Osteoarthritis Cartilage
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. Electronic address:
Published: January 2022
Objective: To investigate the role of Cacalmodulin-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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712369 | PMC |
http://dx.doi.org/10.1016/j.joca.2021.09.001 | DOI Listing |
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