally to this work.
    A. Jiang
    Footnotes
    a The authors contributed equally to this work.
    Affiliations
    Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China

    Department of General Surgery, Beijing Pinggu Hospital, Beijing 101299, China
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  • Author Footnotes
    a The authors contributed equally to this work.
    P. Xu
    Footnotes
    a The authors contributed equally to this work.
    Affiliations
    University of Chinese Academy of Sciences, Beijing 100049, China
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  • Z. Yang
    Affiliations
    Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China
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  • Z. Zhao
    Affiliations
    Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China
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  • Q. Tan
    Affiliations
    Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China
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  • W. Li
    Affiliations
    Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China

    Engineering Research Center of Bone and Joint Precision Medicine, Beijing 100191, China
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  • C. Song
    Affiliations
    Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China

    Beijing Key Lab of Spine Diseases, Beijing 100191, China
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  • H. Dai
    Affiliations
    Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China
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  • H. Leng
    Correspondence
    Address correspondence and reprint requests to: H. Leng, Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China.
    Affiliations
    Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China
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  • Author Footnotes
    a The authors contributed equally to this work.
Published:October 11, 2022DOI:https://doi.org/10.1016/j.joca.2022.08.020

      Summary

      Objective

      The incidence of osteoarthritis (OA) in menopausal women is significantly higher than in same-aged men. Investigating the role of subchondral osteoblasts in estrogen deficiency-induced OA may help elucidate the pathological mechanism, providing new insights for the diagnosis and treatment of menopausal OA.

      Methods

      A classical ovariectomy-induced OA (OVX-OA) rat model was utilized to isolate primary articular chondrocytes and subchondral osteoblasts, which were identified and then cocultured in Transwell. The expression of chondrocyte anabolic and catabolic indicators was evaluated. The differentially expressed proteins in the conditioned medium (CM) of osteoblasts were identified by Liquid Chromatograph-Mass Spectrometer (LC–MS/MS). Normal chondrocytes were treated with osteoblast CM, and then RNA sequencing was performed on the treated chondrocytes. KEGG was used to identify significant enrichment of signaling pathways, and Simple Western was used to verify the expression of related proteins in the signaling pathways.

      Results

      Coculture of OVX-OA subchondral osteoblasts with chondrocytes significantly downregulated the expression of the anabolic indicators and upregulated the expression of the catabolic indicators in chondrocytes. 1,601 proteins were identified in both normal and OVX osteoblast culture supernatants. Protein–protein interaction network analysis revealed that Sparc was one of the hub proteins. The AMPK/Foxo3a signaling pathway of chondrocytes was downregulated by OVX-OA osteoblasts CM. AICAR, the AMPK agonist, partially reversed the catabolic effect of OVX-OA osteoblasts on chondrocytes.

      Conclusions

      Sparc secreted by OVX-OA subchondral osteoblasts can downregulate the AMPK/Foxo3a signaling pathway of chondrocytes, thereby promoting chondrocyte degeneration.

      Keywords

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