Systemic inhibition or global deletion of CaMKK2 protects against post-traumatic osteoarthritis

E. Mével, J. A. Shutter, X. Ding, B. T. Mattingly, J. N. Williams, Y. Li, A. Huls, A. V. Kambrath, S. B. Trippel, D. Wagner, M. R. Allen, R. O'Keefe, W. R. Thompson, D. B. Burr, U. Sankar

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Abstract

Objective: To investigate the role of Ca2+/calmodulin-dependent protein kinase 2 (CaMKK2) in post-traumatic osteoarthritis (PTOA). Methods: Destabilization of the medial meniscus (DMM) or sham surgeries were performed on 10-week-old male wild-type (WT) and Camkk2−/− mice. Half of the DMM-WT mice and all other cohorts (n = 6/group) received tri-weekly intraperitoneal (i.p.) injections of saline whereas the remaining DMM-WT mice (n = 6/group) received i.p. injections of the CaMKK2 inhibitor STO-609 (0.033 mg/kg body weight) thrice a week. Study was terminated at 8- or 12-weeks post-surgery, and knee joints processed for microcomputed tomography imaging followed by histology and immunohistochemistry. Primary articular chondrocytes were isolated from knee joints of 4–6-day-old WT and Camkk2−/− mice, and treated with 10 ng/ml interleukin-1β (IL)-1β for 24 or 48 h to investigate gene and protein expression. Results: CaMKK2 levels and activity became elevated in articular chondrocytes following IL-1β treatment or DMM surgery. Inhibition or absence of CaMKK2 protected against DMM-associated destruction of the cartilage, subchondral bone alterations and synovial inflammation. When challenged with IL-1β, chondrocytes lacking CaMKK2 displayed attenuated inflammation, cartilage catabolism, and resistance to suppression of matrix synthesis. IL-1β-treated CaMKK2-null chondrocytes displayed decreased IL-6 production, activation of signal transducer and activator of transcription 3 (Stat3) and matrix metalloproteinase 13 (MMP13), indicating a potential mechanism for the regulation of inflammatory responses in chondrocytes by CaMKK2. Conclusions: Our findings reveal a novel function for CaMKK2 in chondrocytes and highlight the potential for its inhibition as an innovative therapeutic strategy in the prevention of PTOA.

Original languageEnglish
Pages (from-to)124-136
Number of pages13
JournalOsteoarthritis and Cartilage
Volume30
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • Adenosine monophosphate dependent protein kinase (AMPK)
  • Articular chondrocytes
  • Cacalmodulin-dependent protein kinase kinase 2 (CaMKK2)
  • Destabilization of medial meniscus (DMM)
  • IL-6
  • Interleukin-1β (IL-1β)
  • Osteoarthritis
  • Signal transducer and activator of transcription 3 (Stat3)

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