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CAMKK2 is upregulated in primary human osteoarthritis and its inhibition protects against chondrocyte apoptosis

  • Author Footnotes
    a JD and AS contributed equally to this study.
    J.E. Dilley
    Footnotes
    a JD and AS contributed equally to this study.
    Affiliations
    Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Search for articles by this author
  • Author Footnotes
    a JD and AS contributed equally to this study.
    A. Seetharam
    Footnotes
    a JD and AS contributed equally to this study.
    Affiliations
    Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Search for articles by this author
  • X. Ding
    Affiliations
    Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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  • M.A. Bello
    Affiliations
    Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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  • J. Shutter
    Affiliations
    Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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  • D.B. Burr
    Affiliations
    Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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  • R.M. Natoli
    Affiliations
    Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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  • T.O. McKinley
    Affiliations
    Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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  • U. Sankar
    Correspondence
    Address correspondence and reprint requests to: U. Sankar, 635 Barnhill Drive, MS-5035, Indianapolis, IN 46202, USA. Tel: 1-317-274-7870; Fax: 1-317-856-5710.
    Affiliations
    Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

    Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Search for articles by this author
  • Author Footnotes
    a JD and AS contributed equally to this study.
Published:February 27, 2023DOI:https://doi.org/10.1016/j.joca.2023.02.072
CAMKK2 is upregulated in primary human osteoarthritis and its inhibition protects against chondrocyte apoptosis
Previous ArticleHarmonization of pain scores: comment on Osteoarthritis and Cartilage 2023;31(1):83–95
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      Summary

      Objective

      To investigate the role of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) in human osteoarthritis.

      Materials and methods

      Paired osteochondral plugs and articular chondrocytes were isolated from the relatively healthier (intact) and damaged portions of human femoral heads collected from patients undergoing total hip arthroplasty for primary osteoarthritis (OA). Cartilage from femoral plugs were either flash frozen for gene expression analysis or histology and immunohistochemistry. Chondrocyte apoptosis in the presence or absence of CAMKK2 inhibition was measured using flow cytometry. CAMKK2 overexpression and knockdown in articular chondrocytes were achieved via Lentivirus- and siRNA-mediated approaches respectively, and their effect on pro-apoptotic and cartilage catabolic mechanisms was assessed by immunoblotting.

      Results

      CAMKK2 mRNA and protein levels were elevated in articular chondrocytes from human OA cartilage compared to paired healthier intact samples. This increase was associated with elevated catabolic marker matrix metalloproteinase 13 (MMP-13), and diminished anabolic markers aggrecan (ACAN) and type II collagen (COL2A1) levels. OA chondrocytes displayed enhanced apoptosis, which was suppressed following pharmacological inhibition of CAMKK2. Levels of MMP13, pSTAT3, and the pro-apoptotic marker BAX became elevated when CAMKK2, but not its kinase-defective mutant was overexpressed, whereas knockdown of the kinase decreased the levels of these proteins.

      Conclusions

      CAMKK2 is upregulated in human OA cartilage and is associated with elevated levels of pro-apoptotic and catabolic proteins. Inhibition or knockdown of CAMKK2 led to decreased chondrocyte apoptosis and catabolic protein levels, whereas its overexpression elevated them. CAMKK2 may be a therapeutic target to prevent or mitigate human OA.

      Keywords

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      Article info

      Publication history

      Published online: February 27, 2023
      Accepted: February 15, 2023
      Received: July 22, 2022

      Publication stage

      In Press Journal Pre-Proof

      Identification

      DOI: https://doi.org/10.1016/j.joca.2023.02.072

      Copyright

      © 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

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