Systemic Inhibition or Global Deletion of CaMKK2 Protects Against Post-Traumatic Osteoarthritis

dc.contributor.authorMével, Elsa
dc.contributor.authorShutter, Jennifer A.
dc.contributor.authorDing, Xinchun
dc.contributor.authorMattingly, Brett T.
dc.contributor.authorWilliams, Justin N.
dc.contributor.authorLi, Yong
dc.contributor.authorHuls, Anthony
dc.contributor.authorKambrath, Anuradha Valiya
dc.contributor.authorTrippel, Stephen B.
dc.contributor.authorWagner, Diane
dc.contributor.authorAllen, Matthew R.
dc.contributor.authorO’Keefe, Regis
dc.contributor.authorThompson, William R.
dc.contributor.authorBurr, David B.
dc.contributor.authorSankar, Uma
dc.contributor.departmentAnatomy, Cell Biology and Physiology, School of Medicine
dc.date.accessioned2023-10-18T15:08:13Z
dc.date.available2023-10-18T15:08:13Z
dc.date.issued2022
dc.description.abstractObjective: 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.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationMével 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.2021.09.001
dc.identifier.urihttps://hdl.handle.net/1805/36445
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.joca.2021.09.001
dc.relation.journalOsteoarthritis and Cartilage
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectAdenosine monophosphate dependent protein kinase (AMPK)
dc.subjectArticular chondrocytes
dc.subjectOsteoarthritis
dc.subjectCalcium-calmodulin-dependent protein kinase
dc.subjectNaphthalimides
dc.titleSystemic Inhibition or Global Deletion of CaMKK2 Protects Against Post-Traumatic Osteoarthritis
dc.typeArticle
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
nihms-1739915.pdf
Size:
3.01 MB
Format:
Adobe Portable Document Format
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.99 KB
Format:
Item-specific license agreed upon to submission
Description: