Mével, ElsaShutter, Jennifer A.Ding, XinchunMattingly, Brett T.Williams, Justin N.Li, YongHuls, AnthonyKambrath, Anuradha ValiyaTrippel, Stephen B.Wagner, DianeAllen, Matthew R.O’Keefe, RegisThompson, William R.Burr, David B.Sankar, Uma2023-10-182023-10-182022Mével E, Shutter JA, Ding X, et al. Systemic inhibition or global deletion of CaMKK2 protects against post-traumatic osteoarthritis. Osteoarthritis Cartilage. 2022;30(1):124-136. doi:10.1016/j.joca.2021.09.001https://hdl.handle.net/1805/36445Objective: 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.en-USPublisher PolicyAdenosine monophosphate dependent protein kinase (AMPK)Articular chondrocytesOsteoarthritisCalcium-calmodulin-dependent protein kinaseNaphthalimidesArticle